“Many participants did not .. believe in, antiretroviral treatment”

“A study in Abidjan, Côte d'Ivoire, shows that 80% of pregnant women who agree to undergo HIV testing return to collect their results. But of those who discover they are living with the virus, fewer than 50% return to receive drug treatment for the prevention of MTCT [mother to child transmission] of the virus”

“Many youth not on antiretroviral treatment expressed confusion or skepticism about its purpose and value. Several did not understand why they would take medication that cannot cure them…One youth remakred that medications degrade the quality of life…Many youth [taking drugs] described difficulties with, or fear of, side effects. Some based these fears on what they had heard from others [a subtle way of intimating that these fears are irrational]…One youth said: 'Right now I'm doing okay where I am so I'd rather stay off meds because you get really sick when you start them, you're just like 3 months bedridden and I'm not up for that really.'…However, some youth described difficult personal experiences with side effects, such as a young woman with lipodystrophy: 'I was given a medication and I wasn't told that it would shift the body fat in my body, and I was mortified when I saw these really repulsive changes. It bothered me a lot'”

“The government [of Niger] hopes to put 4,000 people on free life-prolonging ARV treatment, but since it began to supply ARV drugs free of charge in January this year, only 350 people have come forward to receive the medication.”

“HIV antiretroviral drugs accounted for $5.7 billion in sales in 2003 and are expected to enjoy continued growth over the next decade, driven by continued rises in HIV incidence and patient capture/diagnosis. In fact in 2014, Datamonitor forecasts the commercial market to have grown to reach $10.2 billion.”

“national data and published reports studied by the CDC showed that 480,000 HIV-infected people ages 15 to 49 should have been getting antiviral drugs in 2003, yet only 268,000, or 56 percent, were given such medication”

“Anglo American estimated that 24% of its 140,000 workers in east and southern Africa were HIV-positive, said Brink. He said about 8,500 of the group's workers were at the stage of HIV where they needed AIDS drugs, but by the end of last year only 2,100 were on the company's treatment programme. "I wish I knew why," he said, noting that 94% of the miner's workers who took AIDS drugs were well, and were back at work…[a little later…] Brink said that 400 Anglo American workers had joined treatment programmes but quit.”

“Through 144 weeks, the study regimen permanent discontinuation rate was 82 (27%) of 299 in the tenofovir DF group and 100 (33%) of 301 in the stavudine group”

“[from January 1995 through June 1999] at least half of the HIV infected patients were not on anti-retroviral treatment at the time of ICU admission [and only 28% using HAART even when it was widely available in 1998 and 1999]”

“[from Table 2: 15 were taking no antiretroviral therapy, 67 were on mono- or dual-therapy and 372 on HAART]”

“The rollout of ARVs in Swaziland has been slow. Only 3,000 people are eligible for the government's free drugs programme this year, rising to 13,000 in 2005. But activists complain that the delivery system is already inadequate for the task.”

“The rate of self-reported pill use was lower in the FTC–TDF group than in the placebo group at week 4 (mean, 89% vs. 92%; P<0.001) and at week 8 (mean, 93% vs. 94%; P = 0.006) but was similar thereafter (mean, 95% in the two groups)…[remarkably high adherence, but consider]…Among subjects in the FTC– TDF group, at least one of the study-drug components was detected in 3 of 34 subjects with HIV infection (9%) and in 22 of 43 seronegative control subjects (51%) [i.e. adherence was only about 50% by measurement but around 90% by self-report. In addition, adherence by measurement is susceptible to people taking the pills only before a visit]”

“Relative to those with no psychiatric disorders, the hazard probability for discontinuation of HAART was significantly lower in the first and second years among those with SMI [Severe Mental Illness] and in the first year among those with depressive disorders…Among those with psychiatric diagnoses, those with six or more mental health visits in a year were significantly less likely to discontinue HAART compared with patients with no mental health visits.”

“a breath monitoring device developed by scientists at the University of Florida and Xhale Inc…[can monitor] medication adherence in high-risk individuals. ‘For HIV, it’s been shown that if you don’t take a very high percentage of your medication, you may as well not take medication at all,’ said Richard Melker, M.D., a professor of anesthesiology at the UF College of Medicine and chief technology officer for Xhale…Experts have tried literally hundreds, if not thousands, of ways to monitor drug adherence, ranging from daily log books to blister packs that record the time each pill is dispensed. Despite the money, time and effort devoted to these methods, Melker said only one works well: directly observed therapy, or DOT. ‘If you have a disease that is deemed to be a public health risk, authorities can put you into a program where you have to come to the clinic every day and be observed putting the pill into your mouth and swallowing it,’ Melker said…’[This] machine sits in your home and when it’s time for you to take your medication, it makes a beeping noise. If you don’t hit a button after about five minutes, it’s going to beep louder and louder until you come,’ Melker said. ‘If you don’t come after a certain amount of time, the machine can call the clinical trial coordinator and indicate that subject or patient didn’t take the medication as prescribed.’…’The doctor can see how often you took it and exactly what time. If it made the patient really sick or dizzy and they didn’t take it, they can find out why,’ Melker said. ‘It’s not just a question of did I or didn’t I take it, but when you took it or why you didn’t take it.’ The researchers developed the adherence monitor by incorporating minute amounts of an alcohol into a gel capsule. The additive, called 2-butanol, is one of many GRAS – Generally Recognized as Safe – compounds approved by the Food and Drug Administration for use in foods. ‘We wanted (patients) to swallow a chemical and have it transform into something else that’s easy to monitor,’ said Matthew Booth, Ph.D., an assistant professor of anesthesiology at the UF College of Medicine and an investigator in the study. [meaning that it will be easy to bypass the monitor by swallowing a small amount of this alcohol]”

“A LARGE number of Ugandan HIV/Aids patients on antiretroviral treatment have discontinued their treatment for at least one month because of the cost, side-effects or unavailability of the medicines, according to a new study by Makerere University researchers…The main reason given for therapy modification was its adverse effects, reported in 71.8 per cent of the patients who modified at least one drug in their regimen”

“A total of 230 patients were randomized; 199 started ART [anti-retroviral therapy], of whom 74% completed the 48-week study…At week 4, 82% of intervention patients had taken at least 90% of their prescribed ART doses, compared with 65% of controls; this group difference dropped to 12% at week 12 (72% versus 60%) and 11% at week 24 (66 versus 55%)…There were no group differences with respect to HIV-1 RNA throughout the study.”

“”I remember once, before I thought of the trade [selling half his antiretroviral medications to raise money for food], I would take the medicine without any food – just porridge alone. I nearly died. I got so weak, I developed ulcers which have not healed well until now.””

“Many [Canadian HIV youths] described being inconsistent with their treatment regimens, either not taking prescribed medication, taking medications only when they felt up to it, or needing breaks.”

“As the management of HIV improved we began to see longer survival especially for patients who were adherent with treatment…[but] substance abuse and mental health issues were each associated with poorer adherence to antiretroviral therapy [which mean that conclusions that better adherence leads to better outcomes might be false, and that it might be recreational drug abuse that leads to worse outcomes]…Bassetti et al in a Swiss cohort study found that patients not on therapy were more likely active injection drug users and had a lower educational level. Tucker et al found that cocaine, marijuana, amphetamines, sedatives and heavy alcohol usage were associated with poorer adherence”

“Anglo American estimated that 24% of its 140,000 workers in east and southern Africa were HIV-positive, said Brink. He said about 8,500 of the group's workers were at the stage of HIV where they needed AIDS drugs, but by the end of last year only 2,100 were on the company's treatment programme…]Brink said that 400 Anglo American workers had joined treatment programmes but quit. Their reasons varied, he said, but the majority had stopped treatment because of unpleasant side effects or difficulties in sticking to their pill-taking schedules.”

“The practice of forced drugging with [gastrostomy] tubes is also finding support across the country. A June 2000 University of California San Diego/ Northwestern University study of HIV-positive children found that implanting an abdominal tube can reduce a child's drugging time by five minutes. There's no indication that the children in the study were sick, or that the drugs improved their health. The doctors noted that one "older child" had to quit gymnastics because the tube made it too difficult. But she can take drugs faster. And that's what's important. Isn't it?”

“Measurement of adherence is imperfect and lacks established standards. Patient self-reporting is an unreliable predictor of adherence; however, a patient's estimate of suboptimal adherence is a strong predictor and should be strongly considered. A clinician's estimate of the likelihood of a patient's adherence is also an unreliable predictor. Aids for measuring adherence (e.g., pill counts, pharmacy records, "smart" pill bottles with computer chips that record each opening [i.e., medication event monitoring systems or MEMS caps]) might be useful, although each aid requires comparison with patient self-reporting. Clinician and patient estimates of the degree of adherence have been reported to exceed measures that are based on MEMS caps. Because of its complexity and cost, MEMS caps technology might be used as an adjunct to adherence research, but it is not useful in clinical settings.…Patient education should include the goals of therapy, including a review of expected outcomes that are based on baseline viral load and CD4+ T cell counts, the reason for adherence, and the plan for a mechanics of adherence. [improved health is not mentioned as a goal]”

“Aids patients on the government antiretroviral programme have started dropping out in small but worrying numbers that are said to be an indication of a bigger problem in the offing. [the article blames this on the fact that hospitals may charge 'modest' fees for distribution, but does not consider the possibility that toxicity is causing people to drop out]”

“Surgical placement of a gastrostomy tube (g-tube) directly into a patient's gastrointestinal system to support antiretroviral administration is occasionally used to increase adherence in HIV-infected children [i.e. to force reluctant children to take drugs]…Nine HIV-infected children who were receiving a PI- or NNRTI-containing regimen via g-tube were enrolled…Systemic exposure of PIs and NNRTIs in our 9 patients was similar to data from historical oral administration controls…[however, when less was absorbed into the bloodstream] doses were increased, [and] adequate exposure was attained.”

“During the programme’s first 15 months of operations, from February 1998 to the end of May 1999, HIV testing was offered to 9657 women, of which 6982 (72%) accepted the test. (Projet RETRO-CI conducted a randomised controlled clinical trial of the efficacy of short course zidovudine [AZT] at the clinic from April 1996 to February 1998) Of the 884 women who tested positive for HIV-1, 395 (45%) received their test results. Only 118 (35%) of the 333 women who tested as positive for HIV, who received their test results, and who were invited to return for follow up visits during this period eventually started taking zidovudine. Of the 215 women who did not start taking zidovudine, 181 (84%) had refused to return or discontinued follow up visits.”

“Over a 6-month period, 65 patients under antiretroviral regimens all including zidovudine [AZT] (300 mg twice a day) underwent TDM [Therapeutic Drug Monitoring]. Measurable concentrations of zidovudine (limit of quantification 10 ng/ml) were found in 52 patients (80%), whereas no zidovudine was found in 13 individuals [indicating that 20% of patients took no AZT. This is not proof that the remaining 80% were compliant]”

“Participation by the caregivers and child in the decision-making process is crucial, especially in situations for which definitive data concerning efficacy are not available. Issues related to adherence to therapy should be fully assessed, discussed and addressed with the child’s caregiver and the child (when age- appropriate) before the decision to initiate therapy is made.…Evidence indicates that adherence problems occur frequently in children. In a randomized treatment trial, caregivers reported that 30% of children missed one or more doses of antiretroviral medications in the preceding 3 days [65]; 42% of caregivers in an observational study reported at least one missed dose in the past week [68]. Using pharmacy refills to measure adherence, a study at a site with a comprehensive, multidisciplinary adherence program noted that only 42 of 72 children (58%) had refill rates of at least 75% over 6 months [66]. A study of another clinical program found that refill rates of 90% or greater adherence were met for only 12 of 35 children (34%) over one year [69]. These findings illustrate the difficulty of maintaining high levels of adherence and underscore the need to work in partnership with families to make adherence assessment, education, and support integral components of care.”

“…Currently available approaches to measuring adherence have notable limitations, and individual patient assessments by medical providers do not accurately predict adherence…The sensitivity of abnormally low drug levels to detect adherence of 90% or less was poor, ranging from 31 to 56%. Specificity at this threshold was higher, at least 90% for all drugs except indinavir. Sensitivity improved at lower adherence thresholds: at the 60% or less level, the sensitivity for all drugs pooled was 72%, rising to 83% among those of 50% or less. For efavirenz, a particularly long half-life drug, sensitivity at 90% or less was low at 44%; however, specificity was 100%.”

“After a median follow-up of 8.1 months, 61% of patients changed or discontinued their initial HAART regimen; 24% did so because of an adverse event. The events most commonly cited as the cause for discontinuation were nausea, vomiting, and diarrhea…Nausea/vomiting and not having AIDS at the time of HAART initiation [!] were associated with discontinuation due to an adverse event at any time”

“1 in 5 AIDS patients receiving free antiretroviral drugs from the Chinese government abandoned the combination of pills in the first 7 months of the program…Zhang Fujie, director of treatment for China's national AIDS control center…attributed the high dropout rate to the severe side effects caused by the drugs, and blamed the limited mix of low-cost drugs available in China and a shortage of qualified medical staff who can monitor patients and fine-tune treatment to manage side effects.”

“A random group of 283 patients infected with HIV was selected from those who attended a monographic HIV unit between November 2000 and January 2001 and had been prescribed HAART at least 6 months before. The percentage of adherence was measured by the ratio (the number of doses dispensed [divided by] the number of doses prescribed) x 100 and 95% was considered to be the adherence threshold…51.9% of study participants showed a good adherence”

“Mean self-reported adherence (percentage of doses taken as prescribed) for the day preceding each follow-up visit was 79%, and mean self-reported adherence for the week preceding each visit was 78%…Mean MEMS [special pill caps that count how often they are opened] adherence for the day preceding each followup visit was 57% and mean MEMS adherence for the week preceding each follow-up visit was 53%”

“A total of 41.7% (179) declared injecting drug use during the prior 6 months, while only 13.8% (59) were viewed by physicians as 'still actively injecting drugs'…women and older patients (30 years of age or more) were more likely to be perceived as adherent [to AIDS drugs]. Lower viral load and higher CD4 cell counts were also associated by physicians with good adherence [this belief produces a feedback system whereby good 'numbers' lead to a belief that patients are adherent encouraging them to tell patients that adherence to their drugs will result in good 'numbers', with nobody realizing that this is just circular reasoning]…those perceived to have stopped injecting drug use and not necessitating DMT [Drug Maintenance Treatment] (former IDUs) by physicians were also more likely to be considered 'adherent' than patients still viewed as active [illegal drug] users…non-active users in DMT remained to be perceived by physicians as less adherent than former users out of DMT…In the sub-set of 53 patients who [admitted] non-adherence to ART [Anti-Retroviral Therapy], the majority (32; 60.4%) had been classified as adherent by their physicians…among the 143 patients who reported adherence to ART…(30; 21%) [were] viewed as non-adherent by their physicians…although highly active antiretroviral regimens including PIs are usually considered as very hard to comply to, physicians in our study especially tended to underestimate problems of adherence, as they are reported by patients, for those receiving PIs.”

“Of the 213 patients [male and female victims of sexual assault] who were offered PEP [Post-Exposure Prophylaxis], 69 (32%) chose to initiate PEP, and 26 (12% of those initially offered PEP and 38% of those who initiated PEP) returned 1 week later to receive the additional 3 weeks of medications.”

“adherence to highly active antiretroviral therapy (HAART) may be problematic, particularly in HIV-infected children. Reasons for nonadherence include refusal, drug tolerability, and adverse reactions. We assess: 1) the potential benefits of gastrostomy tube (GT) for the improvement of adherence to HAART in HIV-infected children, and 2) the factors that may result in improved viral suppression after GT placement…The medical records of 17 pediatric HIV-infected patients, in whom GT was used to improve HAART adherence, were retrospectively reviewed for clinical and laboratory parameters. Each record was reviewed for the period of 1 year before and after GT insertion. The main outcome parameters were virologic (plasma HIV RNA polymerase chain reaction quantification) and immunologic (CD4 cell counts). [i.e. health was not a consideration]”

“The majority of participants had been placed on antiretroviral therapy by their physicians but, for a variety of reasons, had decided not to take the medication. They complained of side-effects such as diarrhea, loss of appetite, fatigue, neuropathy, and “just not feeling well.” Some developed resistance to their medications and were placed on other combinations of drugs. However, even changes in medication did not ensure adherence. Many protested the inconvenience associated with taking large numbers of pills and having to adjust meal times to coincide with pill schedules. One young man stated, “It’s hard to take that medicine, knowing I’ve got to go to that bottle three times a day keeps me stressed out. I don’t take no medication for anything.” Some indicated fear that medication would hasten death. One participant stated: “The people that were taking the medicine were dying faster than the ones not taking the medicine.”

Only a few spoke of the benefits of taking medications. Those individuals had become accustomed to the routine and had been diagnosed longer. They referred to rising T-cell counts and lower viral loads, weight gain, and a general sense of feeling healthier as evidence of the efficacy of medication. However, they were in the minority.”

“Because there is no gold standard to measure adherence, our assessment used four questions that were spaced throughout the HIV-specific portion of the interview [i.e. there is no way to accurately measure adherence as people are likely to exaggerate their adherence to please their healthcare workers, avoid conflict, retain benefits and so forth]…persons taking three drugs reported greater adherence [than those taking four]…there was no association [of adherence] with viral load, although only 13 person (31%) met all four adherence goals.”

“Both clinical experience and emerging data suggest that many patients with chronic HIV disease do not fully adhere to their highly-active antiretroviral therapy (HAART) regimens…Although available research consistently suggests that antiretroviral adherence is suboptimal, there are few consistent findings about the social, psychological, clinical, and behavioral factors associated with adherence. Studies conducted before highly-active multidrug therapies and viral load testing were available showed that many patients were nonadherent to zidovudine. Social support, attitudes about zidovudine, and belief in zidovudine efficacy were associated with greater adherence, whereas unstable housing arrangements and various measures of psychiatric disturbance were associated with worse adherence [but no word on whether adverse drug effects cause people to skip their doses]…More than one quarter of our study subjects (28%) reported taking on average fewer than 80% of prescribed antiretroviral medications per day over the prior week and were categorized as having poor adherence. Fewer (23%) reported taking on average between 80% and 99% of prescribed antiretroviral agents per day and were categorized as having fair adherence. Half (50%) reported [note that many people may over-estimate their adherence to keep their doctors happy] taking all prescribed antiretroviral agents and were categorized as having excellent adherence. Study subjects most commonly reported that they missed antiretroviral doses because they were busy or forgot, away from home, or experienced a break in their daily routine. Smaller proportions reported missing doses because they felt depressed or overwhelmed, were taking intentional drug holidays, or had run out of medication. [again no word on drug side effects]”

“18% (22) of the 123 patients were nonadherent [based on computerized prescription refill records]…The mean adherence rate among the ‘nonadherent’ patients was 72% and range from 0% to 87%; 77% had adherence rates of 70% to 90%, 14% of 50% to 70%, 5% of 20% to 50% and 5% of <20%…Adverse effects attributable to antiretroviral therapy were commonly documented. However, there was no difference in the rate of reported side effects in adherent patients as compared with nonadherent patients [which could mean that some people were refilling their prescriptions but not consuming all the pills]”

“we estimate that study participants may have experienced suboptimal therapeutic effects for more than 25% of their time on therapy”

“The safety population was composed of 688 patients (ABC/3TC, 343; TDF/FTC, 345). Median exposure to all study medications was 96 weeks. The proportion of grade 2–4 adverse events was similar between treatment groups over 96 weeks; 80% for each group, and 50% vs. 46% (ABC/3TC vs. TDF/FTC) were considered drug related [given no placebo doctors chose which side effects to declare were not associated with AIDS drug use] The most common drug-related grade 2–4 adverse events was diarrhea occurring in 19% of patients in each group…Study withdrawals due to an adverse event were similar between groups [ABC/3TC, 19 (6%), TDF/FTC, 22 (6%)]; events that occurred in more than one patient per group included suspected ABC HSR [hypersensitivity reaction], renal [kidney] failure, diarrhea, vomiting, nausea, hyperlipidemia, increased triglycerides, increased aspartate aminotransferase, and mycobacterium–avium complex infection. The most common adverse events that led to study withdrawals were related to lipid abnormalities in the ABC/3TC group and gastrointestinal abnormalities in the TDF/FTC group. Suspected ABC HSR occurred in 17 patients”

“Mandy Webb, 42, was horrified when she was diagnosed HIV positive, especially as she hadn’t had sex for over a decade…Mandy first noticed something was wrong back in 1990, when her son, Ben, was two. She says: ‘I kept getting bruises…”. She went to her GP for blood tests and the results showed Mandy’s platelets were dangerously low…she was put on steroids to help her blood clot. However the drugs made her weight balloon. In 1991, doctors offered Mandy another option – to have her spleen removed and be given injections of factor Vlll (a blood protein) to help her blood to clot. Mandy went ahead but after surgery she kept getting chest infections. And, over the years, her health deteriorated. Suffering from diarrhoea, Mandy’s weight plummeted to under eight stone and her periods stopped. She developed painful mouth ulcers and night sweats…Her GP diagnosed irritable bowel syndrome and prescribed anti-depressants for stress... which Mandy didn’t take. “I tried to make the best of things,” she explains, “but it got worse and worse…” Then, six years ago, Mandy had problems walking and became disorientated. Her mum took her to another GP, who suggested an HIV test. A stunned Mandy replied: “Why? I haven’t had sex for 14 years!” Ben had been the product of a drunken one-night stand when Mandy was a 21-year-old drama student in Portsmouth. Doctors admitted Mandy to hospital and she was found to be in the third stage of HIV infection – the final one before it progresses to full-blown Aids. As doctors treated her with antibiotics and introduced anti-Aids medications, Mandy slowly began to recover…“No one knew how I’d caught HIV. I believe it was either from unprotected sex in my youth or from contaminated factor Vlll.”… [however] by 1991, when Mandy started having factor-Vlll treatment, blood products were screened. She was told it was unlikely to be the cause…Dependent on her mum to care for her, Mandy left hospital in a wheelchair. After three months, she began to recover and walk again. Today, she has high cholesterol [associated with protease inhibitors] and continuing problems with walking and balance. No one knows yet what permanent damage HIV has had on her [and nobody wants to know what damage the drugs have done]…“It’s World Aids day on Monday and I’m speaking out to try to dispel the myths about HIV and reduce the stigma so that people aren’t afraid to go and get tested…” [despite no good explanation for how she became HIV+, although an immune reaction to Factor VIII causing a false positive HIV test isn’t a bad guess]”

“Annie Nkwabilo Williams is 50 Years old and has been living with HIV for nearly 21 years…She is on anti-retroviral drugs but has much more complicated disabilities; she had 3 strokes, chronic heart disease, Diabetes, Epileptic fits, Hypertension and osteoarthritis [all drug side effects, but none ‘AIDS’]…She fights for asylum seekers to get their medication without discrimination in the UK and for this she will go on fighting until the policy is better and reversed.”

“1301 (93% of total participants) had complete baseline data and were included in this study. Of those, 263 (20%) were women, 225 (17%) were Latino/Latina, and 701 (54%) were black. There were 375 persons who were neither Latino/Latina nor black and were categorized as white/other (338 self-described whites and 37 in all other groups)…38% of participants entered the study with a previous AIDS-defining illness…AZT and 3TC were components in the initial antiretroviral strategy for most patients in all groups, with 3TC being used slightly less frequently among blacks compared with other racial/ethnic groups (78% vs. 85% to 86%). Nelfinavir was the most commonly prescribed PI (61%), followed by a ritonavir-boosted PI (26%), whereas efavirenz was prescribed for 63% and nevirapine for 37% of participants in the NNRTI category…Among 5929 person-years of follow-up, a total of 409 participants had 1 or more grade 4 adverse events, with an event rate of 8.9 per 100 person-years…The frequency of grade 4 adverse events was highest in the hepatic category, followed by gastrointestinal, other hematologic, psychiatric, anemia, cardiovascular, and renal event categories. There were a total of 176 deaths (13.5%) over the 5 years of the study for a rate of 3.0 per 100 person-years. There were no deaths attributed to antiretroviral toxicity [!]”

“Adverse events were very common during the study period, especially during the induction phase. In the efavirenz arm 34 [of 104] patients discontinued study drug medication as a result of side effects and all but one withdrew from therapy during the induction phase compared with 25 [of 105] patients in the lopinavir/ritonavir arm, all of them in the induction phase. In the efavirenz arm dermatological side effects (rash and hypersensitivity reaction) and neuropsychiatric side effects (sleep disturbances and vivid dreams) were significantly more frequent than in the lopinavir/ritonavir arm. Conversely, in the lopinavir/ritonavir arm the incidence of gastrointestinal disorders (nausea and diarrhoea) were more frequent than in the efavirenz arm. At the end of the induction phase, the median increase in total cholesterol, high-density lipoprotein cholesterol and triglyceride levels in the efavirenz and lopinavir/ritonavir group in mg/dl were: 20 and 30.5, 9 and 8, 1 and 65, respectively, with a statistically significant difference in triglycerides. At week 72, median changes from week 24 in total cholesterol, high-density lipoprotein cholesterol and triglyceride levels in mg/dl were 26 and 25, 7 and 2.7, 11 and 62 in efavirenz and lopinavir/ritonavir, respectively, with a statistically significant difference in triglycerides.”

“Fatal hypersensitivity reactions have been associated with therapy with ZIAGEN (abacavir sulfate). Therapy [with] ZIAGEN should be discontinued in patients developing signs or symptoms of hypersensitivity in 2 or more of the following groups: 1) fever, 2) rash, 3) gastrointestinal (including nausea, vomiting, diarrhea or abdominal pain, 4) constitutional (including generalized malaise, fatigue or achiness, 5) respiratory (including pharyngitis, dyspnea, cough and abnormal chest x-ray findings, predominantly infiltrates, which can be localized). To minimize the risk of a life threatening hypersensitivity reaction, ZIAGEN should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (acute onset of respiratory diseases, gastroenteritis or reactions to other medications). The symptoms of a hypersensitivity reaction can occur at any time during treatment with abacavir, but usually occur within the fist six weeks of therapy. ZIAGEN or any other medicinal product containing abacavir must never be restarted following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death. Severe or fatal hypersensitivity reactions can occur within hours after ZIAGEN reintroduction in patients who have no identified history or undiagnosed symptoms of hypersensitivity during their initial period of use of ZIAGEN…Hypersensitivity to abacavir was reported in approximately 8% of 2670 patients (n = 206) in 9 clinical trials…The signs and symptoms of this hypersensitivity reaction [to Ziagen/Abacavir] are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in [upper case]. Gastrointestinal tract: ABDOMINAL PAIN, DIARRHEA, mouth ulceration, NAUSEA, VOMITING; Haematological: Lymphopenia; Liver/pancreas: ELEVATED LIVER FUNCTION TESTS, hepatic failure; Miscellaneous: Anaphylaxis, conjunctivitis, edema, FATIGUE, FEVER, hypotension, lymphadenopathy, MALAISE; Musculoskeletal: Arthralgia, elevated creatine phosphokinase, MYALGIA, rarely myolysis; Neurological/Psychiatric: HEADACHE, paraesthesia; Respiratory tract: Adult respiratory distress syndrome, COUGH, DYSPNEA, respiratory failure, sore throat; Skin: RASH (usually maculopapular or urticarial); Urology: Elevated creatinine, renal failure.”

“John Holloway received a diagnosis of AIDS nearly two decades ago…[he] lives in a housing complex designed for the frail elderly, suffers from complex health problems usually associated with advanced age: chronic obstructive pulmonary disease, diabetes, kidney failure, a bleeding ulcer, severe depression, rectal cancer and the lingering effects of a broken hip…scientists, doctors and patients [are now] encountering a constellation of ailments showing up prematurely or in disproportionate numbers among the first wave of AIDS survivors to reach late middle age…“I look at how gracefully [my 85 year old father has] aged, and I wish I understood what was happening to my body,” Mr. Holloway said…Mr. Holloway is uncomplaining even in the face of pneumonia and a 40-pound weight loss, both associated with his cancer treatment [quite likely caused by AIDS drugs]…[another long term AIDS patient] Jeff, who asked that he not be fully identified, has had one hip replacement because of a condition called avascular necrosis, the death of cells from inadequate blood supply, and needs another to avoid a wheelchair. Many experts think that avascular necrosis is caused by the steroids many early AIDS sufferers took for pneumonia. His bones are spongy from osteoporosis, a disorder that afflicts many postmenopausal women but rarely middle-aged men, except some with AIDS [probably all taking AIDS drugs]. No research has explained the unusual incidence. In addition, Jeff has Parkinson’s disease, which is causing tremors and memory lapses…Many AIDS patients have end-stage liver disease, either from intravenous drug use or alcohol abuse [hmm, somehow they forgot to mention that AIDS drugs can cause liver disease]…[Non-drug] explanations do not satisfy Larry Kramer, founder of several AIDS advocacy groups. Mr. Kramer, 73 and a long-term survivor, said he had always suspected “it was only a matter of time before stuff like this happened” given the potency of the antiretroviral drugs. “How long will the human body be able to tolerate that constant bombardment?” he asked. “Well, we are now seeing that many bodies can’t. Once again, just as we thought we were out of the woods, sort of, we have good reason again to be really scared.”…Marty Weinstein, 55 and infected since 1982, has had a pacemaker installed, has been found to have osteoporosis, and has been treated for anal cancer and medicated for severe depression — all in the last year. He also has cognitive deficits. A former professor of psychology in Chicago, he presses his doctors about cause and effect. Sometimes they offer a hypothesis, he said, but never a certain explanation.”

“after [Vancouver naturopathic doctor Laura] Louie saw the work they were doing with HIV patients at Mae On, she volunteered to help out. Much convincing, cajoling and hands-on demonstrations of acupuncture later, the doctor got the go-ahead from the hospital director to open her own free clinic in a small out-building beside the hospital to treat [with acupuncture] the growing problems that patients were facing living with the side-effects of the antiretroviral drugs they were taking to treat HIV. The pain, fatigue, numbness, loss of appetite and insomnia were badly affecting their quality of life. [apparently treating the cause of their illness, i.e. stopping the drugs, crossed nobody’s mind]”

“The life-prolonging ARV drugs have been labelled “death drugs” because of the effect they have on patients who take them without adequate food, according to Ahmed Mohamed Patel, a volunteer with the Kenya Red Cross in Isiolo, in Kenya’s Eastern Province, which borders Ethiopia in the far north of the country…Health workers said many HIV-positive people were opting to stay off the drugs rather than suffer the side effects of taking them on an empty stomach.”

“The first-line antitubercular and antiretroviral drugs share many of their adverse effects: skin rashes, gastrointestinal intolerance, hepatoxicity, central nervous system symptoms, peripheral neuropathy, and blood dyscrasias”

“ELISA and Western blot tests for HIV were positive. CD4 cell count was 17/µ l, and CD8 cell count was 239/ µ l, CD4 % was 4.13%, CD8 % was 57.02%. She was diagnosed as AIDS (CDC Clinical Stage C) with disseminated cryptococcosis with raised intra cranial pressure. Her X-ray film revealed bilateral hilar prominence with infiltrates in all lung fields. Chest CT also showed evidence of infiltrates with bronchiectasis. Head CT was normal. ELISA for HIV infection in the father and mother were negative. She was started on antiretroviral therapy with nevirapine, lamivudine and stavudine and specific anti fungal therapy with amphotericin B and flucytosine. Decongestive measures with drugs like dexamethasone, acetazolamide, glycerol and mannitol were also administered. In addition, 15-20 ml CSF was removed daily to reduce the intra cranial pressure. The child also received broad spectrum antibiotics. Despite these measures [because of them?] the child showed a progressive downhill course. The repeat CSF done after two wk of specific therapy was still positive for cryptococcus and there was only a moderate fall in the antigen titers. The child succumbed to her illness after 20 days of specific anticryptococcal therapy.”

“A 25-year-old woman tested positive for HIV-1 during a screening blood test. Her CD4 cell count was 234 cells/µl (14%) and 311 cells/µl (14%) in two consecutive controls a few weeks apart, whereas HIV RNA was 56 822 copies/µl and 34 000 copies/µl, respectively…she started a once-a-day regimen including tenofovir plus emtricitabine and efavirenz. After 10 days she developed a diffuse rash with fever and glossitis [inflammation of the tonue]. Efavirenz was discontinued but her clinical conditions worsened over the following 3 days, so both tenofovir and emtricitabine were stopped, with a dramatic resolution of symptoms within 24 h. After 10 days the patient was restarted on a completely different regimen of zidovudine plus didanosine and ritonavir-boosted fos-amprenavir as both efavirenz and tenofovir might have played a role in the allergic reaction and the patient was distressed over the event. After one week the patient again presented with a diffuse rash and the treatment was discontinued. She restarted 7 days later with only zidovudine and didanosine and within a few days the rash appeared again. So the recurrence of rash after rechallenge was reasonably caused by didanosine…[this history] suggests that she is allergic to at least two different drugs [tenofovir and didanosine]”

“The safety analysis compares etravirine [TMC125] doses. Control data are presented for completeness, although the significant difference in treatment duration confounds comparisons with the etravirine groups [37 out of 40 people on the control therapy withdrew from the study]…Overall, the incidence of psychiatric adverse events with etravirine was 10.7%. Psychiatric events considered to be possibly etravirine related were mood swings and nightmares (one subject each) in the 400 mg group and abnormal dreams, anxiety and depression (one subject each) in the 800 mg group. There were no grade 3/4 psychiatric events or discontinuations because of psychiatric events. The most common nervous system events with etravirine were headache and insomnia. Neither of these events led to discontinuation. The most common adverse events with etravirine, irrespective of causality, were diarrhea, enfuvirtide related injection site reactions, pyrexia [fever], fatigue, nausea, headache and insomnia. There was no etravirine dose effect on grade 3/4 adverse events. There were four deaths during the study period, one in the control and three in the etravirine 400 mg group…No single adverse event led to discontinuation in more than two patients, except drug-related rash in five patients (3.1%), of which four received etravirine 800 mgæThe most common treatment-emergent grade 3/4 laboratory abnormality with etravirine was elevated pancreatic amylase, occurring in 13 patients (8.2%)…Three etravirine patients had clinical pancreatitis but all had other risk factors (didanosine with and/or without tenofovir or previous pancreatitis). One patient permanently discontinued because of clinical pancreatitis and one because of elevated pancreatic amylase and lipase levels, both of whom received 400mg etravirine.”

“We report three patients who had gastrointestinal intolerance to Truvada”

“A 31-year-old Ugandan man with advanced HIV-1 disease was admitted in September 2004 with increasing breathlessness as a result of relapsed disseminated Kaposi’s sarcoma causing bilateral pleural effusions. His medications were HAART; lamivudine, tenofovir and efavirenz started in November 2003; prophylactic fluconazole (for previous cryptococcal meningitis) and co-trimoxazole…15 days after admission, he developed initially watery, non-bloody diarrhoea, progressing to mucoid bloody diarrhoea…Diarrhoea is a very common symptom in HIV disease. In the era of HAART, antiretroviral drugs are a common cause”

“A total of 1507 individuals (517 men and 990 women), whose median age was 35 years were included in the study [of people starting antiretroviral therapy in Malawi]. There were a total of 190 (12.6%) deaths on ART of which 116 (61%) occurred within the first 3 months (very early mortality) and 150 (79%) during the first 6 months of initiating ART. Significant risk factors associated with such mortality included WHO stage IV disease, a baseline CD4 cell count under 50 cells/microliter and increasing grades of malnutrition…Individuals who were severely malnourished [body mass index (BMI) < 16.0 kg/m] had a six times higher risk of dying in the first 3 months than those with a normal nutritional status. CONCLUSIONS:: Among individuals starting ART, the BMI [body-mass index] and clinical staging could be important screening tools for use to identify and target individuals who, despite ART, are still at a high risk of early death.”

“the use of antiretroviral therapy is now associated with a series of serious side effects and long-term complications that may have a negative impact on mortality rates. More deaths occurring from liver failure, kidney disease, and cardiovascular complications are being observed in this patient population.”

“A survey of nearly 2,000 people with HIV/AIDS in Britain revealed that 69 percent did not feel sufficiently informed about the long-term effects of their medications. Participants first feared the long-term toxic effects of the drugs, then noted concerns about other illnesses or opportunistic infections caused by HIV. Third on the list of concerns was worry about short-term side effects of the drugs…Nikk Bowden, an HIV patient for seven years, noted that many of the drugs have not been around long enough for researchers to know what impact they can have after patients take them for decades. 'It is a worry that you could be taking something that isn’t fully understood over a period of time,' Bowden said. 'The payment is that I get extra years of life through taking the medication. It is the best part of a bad deal, I suppose.' [Note that there have been no long term placebo-controlled studies that show that AIDS drugs lengthen life, so this 'payment' may be defaulted on.]”

“Fifty men were enrolled in AI-02-001 at the University of Washington Primary Infection Clinic [with symptoms of PHI – Primary HIV Infection]…Nine (18%) subjects experienced symptoms consistent with suspected abacavir hypersensitivity”

“Between August 1998 and April 2002, 404 HIV-1-infected adult patients (age > 15 years) were enrolled in the Senegalese antiretroviral drug access initiative in Dakar and included in an observational cohort…Overall, 93 deaths were recorded. Half of the deaths occurred within the first 12 months…The probability of dying reached 7.2%, 17.4% and 24.6% at 6, 12, 24 and 60 months, respectively. Under the hypothesis that the patients lost to follow-up were dead, probabilities of dying were respectively 13.4% and 21.0% at 12 and 24 months of follow-up…the peak in mortality rates was reached within the second semester [six months] after starting HAART…a clinical stage C [AIDS] versus A/B, a body mass index less than 19 kg [per square meter], a haemoglobin level less than 10 g/dl, a total lymphocyte count less than 1200 cells/ml and a CD4 cell count less than 200 cells/ml were associated with a worse survival…[most of the deaths were due to Tuberculosis and other infections which, after the initiation of AIDS drugs are known as 'Immune Reconstitution Disorder' but] Five patients died from acute liver failure. Three patients on protease inhibitors died from metabolic disorders (diabetes, hyperamylasaemia in a patient receiving didanosine, metabolic acidosis) [these two conditions are almost certainly due to AIDS drugs]”

“free food is essential for many ARV patients [in Zambia], nurses said. Patients taking ARVs risk malnutrition and harmful side effects unless they can increase their overall caloric intake by as much as 40 percent. Many Aids patients in Zambia have difficulty getting enough food to tolerate the highly-toxic drugs.”

“[AIDS combination] Drug treatment has not been without its downside: adverse effects include mitochondrial damage, metabolic disease, hepatotoxicity and neuropsychiatric reactions.”

“Primary Outcomes: Life-threatening adverse events attributable to study drugs; dose-limiting toxicity, defined as adverse events of Grade 3 or greater attributable to study drug and require dose reduction or interruption but are not judged to be life-threatening by the protocol team. [In other words, the experimenters will try to find out just how much AIDS drugs they can give these children without quite killing them]

Secondary Outcomes: Pharmacological success, defined as achieving an inhibitory quotient (IQ) of 15 after 2 weeks on high-dose LPV/r without life-threatening or dose-limiting toxicity; virologic success, defined by optimal response (undetectable viral load) at Week 24 or adequate response (0.75 log drop in viral load or more) from baseline to Week 24; immunologic success, defined as a CD4% increase from baseline of 5% or more points by Week 24; minimal criterion for overall success, defined as a 0.75 log drop in viral load or more or 5% point increase in CD4% from baseline to Week 24; virologic failure, defined as an inadequate (less than 0.75 log drop in viral load) or suboptimal (confirmed viral load of greater than 400 copies/ml) response at Week 24. [Note the absence of any real health outcomes]

Expected Total Enrollment: 48”

“At the Capitol, [Greg] Gour told how he had decided to quit fighting the AIDS virus but knows [experimental AIDS drug] AB 651 probably won't be enacted in time to help him…He said he's seen both firsthand, caring for two roommates and a partner who died from AIDS-related [or AIDS-drug-related] complications from 1992 to 1996. One was paralyzed. Another, a former championship bodybuilder, went blind and starved to death. Both spent most of their final days unconscious from the morphine used to dull their pain…Gour said he was first diagnosed with HIV 24 years ago, so he's spent half his life fighting this disease. He has taken the various drug combinations to stay alive and suffered more from the medications' side effects than from the underlying virus, he said. Over the years, he has had to change his medication as his body became resistant to certain drugs. With each new regimen, he said he encountered another set of side effects. Eighteen months ago, when his doctor prescribed a new regimen of drugs that included two injections a day, Gour said he'd had enough. 'My quality of life meant I did not want to be reminded twice a day that I had a disease and suffer the side effects, all when I had not had any of the illnesses from the disease,' he said. 'I was only suffering from the stuff preventing the disease.' As an accountant with a "computer-like brain," Gour said, he decided to take control of his life by giving up the medications that made him sick. At the moment, Gour looks surprisingly robust. 'Part of the reason I am so vibrant is because I am back in control of my life," he said. "I am not waiting for the next HIV meds to come through.'”

“Abacavir, a carbocyclic nucleoside analogue reverse transcriptase inhibitor, is used in combination with other antiretroviral agents for the treatment of HIV-1 infection. The major toxicity associated with therapy is a potentially life-threatening hypersensitivity reaction occurring in approximately 3–5% of patients, usually during the first 6 weeks of treatment, with a median time to onset of 8 days [1,2]. Clinical manifestations most frequently include fever, rash, fatigue, gastrointestinal symptoms such as nausea, vomiting,diarrhea and abdominal pain,and respiratory symptoms such as pharyngitis [swelling of the throat], dyspnea [difficulty breathing] and cough. Although the described respiratory symptoms are usually mild, we report here the case of a man who developed acute, severe pneumonitis leading to acute respiratory distress syndrome after 11 days of therapy with abacavir.”

“Tuberculosis is the most common serious opportunistic infection associated with HIV infection in sub-Saharan Africa, and a strong case has been made for integrating tuberculosis and HIV care…Current guidelines, such as those from the US Department of Health and Human Services, suggest that regimens based on the non-nucleoside reverse transcriptase inhibitor efavirenz be used as first-line choices in patients receiving concomitant rifampicin [for Tuberculosis]. Therapy choices become far more difficult in the face of treatment-limiting toxicities, virological failure or pregnancy. In these cases, a protease inhibitor-based regimen is needed as nevirapine may not be an appropriate option because of its interaction with rifampicin and additive hepatic [liver] toxicity. The guidelines suggested the use of ritonavir-boosted saquinavir. Although the ability of ritonavir to boost plasma concentrations of saquinavir is well described, there is only limited evidence that this combination is adequate to counteract the enzyme induction caused by rifampicin and is clinically effective [3,4]. The issue of a ‘Dear Health Care Provider’ letter by Roche Pharmaceuticals on 7 February 2005 has now caused considerable additional uncertainty…Of 28 patients given rifampicin 600 mg once a day together with ritonavir 100 mg and saquinavir 1000 mg twice a day, 11 (39.3%) had developed significant hepatocellular toxicity during the 28-day study period…The newly described toxicity of the rifampin, saquinavir, ritonavir regimen thus vividly highlights the great need for research, particularly pharmacokinetic studies, also to address the ART options appropriate for resource-limited settings, and in particular, in this instance, for co-administration with rifampicin containing tuberculosis treatment.”

“61 patients (23 female) were enrolled in the study…16% of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV [indinavir] dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd…was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters.”

“Epzicom, GSK’s latest FDC [fixed dose combination] combining Epivir with Ziagen (abacavir), also offers once-daily, single tablet dosing, Harris says. “However Ziagen is associated with a range of side effects, including the potentially fatal hypersensitivity reaction (HSR) and this has precluded switching by some physicians.”…Epzicom is expected to experience relatively strong growth- a 2005-14 CAGR [compound annual growth rate] of 9.9% - reaching peak sales of $490m in 2009.”

“Reisler et al reviewed data from 2947 patients enrolled in 5…studies. They found that 23% of patients developed a severe adverse event presumed secondary to HAART therapy. The mortality from these adverse events approached the mortality for a first AIDS defining event…More HIV infected patients are dying of non AIDS causes. In a retrospective study from Parkland Hospital…the leading causes of death in HIV infected patients between 1999 and 2000 were non AIDS associated infections and end stage liver disease.”

“FDA on Tuesday made public a letter ordering Abbott Laboratories to stop circulating two advertisements for its antiretroviral drug Kaletra because the agency said the ads "exaggerat[e]" the drug's benefits and omit information about possible "life-threatening safety risks," Both ads, one of which ran in the May 2004 issue of POZ magazine and the other which is meant for posting in restrooms, feature photographs taken over a four- or five-year period of a "healthy-looking" man, the Wall Street Journal reports. The caption beneath the photographs says, "Where do you see yourself in five years?…"…FDA's Division of Drug Marketing, Advertising and Communications in a letter to Greg Murawski, Abbott's manager of regulator affairs, said, "The ad thus implies that the man shown in the photographs has been healthy over the past several years and that this positive outcome is a direct result of taking Kaletra"…The letter said that "FDA is not aware of substantial evidence or substantial clinical experience to support claims of survival, good health, undetectable HIV RNA levels and disease control for five years". FDA also said that the ads are "misleading" because they fail to mention potential side effects of Kaletra, which include potentially life-threatening interactions with other drugs, Reuters reports…Kaletra has been a "blockbuster" for Abbott since it gained FDA approval four years ago and is projected to generate more than $800 million in worldwide sales this year, the Chicago Tribune reports.”

“104 adults were recruited…from HIV outpatient clinics throughout Ontario, Canada…All patient interviews and 96% of medical charts revealed the use of at least one drug. 85% of patients reported use of antiretroviral medications; nearly 70% used highly active antiretroviral therapy. Patients used significantly more drugs by patient report (15.7 – 7.7) than by medical chart review (8.4 – 5.0) reporting up to 39 drugs per person. Pill burden was substantial, averaging 20.7 – 12.5 and ranged up to 69 "pills-per-day." Patient-reported physician awareness of drug use was highest for prescription drugs and lowest for social/recreational drugs; correspondingly agreement between medical chart and patient report ranged from 80% for antiretrovirals to 10% for non-prescribed drugs…Our findings emphasize…the need for comprehensive drug assessment, particularly because of the risks of drug-drug interactions and decreased adherence secondary to therapeutic complexity.”

“There is also increasing recognition that adverse events associated with antiretroviral treatment remain an important source of morbidity and even mortality, such as in advanced disease, in which non-AIDS serious adverse events continue to outweigh AIDS-related events in frequency and overall detrimental effects on quality of life.”

“the use of continuous HAART…might be discontinued for numerous reasons, including treatment failure, drug toxicity or side-effects”

“Treatment-emergent adverse events observed [in this trial of two nucleoside analogs] with a significant difference between groups were diarrhea, nausea, lactic acidosis, lipodystrophy, abnormal dreams, neuropathy, paresthesia ['pins and needles' or other sensations indicating damage to peripheral nerves], skin discoloration, and and increased cough…Pancreatitis and symptomatic hyperlactatemia/lactic acidosis, were observed only in the stavudine group…The probability of developing a treatment-limited adverse event through week 60 was statistically greater in the stavudine group (15%) vs the emtricitabine group (7%)”

“Toxicities that have been attributed to mitochondrial toxicity (peripheral neuropathy, lipodystrophy, and lactic acidosis) were reported in 100 patients, 83 (28%) of 301 in the stavudine group and 17 (6%) of 299 in the tenofovir DF group. Neuropathy [peripheral nerve damage] was observed in 31 (10%) of 301 and 9 (3%) of 299 patients in the stavudine and tenofovir DF groups, respectively. Investigator-defined lipodystrophy was reported more often in patients receiving stavudine vs tenofovir DF (58 [19%] of 301 vs 9 [3%] of 299, respectively)…significantly less total limb fat was observed in the stavudine group at week 96 (7.9 kg tenofovir DF [n=128] vs 5.0 kg stavudine [n=134]) and week 144 (8.6 kg tenofovir DF [n=115] vs 4.5 kg stavudine [n=117]). Investigator-defined lactic acidosis occurred in 3 patients, all of whom were in the stavudine group…Through 144 weeks, the renal [kidney] safety profile was similar between the 2 groups. Two patients in each group developed a creatinine level of more than 2.0 mg/dL ( 176.8 µmol/L), while hypophosphatemia ( 2.0 mg/dL [ 176.8 µmol/L]) was observed in 10 patients receiving tenofovir DF and 8 patients receiving stavudine. The incidence of proteinuria and/or glycosuria was similar between the two groups.”

“Citing deaths they claim are due to the improper introduction of antiretroviral (ARV) drugs in Swaziland, AIDS activists have called for an urgent public education campaign and proper testing facilities to monitor patients' reaction to the drugs…Hannie Dlamini, president of the Swaziland AIDS Support Organisation…said members of his group, which counsels people living with HIV and AIDS, and dispenses ARVS, have died of liver poisoning, allegedly due to Nevirapine…"People are given ARVs, and two weeks later you see in the papers they are late [dead]. If it were my country, I'd stop distribution now. There must be a six-month public education campaign before they are reintroduced," Dlamini said.”

“In recent years, there has been increasing awareness that highly active antiretroviral therapy (HAART) may contribute to the development of autoimmune manifestations…In a prospective study of 150 HIV patients treated with HAART, we analysed the incidence of SS after starting HAART. We looked at HIV-positive patients treated with HAART compared with 250 agematched patients not treated with HAART to determine the incidence and clinical outcome of cases of SS during the period Janaury 1997 to October 2003…No patients not treated with HAART developed SS during the study period. The most common clinical features in these four patients with SS included xerostomia [dry mouth], xerophtalmia [dry eyes], fatigue, parotid [salivary gland] swelling and polyarthralgia [pain in multiple joints]. These clinical manifestations occurred after 6–48 months after the introduction of HAART.”

“During the follow up [36 months], the antiretroviral treatment was modified at least once in 72 (75%) [of the] treated patients”

“We report a peculiar case of cryptococcal meningities and subsequent immune reconstitution inflammatory syndrome (IRIS) occurring shortly after the initiation of highly active antiretroviral therapy (HAART).”

“during clinical trials of Kaletra [combination of the protease inhibitors Lopinavir and Ritonavir], approximately 1 in 4 treatment experienced patients saw a serious or life-threatening laboratory abnormality.…The most common laboratory abnormalities [found with Kaletra, a combination of the protease inhibitors Lopinavir and Ritonavir] are [liver disorders] as well as increases in triglycerides and total cholesterol…As a class, PIs [protease inhibitors] are associated with metabolic (mainly sugar and lipid)…changes, including the development or worsening of diabetes.”

“Mitochondrial enzyme activity was assessed in adipocytes [fat cells] from 7 patients initiating nucleoside reverse transcriptase inhibitor (NRTI) regimens. After 6–12 months of therapy, adipocytes from six patients demonstrated cytochrome C oxidase (COX) activity reduced from baseline, correlating positively with mitochondrial DNA levels [mitochondria are the energy regulating organelles critical to the correct functioning of every living cell], concomitant with evidence of cellular toxicity.”

“The nucleoside analogue abacavir can cause a hypersensitivity reaction (HSR) in approximately 5% of patients, typically occurring as a progressive syndrome during the first few days to weeks of treatment. A more severe reaction has also been reported within minutes to hours of rechallenge, in patients with or without a definite history of previous HSR. We report here a case of an HIV-infected man who developed an immediate, life-threatening reaction compatible with abacavir HSR upon his first documented exposure to abacavir.”

“Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were enrolled into 1 of 5 CPCRA [Terry Beim Community Programs for Clinical Research on AIDS] clinical trials…for this analysis…All patients in this cohort were prescribed ART following enrollment. At 12 months of follow-up, 1951/2120 (92%) were [still] prescribed ART with 1475/2120 (70%) on protease inhibitor –based regimens, 421/2120 (20%) on nonnucleoside reverse transcription inhibitor–based regimens (no protease inhibitor), and 55/2120 (3%) solely on nucleoside reverse transcription inhibitors. Median follow-up was 20.7 months, a total of 5940 person-years…675 patients experienced a grade 4 event [serious or life threatening]; 332 developed an AIDS event; and 272 died (4.6 per 100 person-years)…The cumulative percentage of patients with a grade 4 event after 12, 24, and 36 months are, respectively, 15.6%, 23.7%, and 30.8%. Corresponding percentages for AIDS are, respectively, 7.3%, 10.8%, and 16.5% and corresponding percentages for death are, respectively, 3.9%, 7.9%, and 13.1%. The most common grade 4 events were: liver related (148 patients; rate = 2.6 per 100 person-years); neutropenia (89; 1.5/100 person-year); anemia (64; 1.1/100 person-year); cardiovascular (51; 0.89/100 person-year); pancreatitis (50; 0.85/100 person-year); psychiatric (44; 0.75/100 personyear); kidney-related (34; 0.58/100 person-year); thrombocytopenia (32; 0.54/100 person-year); and hemorrhage (25; 0.42/100 person-year) [these are much more likely to be therapy-related than HIV-related]…the rate of grade 4 events is greater than the rate of AIDS events, and the risk of death associated with these grade 4 events was very high for many events”

“Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear…The A/S/D [Abacavir/Stavudine/Didanosine] arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms…The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.”

“A daily dose of [Protease Inhibitors] includes about 1 gram of one or more DNA chain-terminators [AZT, 3TC etc.] per clinically ill person and 0.5 grams per asymptomatic HIV positive [person] per day, which is the equivalent of 1.5-3 million molecules of DNA chain terminators per body cell!”

“We are writing to express our dismay with the July 14, 2003 DHHS [US Dept. of Health and Human Services] Treatment Guidelines update. Namely, the placement of stavudine (d4T) in the position of a preferred first line combination regimen without qualification, despite numerous studies linking d4t with a variety of serious side effects. We are especially concerned with the irreversible facial lipoatrophy caused by d4t which causes significant quality of life issues and thereby raises adherence issues for many HIV+ patients”

“However, laboratory values do not tell the whole story. We see immunologic benefit in the apparent absence of virologic control. We see clinical improvement in the absence of immunologic improvement. Clearly these changes translate into improved quality and longevity of life for patients with HIV/AIDS. When highly active combination therapies fail to keep a patient feeling well or cause intolerable pill burden or side effects, they should be discontinued. ‘Suboptimal’ regimens can be considered if they offer some slowing of disease progression without undue burden. These regimens would not be considered if decisions were based solely on medication treatment history and genotypic analysis. But in palliative care, we have permission to look to the patient first and offer care that is helpful, even if it is not ‘standard’ in the traditional sense. [and, when the patient has not been written off, the patient doesn’t come first?]”

“Caution - Pharmaceutical agent [Epivir=3TC=Lamivudine]. Health effects information is based on hazards of components. May produce adverse effects on the development of human offspring. Possible effects of overexposure in the workplace include: abdominal pain; nausea; vomiting; headache; fatigue; rash…This product contains lamivudine which produced evidence of DNA damage in the following assay(s): mammalian cell mutation assay (L5178Y mouse lymphoma thymidine kinase locus assay); cultured human lymphocytes.”

“A total of 1064 treatment-emergent events were reported by 70 of the ITT patient set (100.0%), the majority of which (925 events; 86.9%) were grade 2 or less in severity. Just under 50% of patients experienced diarrhea and 44% reported experiencing nausea. Hyperlipidemia and neuropathy were reported in 25% and 10% of patients, respectively. Approximately 19% of patients developed rash and approximately 7% reported a general allergic reaction. No rash or allergic reaction was defined by an investigator [!] as a hypersensitivity reaction. In total, 266 events (25%) were considered by [!] the study investigator to be treatment related. The most common treatment-related adverse events were associated with the injection of enfuvirtide, with 52 patients (74.3%) experiencing at least one injection site-related adverse event…Treatment-related diarrhea was experienced by 8 patients (11.4%), and nausea and asthenia by 6 patients each (8.6%)…Of the 266 treatment-related adverse events, most (236, 88.7%) were classified as grade 1 or grade 2. Such events were reported by 58 (82.9%) and 26 patients (37.1%), respectively. Injection site reaction was the most common treatment-related grade 1 event reported (31 patients, 44.3%). Grade 1 injection site mass was reported by 21 patients (30.0%). Grade 1 injection site pain and injection site inflammation were reported by 16 (22.9%) and 11 patients (15.7%), respectively. Grade 2 asthenia, injection site pain, diarrhea and insomnia were each reported by three patients (4.3%)…44 serious adverse events were reported and 10 of these, reported by 7 patients (10.0%), were considered in the opinion of the investigator [!] to be potentially related to enfuvirtide…There were five deaths during the study, all of which were related to the progression of HIV disease and were not considered to be [!] attributable to enfuvirtide administration.”

“Use of protease inhibitors was strongly associated with the likelihood of having a myocardial infarction and correlated with diabetes mellitus and hyperlipidaemia”

“We tested the long-term mitochondrial toxicity of NRTI [Nucleoside Reverse Transcriptase Inhibitors] with respect to mtDNA [Mitochondrial DNA], mtDNA-encoded respiratory chain protein and cell function (lactate production, intracellular lipids and cell proliferation) and confirm previous findings that NRTI are able to mediate a rapid decline of mtDNA [Mitochondria are the energy regulating organelles in every living cell]…We observed increased toxicity in some NRTI combinations, namely ddC–d4T and ZDV[AZT]–3TC, whereas the d4T–ddI combination did not result in increased toxicity…The fact that some NRTI at clinically relevant concentrations were able to decrease mtDNA beyond 25 days of exposure, suggests that studies on mitochondrial toxicity must be long-term investigations [not even a hint that people should stop taking these drugs, even though damaging mitochondria has extremely serious long-term health consequences, eventually fatal]”

“Our study shows that significant mitochondrial damage [mitochondria are the energy regulating units in every living cell] is present in HIV-infected patients with severe adverse effects after long-term antiretroviral treatment…Several lines of evidence support the clinical relevance of the mitochondrial damage…The level of lactate in CSF [Cerebro-Spinal Fluid] was correlated to the clinical severity…[Secondly, ] biochemical analyses of the respiratory chain…confirm the ubiquitous tissue dysfunction indicated by the clinical sympmtoms…[Thirdly ] the activities of respiratory chain in muscle and liver were significantly low both in individual patients and in the patient group taken as a whole…1 HIV patient without long-term antiretroviral therapy…[but with] chronic myalgias [muscle pain] for more than 10 years…had completely normal muscle mitochondrial function”

“the HIV protease inhibitor ritonavir at concentrations near clinical plasma levels is able to directly cause endothelial [blood vessel lining] mitochondrial DNA damage and cell death…This study suggests that HIV protease inhibitor-mediated endothelial injury may contribute to its cardiovascular complications.”

“In a short period of time we have observed three patients taking indinavir/ritonavir combined therapy who developed striking alopecia [hair loss] a few weeks after beginning treatment. In two of these patients the alopecia was severe, affecting the scalp, eyelids, eyebrows, beard, axilar [armpit] and pubic areas, and body hair. In all the patients alopecia was rapidly reversible after withdrawing drugs.”

“Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease.”

“The toxicity and tolerability of HAART…are increasingly important factors in the decision to prescribe one of the more than 3000 potential regimens, because side-effects are frequent (74% of adults in the largest survey) and because long-term benefits depend on near perfect (>95%) and life-long adherence, which in turn are affected by tolerability (and human factors)…In view of the effect of adverse events on successful HAART, the fact that their study, analysis, and reporting by academia, industry, regulators, conference presenters, report writers, and journal editors has been poor, although not unique to HIV-1, is disappointing…The only adverse events that have to be studied to gain regulatory approval relate to essential (central nervous system, cardiovascular, and respiratory) organs. Blood, liver, and kidneys are invariably studied, although usually only by chemical analysis rather than by clinical assessment. However, many organs relevant to HAART toxicity were rarely studied in HAART trials…Adequate safety data for accelerated regulatory approval are thought to be generated from 400 to 500 patients who receive treatment for 6 months in controlled, blinded trials, and from about 100 patients treated for 12 months (500 for traditional approval--ie, 48-week, randomised data, usually with clinical endpoints), but not necessarily in randomised studies. The pooled data identify adverse events with 1% and 3% incidence with 3 months' and 12 months' therapy, respectively. The 23 HAART trials assessed [in this study] had a median of only 81 patients per group, and so individually had less power to detect adverse events (those with about 15% incidence)…Despite the many long-term adverse effects associated with HAART, phase 3 antiretroviral studies are often shorter than they used to be before HAART became available because of accelerated licensing and because of the emphasis placed on 24-week virological data as a marker of clinical benefit. Only half of 60 antiretroviral therapy trials done before 1997 and three of the 23 HAART trials reported post-week 48 data [yet people are expected to take these drug regimens for life]…Chronic, low-grade events, which are often not reported by patients and do not lead to immediate change in therapy, rather than acute, severe events, which are well reported and lead to early change in therapy, affect adherence to treatment in cohort studies. It is disappointing, therefore, that only two HAART studies reported adherence, and that no HAART study reported what adverse events resulted in poor adherence…Patients prevented from dying or developing AIDS by HAART can be thought of as having an increased quality of life. The same cannot be said, however, for asymptomatic patients at low risk of AIDS. And yet, as with adherence, quality of life was reported in only two of the 23 HAART studies…Additional weaknesses with respect to the study of adverse events include the absence of any systematic approach for identification of cause, prevention, and management of many adverse reactions, especially if unexpected…The number of individuals treated after approval of a drug is generally more than 1000 times that exposed before approval.2 An adverse reaction with a one in 1000 incidence has about a 50% chance of arising once before approval, but will arise in hundreds of patients after licensing…Additionally, any incidence often triples after licensing (and includes more severe events) because patients excluded from studies for various reasons are treated but studied less intensively…The aim of post-marketing surveillance, therefore, is to assess real-world safety, but passive surveillance is spontaneous and voluntary, with only occasional detailed, long-term monitoring. Passive surveillance is judged "the most cost-effective approach" (although this assertion has not been tested), but cannot reliably ascertain prevalence or risk factors, or compare drugs…The effect of post-marketing surveillance is further limited in that, for adverse events identified after approval of a drug, there is no standardised approach for the study of the association between the implicated drug or drug class and such adverse events…To account for individuals who withdraw from a study or who stop taking the study drug, plasma HIV-1 RNA is analysed by intention-to-treat, and missing values classified as virological failures (ITTM=F). Many HAART studies did not state, however, whether patients with undetectable HIV-1 RNA at study conclusion and who switched study drug during the trial were classified as virological failures. ITTM=F overestimates tolerability and adherence if it does not account for backbone antiretroviral drug switching for toxicity or if study drug continues only because another drug is initiated to control toxicity. Results of one study showed that 10% of patients ceased one backbone drug but continued to participate in the study with undetectable viral load at week 52. No study reported what proportion of patients required concomitant therapy to continue HAART…There are clear guidelines with respect to analysis and reporting of adverse events for regulatory submissions…Most reports do not, however, provide these data.”

“The two matched groups consisted of 283 treated [voluntarily with HAART] and 283 untreated patients [voluntarily untreated, matched for various characteristics]…The first AIDS-defining diseases consisted of 1 versus 3 esophageal candidiasis, 1 versus 1 Pneumocystis carinii pneumonia, 0 versus 2 cases of tuberculosis, 0 versus 1 recurrent bacterial pneumonia, 1 versus 3 Kaposi’s sarcoma, 2 versus 1 non-Hodgkin’s lymphoma, 0 versus 3 AIDS dementia, and 0 versus 2 others…Patients with the transmission category of IDU [Intravenous Drug User] had higher progression rates, but the groups also differed when only patients without IDU were considered…3 versus 8 (2.8%) deaths occurred in the treated and untreated group, respectively…Only 64 (25%) patients remained on the same, initial, unchanged regimen, whereas 12 (4.7%) patients added one or more drugs, and 181 (70%) patients replaced, interrupted, or stopped one or more drugs of their initial HAART regimen…The entire antiretroviral regimen was interrupted at least once by 117 (46%) patients, and 61 (24%) of 252 patients who were alive and did not participate in the trial of structured treatment interruptions had no anti- HIV treatment anymore at the end of follow-up. Reasons for stopping all antiretroviral drugs was virologic failure in 2 patients, intolerance/adverse events in 16, patient’s wish in 26, physician’s recommendation in 13, and other in 4.”

“Bacillary splenitis occurred during immune restoration induced by highly active antiretroviral therapy (HAART) [by this theory, the problem with pathogens is the inflammatory reaction that they cause, something that is suppressed by HIV]…We report a case of B. henselae infection contracted during the phase of immune restoration by HAART in a young HIV-positive woman, with an unusual evolution…The excised spleen weighed 339 g and bore multiple nodules and abscesses.”

“In a warning letter to physicians Bristol-Myers Squibb has reported 22 cases (including 7 deaths) worldwide of a stavudine-associated rapidly ascending neuromuscular weakness and respiratory failure mimicking Guillain–Barré syndrome (GBS)...All 22 cases occurred in the context of hyperlactatemia, a recognized stavudine effect. Preliminary analysis of 15 of the cases showed symptom onset 12 months on average (range 4–30 months) after the start of treatment and that most of the patients had only modestly elevated lactate levels...Stavudine (d4T), a thymidine analogue and nucleoside analogue reverse transcriptase inhibitor (NRTI), is often used in combination with other HIV drugs. A known side effect of the drug is a peripheral neuropathy (numbness, tingling or pain in the hands or feet). Stavudine is also associated with a spectrum of lactic acid abnormalities, from asymptomatic, mild hyperlactatemia to a potentially fatal lactic acidosis syndrome (LAS). NRTI-related lactic acidosis can be associated with myopathy (causing muscle wasting, myalgia, fatigue, weakness and elevated creatinine kinase levels), lipoatrophy, hepatic steatosis [loss of fatty tissue in the liver], liver dysfunction and possible fulminant liver failure, and pancreatitis. The toxic effects appear to result from mitochondria damage as a result of DNA polymerase gamma inhibition, but it is unknown whether the new GBS-like symptoms are mediated similarly.

Hyperlactatemia (and LAS) is often associated with symptoms of generalized fatigue, nausea, vomiting, sudden weight loss, abdominal pain and distension. Tachypnea and dyspnea are not reliable early signs of LAS and may signal a preterminal state. Similarly, although serum transaminase levels can eventually rise in patients with LAS, they are often normal at presentation.4 An elevated plasma lactate level is diagnostic of hyperlactatemia (mild 2–5 mmol/L, severe > 5 mmol/L),7 and patients with LAS often have an additional anion gap metabolic acidosis.

The prevalence of moderate or severe hyperlactatemia (plasma lactate level > 2.2 times the normal limit) was determined to be 1% (9 of 880 patients) in a cross-sectional study of HIV-infected patients, with stavudine predisposing to high lactate levels more than other drugs.5 The incidence of hyperlactatemia in stavudine-treated patients has been estimated to be 1.2% per year.6 In most patients in whom lactate levels rise, the levels tend to remain only slightly elevated; however, LAS can develop in these patients, and sudden onset is possible in those with initially normal lactate levels.7,8 Obesity, prolonged drug exposure, and female sex and pregnancy may be risk factors for hyperlactatemia.3 The role of riboflavin and other agents in treating hyperlactatemia7 is evolving.

What to do: Patients should be warned of stavudine-associated LAS and the possibility of potentially lethal neuromuscular failure. If severe hyperlactatemia or motor weakness develops, the drug should be stopped immediately and appropriate supportive care (e.g., ventilation) introduced as needed. Physicians should consider monitoring the lactate levels of patients taking stavudine (recognizing that asymptomatic, mild hyperlactatemia poorly predicts progression to LAS) particularly if symptoms such as fatigue, weight loss, abdominal pain, nausea, vomiting or dyspnea develop.”

“[Chapters in this guide are entitled Introduction, Appetite loss, Body distortions (lipodystrophy), Bone death and destruction, Cardiac concerns, Diarrhea, Fatigue, Gas and bloating, Hair loss, Headaches, Insulin resistance and diabetes, Kidney stones, Liver toxicity, Muscle aches and pains, Nausea and vomiting, Nightmares, daymares and sleeping difficulties, Pancreatitis, Peripheral neuropathy, Skin problems, Sexual difficulties, The end]”

“Unfortunately, complications of HAART and complications of HIV infection, particularly in patients with advanced disease and AIDS, overlap significantly”

“The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24%, mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch.”

“The clinical paradigm of treating HIV disease from the onset of infection, for life, is now under intense scrutiny...HIV...is unlikely to be eradicated even with decades of therapy. HIV therapy itself has produced an entirely new set of serious complications for HIV-infected patients including body deformities, insulin resistance, lactic acidosis, osteoporosis, neuropathy, osteonecrosis, lipid abnormalities, and cardiovascular disease. Most disconcerting is the fact that both the mechanisms of these toxicities as well as the long term consequences are unknown...Interventions may harm the host more than the virus before progression to AIDS...Are we outsmarting the virus, or once again, will the follies of our thinking be exposed?”

“[In this study, patients in the HAART era (1997 through 2000) were significantly healthier than patients seen in the pre-HAART era (1993 through 1995) BEFORE therapy -- higher CD4 cell counts (155 vs 71), less likelihood of prior PCP (30% versus 74%) and prior cytomegalovirus (7% versus 43%), however]...HAART was protective against PCP [pneumonia] only when CD4 cell count was not included in the regression model. HAART was associated with [greater than two times] increased risk of developing bacterial pneumonia and [a 15-fold increase in the likelihood of developing] NHL [Non-Hodgkins Lymphoma]…Perhaps the development of lymphoma is somehow triggered by the therapy itself”

“the treatment [HAART; Highly Active Antiretroviral Therapy] often has significant adverse effects. This is the case with virtually all drugs in the various classes of antiretroviral compounds...Because of the increasingly reported serious adverse effects of the diverse drug constituents of HAART, studies were conducted to attempt to determine the time at which initiation of ART [anti-retroviral therapy] was most efficacious...most patients could be monitored closely [for declines in CD4 cell counts, not declines in observable health] rather than immediately beginning therapy with drugs that have potential significant adverse effects over several years of therapy (e.g. lipodystrophy [fat redistribution], mitochondrial toxicity [damage to the energy regulating mechanisms within every living cell], lipid abnormalities [potentially fatal metabolic abnormalities], osteopenia [loss of bone mass] and lactic acidosis [buildup of lactic acid]).”

“Around 40% of the patients in our analysis experienced some change in their antiretroviral therapy during the first 40 weeks... It previously has been shown that most early changes are due to toxicity.”

“47% (545 of 1160) of patients presented with clinical and 27% (194 of 712) with laboratory adverse events probably or definitely attributed to antiretroviral treatment. Among these, 9% (47 of 545) and 16% (30 of 194), respectively, were graded as serious or severe...Compared with single-PI treatment [drug combination including one type of protease inhibitor], use of dual-PI-antiretroviral treatment and three-class-antiretroviral treatment was associated with higher prevalence of adverse events (odds ratio [OR] 2.0, and 3.9, respectively). Compound specific associations were identified for zidovudine, lamivudine, stavudine, didanosine, abacavir, ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, and nevirapine.”

“combination drug therapy, or the triple-drug “cocktail,” demands a complicated dosage regimen that is difficult to maintain and often provokes severe side effects… “These drugs are as dangerous as chemotherapy,” warned Dr. James Kahn, UCSF associate professor of medicine…“General practitioners should not be using them. You really need a skilled HIV specialist to prescribe the medications and closely monitor the patient’s adherence and response to treatment.””

“Clinicians should have a high index of suspicion for lactic acidosis in a patient on NRTIs [nucleoside analog reverse transcriptase inhibitors such as AZT] and the medications should be stopped at the earliest sign of toxicity…At autopsy patients were found to have hepatic steatosis [fatty deposits in the liver] without a source for lactate production. This syndrome is thought to be the result of mitochondrial dysfunction due to selective inhibition of DNA polymerase gamma by the NRTI class of antiretrovirals…A 55-year-old Hispanic female with bipolar mood disorder and HIV infection…presented with fever and respiratory distress…She had been maintained on various antiretroviral medications…There was no history of alcohol or substance abuse…On hospital day 8 [after extensive medication] the patient went into respiratory failure…with worsening lactic acidosis…Treatment was initiated with 50 mg of riboflavin daily…on hospital day nine. Over the next several days the arterial lactate progressively decreased and the anion gap normalized. Nonetheless, the patient continued to deteriorate developing ARDS with multisystem failure and expirred on hospital day 15…Our patient's response to riboflavin treatment was dramatic with reduction in arterial lactate despite progression of multiorgan failure. Riboflavin administration reversed the progression of lactic acidosis that is consistently reported with NRTI toxicity [Conclusion: Treatment was successful, but the patient died]”

“The authors studied the occurrence of IRV [Immune Recovery Vitritis], defined as symptomatic (vision decrease and/or floaters) vitritis of 1+ or greater severity associated with inactive CMV retinitis. ...19 (63%) of 30 HAART responders [improvements in CD4 cell counts] developed IRV (26 eyes). The clinical spectrum of inflammation included vitritis, papillitis, macular edema, and epiretinal membranes. Eyes with CMV surface area >30% of the retina were at the highest risk (relative risk = 4.5) of developing IRV”

“A decrease in mtDNA [DNA of the mitochondria; the autonomous energy regulating entities within every cell] content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts...Lipodystrophy with peripheral fat wasting following treatment with NRTI[Nucleoside Reverse Transcriptase Inhibitor]-containing HAART is associated with a decrease in subcutaneous adipose [under the skin fat] tissue”

“ANTHONY FAUCI [US Government AIDS researchers]: Well, I think a lot of what we've discussed tonight-- clearly therapies make a difference in a positive way for people who have advanced disease...MARTIN DELANEY [AIDS treatment activist]: Well, and I think the dilemma here is we've got to learn from what has happened here in the last 18 years and try not to repeat it, as we move into--into Africa and Asia and India. I can't overstate...how severe the problems are with the current therapies. Clearly they have helped people in all the ways that we've heard but they've also hurt people. People are dying from the effects of the therapies themselves in some cases...People are suffering from severe life-threatening complications of drugs. And a lot of them get to the point where they simply can't use them anymore. So as we talk about bringing therapy to Africa, even if we can solve the problem and cost and infrastructure and delivery...are we doing the right thing with these drugs? Or are we unleashing another kind of epidemic over there of drug side effects as well?”

“There was...a striking increase in [oral] warts: threefold for patients on antiretroviral therapy and six-fold for those on HAART (p = 0.01). This pattern of oral disease in a referral clinic suggests that an increase in oral warts could be occurring as a complication of HAART.”

“We report two patients with a history of remote sarcoidosis who later in life contracted HIV infection and developed recurrent, progressive pulmonary sarcoidosis [small tumors in the lungs] while receiving highly active antiretroviral therapy (HAART)”

“Stavudine [Zerit, d4T] is a potent drug for the treatment of HIV infection. Handle material as a potent compound with potential adverse effects noted in humans of peripheral neuropathy and liver changes. Possible carcinogen…Physical and health hazards have not been fully evaluated for the finnished product…Ingestion of therapeutic doses of Stavudine may result in symptoms such as peripheral neuritis, elevation of liver enzymes (hepatoxicity), mild nausea and vomiting and allergic reactions…Allergic reactions were reported in less than 5% of patients. Symptoms of peripheral neuropathy (numbness, tingling and pain in the extremities) were the most common adverse effect. Headache, nausea, vomiting, abdominal pain, diarrhea, cough, and difficulty breathing were also reported. Pancreatitis occurred in some patients who were considered to be at higher risk for development of this event. Bone marrow suppression and elevation of liver enzymes were also noted.”

“Adverse events were evaluated using the Division of AIDS Table for grading severity of adult adverse experiences. Adjudication of safety and adverse event data were performed by study investigators blinded to patient treatment assignment, except in cases of medical emergencies…4 deaths were reported during the study [out of 562 patients who received any medications, although only 316 completed the 48-week trial]. In the abacavir-lamivudine-zidovudine group, 1 death was attributed to hypersensitivity reaction that occurred following rechallenge with abacavir approximately 3 weeks after initiating study treatment, and 2 were attributed to cardiac arryhthmia and myocardial infarction occurring 30 to 35 weeks after initial study treatment.”

“Altering a long-held policy, federal health officials are now recommending that treatment for the AIDS virus be delayed as long as possible for people without symptoms because of increased concerns over toxic effects of the therapies. . . . More recently, concern has grown over nerve damage, weakened bones, unusual accumulations of fat in the neck and abdomen, diabetes and a number of other serious side effects of therapy. Many people have developed dangerously high levels of cholesterol and other lipids in the blood, raising concern that H.I.V.-infected people might face another epidemic–of heart disease. . . . Dr Fauci, who is co-chairman of the panel, said in an interview, ‘We are adopting a significantly more conservative recommendation profile’”. (According to the panel), “Much remains to be learned about how best to treat H.I.V.-infected individuals.”

“In two of 15 patients coinfected with HIV and hepatitis C virus who received interferon- plus ribavirin in addition to HAART, we observed multiorgan dysfunction and lactic acidaemia. As ribavirin is a nucleoside analogue, an increased risk of mitochondrial toxicity can be induced in HIV-infected patients already treated with nucleoside analogues, leading to clinical deterioration in some cases.”

“The effect of highly active antiretroviral therapy (HAART) in the treatment of HIV infection is usually measured by survival, CD4 lymphocyte counts, HIV-1 RNA viral load testing, and the occurrence of opportunistic infections. This pilot study sought to measure the impact of HAART treatments on a wide range of clinical outcomes and psychological variables...The only psychosocial measure that improved significantly with treatment was depression. Ratings of pain intensity, physical and psychological symptom distress, and overall quality of life did not change. Of the 70 patients studied, 84% were still alive after the 3-month study period...17 surviving patients (24%) had HAART regimens discontinued due to drug intolerance and 11 (16%) expired [died] during the study period...During the 3-month period [the following illnesses arose - ] wasting syndrome (4), AIDS dementia (1), resistant esophageal candidiasis [fungal throat infection] (1) and acute herpes zoster (1). In addition, there were a number of other infectious medical events that occurred...The causes of death were progressive wasting (5), bacterial pneumonia (3), disseminated Kaposi sarcoma (1), non-Hodgkin lymphoma (1) and end-stage renal disease (1)”

“FDA received reports of 22 cases of serious adverse events related to NVP [Nevirapine/Viramune] taken for PEP [post-exposure prophylaxis] from March 1997 through September 2000. These 22 events included hepatotoxicity (12), skin reaction (14), and rhabdomyolysis (one); four cases involved both hepatotoxicity and skin reaction, and one case involved both rhabdomyolysis and skin reaction.”

“1 patient [out of a grand total of 10 in this 72 week clinical trial of combination therapy with nucleoside analogs (zidovudine-AZT, lamivudine-3TC and didanosine-ddI), Protease Inhibitors (saquinavir and ritonavir) as well as interleukin-2] suffered from severe anemia resulting from ZDV [AZT] therapy and was switched to d4T [another nucleoside analog] at week 20...8 patients had minor gastrointestinal side effects on initiation of HAART. All patients presented with either fatigue low grade fever, or pruritus [itching] at the injection site during IL-2 administration”

“A severe hypersensitivity reaction is a known complication of nevirapine and can present as a fulminant hepatitis or as a systemic syndrome with predominant cutaneous manifestations referred to as hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms. We report a case of a severe systemic reaction with rash in a health care worker shortly after administration of a nevirapine-containing PEP [post-exposure prophylaxis] regimen...In light of the increased reports of severe hypersensitivity reactions to nevirapine, we suggest that this agent not be used for PEP until the incidence and full spectrum of nevirapine toxicity is clear, particularly if the risk of HIV seroconversion following a needlestick (0.3%) is equal to or less than the risk of this life-threatening complication.”

“the severity of the HIV epidemic led to accelerated licensing of many antiretroviral agents, often with very little known about long-term safety...drug-related toxicity is being increasingly recognised because of the declining incidence of HIV-1-associated opportunistic disease...the number of possible HAART combinations is huge. Choosing between many of these combinations is, therefore, increasingly dependent upon knowledge of antiretroviral toxicities...[which includes] myopathy (zidovudine), neuropathy (stavudine, didanosine, zalcitabine; hepatic steatosis and lactic acidaemia (didanosine, stavudine, zidovudine); and possible also peripheral lipoatrophy and pancreatitis (didanosine)...drug hypersensitivity...[which] is about 100 times more common [in HIV infected people] than in the general population...a syndrome (or syndromes) of lipodystrophy...[including] peripheral fat loss (Presumed lipoatrophy in the face, limbs and buttocks) and central fat accumulation (within the abdomen, breasts and over the dorsocervical spine [so-called buffalo hump]...[and prevalent in] about 50% [of patients] after 12-18 months of therapy...Metabolic features significantly associated with lipodystrophy and protease-inhibitor therapy include hypertriglyceridaemia, hypercholesterolaemia, insulin resistance...and type 2 ...diabetes mellitus. Dyslipidaemia at concentrations associated with increased cardiovascular disease occurs in about 70% of patients. These metabolic abnormalities are more profound in those receiving protease inhibitors...Most cases of diabetes have been identified in recipients of protease inhibitors, but a causal relation has not been established...Anemia and granulocytopenia affect about 5-10% of patients who receive zidovudine...Virtually all antiretroviral medications can cause nausea, vomiting, or diarrhoea early in therapy, but these are often transient...Diarrhoea is probably most common with protease inhibitors...Most antiretroviral agents have been associated with hepatic [liver] toxicity...Most protease inhibitors seem to result in increased rates of spontaneous bleeding (bruising, haemarthrosis, and rarely intracranial haemorrhage) in haemophiliacs...Combination therapy for about 4 weeks after high-risk exposure to HIV-1 [e.g. needle-stick injury] is recommended...but 25-35% of patients cannot tolerate [Zidovudine monotherapy] or triple combination therapy for 4 weeks...antiviral potency should not be sacrificed at the expense of tolerability if possible.”

“Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts [normally considered signs of success of therapy]”

“The incidence of MI [Myocardial Infarction (heart attack)] in HIV infected patients increased in our cohort after the introduction of HAART”

“Previously published data on CD4 cell count changes during therapy interruptions have mainly consisted of reports on very small numbers, but there has been a tendency to observe a distinct fall in numbers. The relatively rapid early fall in CD4 cell count after interrupting therapy may correspond to the relatively rapid increase in CD4 cell count after initiating therapy, which has been ascribed to the redistribution of cells from the lymphoid tissue”

“Since the introduction of HAART there has been a dramatic decrease in HIV-related mortality. For example, at the University Hospitals of Cleveland John Carey Special Immunology Unit, the annual observed number of deaths decreased by approximately 80% between 1995 and 1998 [but later in this paper it is revealed that deaths increased from 20 in 1998 to 32 in 1999!]...There is reason to be concerned that the spectrum of morbidity and mortality in HIV disease is changing rapidly to include metabolic complications of therapies and infectious complications, such as hepatitis C. Of recent HIV-related deaths occurring in the John Carey Special Immunology Unit of University Hospitals of Cleveland (number of deaths ranging from 20 in 1998 to 32 in 1999), although OIs [Opportunistic Infections] constituted less than 25% of deaths in 1999, end-organ failures [which could well be caused by medication] constituted nearly half. Importantly, the median CD4 cell count among the patients who died in our clinic has risen, from 0/L in 1995 to 75 million/L in 1999, and about 20% of recent deaths have occurred among patients with plasma HIV RNA levels below the limit of detection.”

“We report 2 cases of neutrophil-rich ALCL [Anaplastic Large Cell Lymphoma] of T-cell lineage involving the scalp of HIV-positive men. Despite chemotherapy, both patients died within 6 months of infectious complications...Both patients were being treated with antiretroviral therapy (stavudine and lamivudine) [prior to admittance for cancer]”

“I just had a dental checkup yesterday. Damn depressing.... The dentist told me all my teeth's enamel had been eaten up by the drugs; that I had so many cavities he was wondering how I could manage to eat and sleep; and that it was beyond his capacity to do anything. When I got out I was crying like a baby. We looked at the x-rays. I got cavities directly in the bones. He's flabbergasted by the unexpected side effects. Has anyone heard of this shit with crix [Crixivan, a protease inhibitor], 3TC [a nucleoside analog] and d4t [a second nucleoside analog] combo?”

“NRTIs [Nucleoside Reverse Transcriptase Inhibitors] do inhibit mitochondrial DNA synthesis but many also interfere with mitochondrial RNA formation. Although base excision repair operates in mitochondrial DNA, no repair mechanisms have been established for mitochondrial RNA. [Note that mitochondria are the energy producers present in all living human cells]”

“Adverse effects attributable to antiretroviral therapy were commonly documented.”

“One of the major barriers to effectively treating HIV is that most people do not feel sick at the time that they are offered anti-HIV medications. In fact, it is only after starting the medications that they begin to feel sick...Side effects, onset of new diseases caused by the treatment for HIV and the immense pill burden are new problems that many individuals with HIV must adapt to. The lives of many patients have become governed by their drug ‘cocktails’, which for some patients involves as many as 40 pills a day.”

“HAART use had an independent effect on REE [Resting Energy Expenditure]...Compared with the subjects who were not on HAART, the adjusted REE was 339 kJ/day higher in the patients receiving HAART.”

“The incidence of diarrhea was 14.2 per 100 person-years (95% confidence interval, 13.0-15.4). Among patients with CD4 cell counts below 0.05 x 10**9/L, the probability to develop diarrhea within 1, 2, and 3 years was 48.5%, 74.3%, and 95.6%, respectively. The risk to develop diarrhea was increased among patients with severe immunodeficiency, homosexual men, and patients taking antiretroviral therapy...Diarrhea was an independent negative predictor of survival.”

“...we examined 304 anti-retroviral-experienced patients who were placed on HAART for a period of 18 months. The baseline CD4 count was 385x10(6)/1 and HIV RNA level was 3.2 log[10] copies/ml. At baseline, 39% were classified as asymptomatic, 33% were symptomatic, and 28% had an AIDS defining illness. The HAART regimens included 3-5 anti-retroviral agents at least one of which was a protease inhibitor...After 18 months, 14% of the population remained asymptomatic, 10% of which had an undetectable viral load. 39% were symptomatic and 47% of the population had an AIDS defining illness. The average CD4 count after 18 months on HAART was 301.79x10(6)/1 and HIV RNA level of 3.2 log[10] copies/ml. [i.e. HAART did not prevent progression, reduced CD4 counts and did not affect HIV RNA levels]”

“Recently, we observed an unusual cluster of cases of rapidly progressing multicentric Castleman's disease. Fever, weakness, generalized enlargement of lymph nodes, and marked polyclonal gammopathy developed in three patients with AIDS...Two of these patients died within one week after the diagnosis, with generalized involvement of the lymphatic system, liver, and bone marrow at autopsy. A fourth patient with AIDS who died equally rapidly after the diagnosis of multicentric Castleman's disease had been seen in our hospital 14 months earlier... symptoms of multicentric Castleman’s disease started after the initiation of highly active antiretroviral therapy in these three patients.”

“This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to HAART. We followed 30 HAART-responders with CD4 cell counts of >=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients”

“among health care workers who receive postexposure treatment with zidovudine[AZT], at least one third discontinue therapy because of drug intolerance. Unfortunately, data on long-term toxicity of zidovudine and on the safety of combination antiretroviral treatment in uninfected adults are not yet available.”

“We report on the occurrence of autoimmune hyperthyroidism in three patients with AIDS after 16-22 months of taking highly active antiretroviral therapy (HAART). A woman aged 41 years with AIDS presented with progressive weight loss, asthenia [loss of strength], tachycardia [abnormally rapid heartbeat], tremor and swollen eyelids. She had been taking indinavir, stavudine and lamivudine for 19 months...A male aged 42 years with AIDS presented with progressive weight loss, tremor,, and tachycardia....The patient had been on indinavir, stavudine, and lamivudine for 16 months...A man aged 36 years with AIDS was started on ritonavir, stavudine and lamivudine in April, 1996. In February, 1998, he presented with progressive weight loss, tremor, and hypertension...Although the number is small and the onset of hyperthyroidism could be coincidental to AIDS, autoimmunity probably relates to incomplete or unbalanced immune restoration under HAART [or direct toxic effects of these medications?]”

“We selected treatments for HIV-1 infection, where drug toxicity is common and drugs are mostly new, and so safety should be a priority…most trials (81.7%) reported how many discontinued study treatment, reasons were only given in 38.3%. The severity of adverse events and abnormal laboratory tests was adequately defined only in 33.3% and 61.7% of reports, and partially defined in a further 20%…Randomised comparative trials offer the best opportunity for obtaining controlled data for medical decisions involving risk-benefit considerations. Without rigorous reporting including - at a minimum - functional definition of severity and estimates of the frequency of the main severe adverse events and reasons for treatment discontinuation, medical decisions are left to personal experience and pharmaceutical advertisement.”

“Apart from the inheritable route, mtDNA [mitochondrial DNA] defects can also be acquired exogeneously by toxic agents such as alcohol, tobacco and drugs. In the latter group, drugs that have been shown to induce mitochondrial toxicity are nucleoside analogues used in chemotherapy and antiretroviral therapy, such as HIV RTI [reverse transcriptase inhibitors]…Since these nucleoside analogues elicit complete mtDNA replication deficits, clinical features can be regarded as a compilation of those seen in the genetic mitochondriocytopathies. These features include myopathy [muscle wasting], cardiomyopathy [heart muscle damage], neuropathy [nerve damage], lactic acidosis [lactic acid build-up in the blood], exocrine pancreas failure, liver failure and bone-marrow failure…A 5-year follow-up study with ddI among 72 patients exposed pancreatitis and peripheral neuropathy as the most important clinical toxicities of this agent…Development of peripheral neuropathy or pancreatitis has also been seen in ddC and D4T therapy…Fatal outcome due to this hepatic steatosis [fat deposits in the liver] with severe lactic acidosis has been reported for several NRTI (ZDV [AZT], ddI and D4T) after several months of treatment…Bone-marrow toxicity has been demonstrated for ZDV, but ddC, ddI and D4T also show in vitro toxicity to haematopoietic progenitor cells [blood creation cells]…Herskowitz et al. reported six patients with cardiomyopathy out of 13 who received RTI therapy with ZDV, ddC or ddI”

“The use of antiretrovirals and PCP prophylaxis before AIDS were associated with a significantly poorer survival after AIDS [median of 16 months before death with antiretrovirals, 25 months without; 14 months in those using PCP prophylaxis before diagnosis, 23 months in those not using PCP prophylaxis before diagnosis].”

“Of 5,574 SCKP members identified with HIV infection, 429 (7.7%) were diagnosed with a malignancy between 1991 and 1995, of which 57 (13.3%) were non AIDS defining (NAD). Although cohort member census declined slightly in successive study years, the number of NAD malignancies diagnosed tended to increase over time, with six, eight, 13, 15, and 15 such neoplasms occurring in 1991-1995, respectively. The most frequent NAD cancers included anorectal (14); Hodgkin's disease (9); lung/intrathoracic cancer (9); and melanoma (8). Less frequently seen malignancies included leukemias (2); testicular seminoma (2); prostate cancer (2); urinary tract cancer (ureters) (1); vaginal cancer (1); multiple myeloma (1); and "other and unspecified" malignancies (3). [the possibility that non-AIDS cancers are caused by the therapy was apparently not considered by the authors]”

“The overall rate of adverse events was 37A%, 32%, and 60%, respectively, for the nucleoside, 1-mIU interforn, and 6-mIU interferon combination groups. 26 patients (43%) had a serious treatment-related toxicity”

“The study treatments were generally well tolerated for up to 52 weeks. 1 patient withdrew from the study because of an adverse event (nausea). Elevated bilirubin levels and clinical nephrolithiasis…occurred more often in the patients receiving indinavir. There were no other significant differences among the groups [taking different combinations of drugs, but without a true placebo] in the occurrence of severe, drug-related clinical events or clinically important laboratory abnormalities [So, that’s what ‘generally well tolerated’ means!]”

“The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection. [apparently the possibility that drug treatments could be causing this was not considered.]”

“Overall rates [of adverse drug reactions] ranged from 16.2 to 37.0 events for 100 person-years of follow-up on [Zidovudine, Didanosine, Zalcitabine, Cotrimoxazole, Dapsone]. For all of these drugs except dapsone, there was an increasing risk of adverse events as the CD4+ count declines.”

“The precise duration of HIV suppression [low viral load] necessary to result in measurable clinical benefit still needs to be clearly defined [and there is no guarantee that people taking these drugs can withstand the toxic side effects long enough for the clinical benefits to materialize]”

“41 patients were enrolled into the study [with 5 different treatment arms and with about half of the patients having previously taken AZT]…5 patients had 7 reported episodes of severe adverse events during the study period, including 1 episode each of grade 3 nausea, fever, abnormal liver function tests, and 4 episodes of neutropenia [deficiency in neutrophil blood cells] in 2 patients. Only the episodes of neutropenia were attributed by the investigators to study medications…During the maintenance phase after completion of the study, 2 additional patients showed signs of severe hematologic toxicity, and one patient had severe myopathy. These toxicities were attributed to ZDV [AZT]. Other adverse events reported frequently during the study period included fatigue (39.0%), fever (22.0%), headache (46.3%), anorexia (24.4%), stomatitis [mouth inflammation] (22.0%), diarrhea (26.8%), oral leukoplakia [thickened white patches in mouth], nausea (31.7%), oral candidiasis (22.0%), anemia (12.2%), myalgias [muscle pain] (12.2%), parasthesias [hallucinations] (14.6%), decreased reflexes (12.2%), cough (34.1%), pharyngitis (24.4%), sinusitits (24.4%), acne (12.2%), rash (26.8%), pruritus [itching] (19.5%), and dysgeusia (12.2%)…Concurrent administration of rCD4-IgG and ZDV was well tolerated in this study[!]. No unusual toxicities were observed with the combination.”

“An undesirable effect associated with the chronic use of [nucleoside analog] drugs is toxicity to normal tissues or cells limiting the dosage or length of time with which the therapeutic [drug] can be used”

“Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir [a nucleoside analog] was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir-treated patients.”

“[Black box warning] LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS…Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of VIREAD…decreases in bone mineral density (BMD) were seen at the lumbar spine and hip…Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed…Immune reconstitution syndrome has been reported…the long term effects of TRUVADA are unknown…Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ³3% in Any Treatment Group in Study 934 (0–48 Weeks) [include] Diarrhea (7%), Nausea (8%), Fatigue (7%), Sinusitis (4%), URI (3%), Nasopharyngitis (3%), Sleepiness (3%), Headache (5%), Dizziness (8%), Depression (4%), Insomnia (4%), Abnormal dreams (4%), rash (5%)…Significant Laboratory Abnormalities Reported in ³1% of Patients in Any Treatment Group in Study 934…Any ³Grade 3 [serious] Laboratory Abnormality (25%), Fasting Cholesterol (15%), Creatine Kinase (7%), Serum Amylase (7%) [etc.]…other adverse events that occurred in at least 5% of patients receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia [joint pain], increased cough, dyspepsia [upset digestion], fever, myalgia [muscle pain], pain, abdominal pain, back pain, paresthesia [hallucination of any sense], peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis [inflamed nose] and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).”

“The most common side effects attributed to abacavir [a nucleoside analog] are gastrointestinal signs and symptoms (loss of appetite, nausea, vomiting, and diarrhoea), headache, malaise, and asthenia. These untoward events usually appear in the first few weeks of therapy, tend to resolve spontaneously, and are usually mild-to-moderate in severity [which could be because the body adapts to the drug or because patients lose patience and stop taking it]…The most serious adverse event caused by abacavir is the hypersensitivity reaction, a severe allergic reaction that has been estimated to occur in around 8% of persons who begin abacavir therapy, usually within the first 6 weeks of treatment. Its multiform clinical manifestations include fever, rash, gastrointestinal, or respiratory symptoms, and may lead to life-threatening hypotension, renal failure and death, especially in the event of rechallenge with abacavir after a prior episode of hypersensitivity…In our patient, a potentially life-threatening neutropenia occurred 4 weeks after the start of abacavir therapy and was associated with fever, skin rash, and anaemia. The neutrophil count started to increase and themajority of clinical signs and symptoms resolved within 3–4 days after stopping abacavir, whereas absolute neutrophil count and haemoglobin level became normal after 10 days. Consistent clinical manifestations, a positive HLA-B 5701 testing, and the rapid recovery of our patient suggest that these adverse events may be immune mediated, probably due to the secretion of drug-related antibodies.”

“We describe a 62-year-old male who was diagnosed with HIV-1 in 2001 and died with lactic acidosis under treatment with didanosine [ddI/Videx] and stavudine [d4T/Zerit]…Lactic acidosis is a life-threatening complication of HAART. The onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. The outcome can be fatal due to liver failure and cardiac arrhythmia. Didanosine and stavudine are strong inhibitors of polymerase-gamma, which are known to induce mtDNA [mitochondrial DNA] depletion in subcutaneous adipose tissue and in liver”

“Abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor, can cause hypersensitivity reactions in 3–5% of patients started on the drug, and 90% of cases occur within the first 6 weeks after initiation (median time 11 days). The most common symptoms of abacavir hypersensitivity are fever, rash, and gastrointestinal symptoms. Respiratory symptoms such as dyspnea, cough, and pharyngitis are prominent in 30% of cases and mimic pneumonia…From our observation [on a patient], abacavir can cause acute lung injury clinically presenting as ARDS [acute respiratory distress syndrome], presumed to be a hypersensitivity reaction and pathologically showing AFOP [acute fibrinous and organizing pneumonia]. The early recognition and discontinuation of the drug is the only established treatment. None of the patients with fulminant AFOP recovered in the previous studies, but AFOP secondary to abacavir hypersensitivity was reversible in our patient. This highlights the characteristic of abacavir hypersensitivity: fulminant exacerbation with continuation of the drug and rapid recovery after discontinuation of the drug.”

“Nucleoside analogues remain an important backbone of antiretroviral therapy.”

“Adults: Selected clinical adverse events with a ³5% frequency during therapy with Epivir [lamivudine/3TC) 150 mg twice daily plus Retrovir [Zidovudine/AZT] 200 mg 3 times daily compared with zidovudine [Retrovir/AZT] are…Headache [35%], Malaise & fatigue [27%], Fever of chills [10%], Nausea [33%], Diarrhea [18%], Nausea & vomiting [13%], anorexia and/or decreased appetite [10%], abdominal pain [9%], abdominal cramps [6%], dyspepsia [5%], neuropathy [abnormal sensations such as burning or numbness in the skin – 12%], insomnia & other sleep disorders [11%], dizziness [10%], depressive disorders [9%], nasal signs & symptoms [20%], cough [18%], skin rashes [9%], musculoskeletal pain [12%], myalgia [muscle pain; 8%], arthralgia [joint pain – 5%]…”]

“WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).”

“LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS). [Atripla is a combination of two nucleoside analogs and one protease inhibitor]”

“WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).”

“In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue–induced toxicity affected neurologic development.”

“this rare but often life-threatening syndrome, now named ‘severe nucleoside-associated lactic acidosis’ (NALA) has been reported increasingly often. Hepatic steatosis [loss of fat in liver] and lactic acidosis are thought to be caused by nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial toxicity…Low levels of hyperlactatemia have been reported in 21% of NRTI-treated patients, although the majority of these patients are asymptomatic…From 1997 through 2000, we identified 12 HIV-infected patients treated with NRTIs who developed unexplained metabolic acidosis…A total of 5400 patients treated with NRTIs were observed in these [Spanish] hospitals during the study period. In all cases, known causes of lactici acidosis other than antiretroviral therapy were ruled out…Cases of NALA have been reported as soon as 1 month and as late as 20 months after the start of antiretroviral treatment…NALA can develop at any stage of HIV disease…The mortality rate among patients with lactic acidosis is very high: 33% for our series of patients and 57% for the patients described in the literature.”

“Bristol Myers Squibb (BMS) has chosen to inform doctors of rapidly ascending muscular weakness as new symptom of nucleoside-related lactic acidosis and hyperlactataemia...A review by the EMEA of nucleoside analogue-related LA [lactic acidosis] and HL [hyperlactataemia] has highlighted seven cases of rapidly ascending muscular weakness, similar to that symptoms seen with Guillain-Barré Syndrome, and a further seven cases of muscular weakness or pain which preceded the development of LA and HL...Early symptoms of LA and HL include nausea, vomiting, diarrhoea, rapid and deep breathing, stomach cramp, myalgia [muscle pain] and paresthesia [numbness]. Ascending neuromuscular weakness should now be added to this list. Severe complications which currently include pancreatitis [pancreas failure] and liver failure should now be broadened to include motor paralysis...All nucleoside analogues have been associated with symptoms of LA and HA...Severe lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, renal failure, or motor paralysis.”

“FDA and Bristol Myers Squibb are warning health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine (Zerit) and didanosine (Videx or Videx EC) with other antiretroviral agents.

Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of Videx and Zerit.

This new warning follows three reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking Zerit and Videx in combination with other drugs used to treat HIV.”

“Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia [elevated lactic acid levels that can result in fatal lactic acidosis] during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia [abnormally rapid heart beat], abdominal pain, weight loss, peripheral neuropathy [surface nerve damage], and more specifically exercise-induced dyspnoea [shortness of breath] occurring despite effective antiretroviral treatment [note: effectiveness is defined by elevated CD4 cell counts/reduced viral load not improved health]. FRT [functional respiratory tests] showed a metabolic deviation towards anaerobiosis with a high lactate/ pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction...One patient developed severe lactic acidosis...and died. Another was lost to follow-up. Among the remaining 12 patients, nucleoside analogue therapy was stopped in 10, as clinical improvement was combined with a decrease in lactate levels...The improvements observed in the next few weeks after drug withdrawal or modification suggest that antiretroviral drugs are responsible for the occurrence of symptomatic hyperlactataemia. Furthermore, symptomatic hyperlactataemia has never been diagnosed in naive untreated HIV-infected subjects followed up in our unit...Stavudine [d4T/Zerit] was strikingly involved in treating all these hyperlactataemic patients.”

“Glaxo Wellcome on Sunday played down renewed fears about its Ziagen [Abacavir, a nucleoside analog] HIV treatment and said it planned to proceed with this year's European launch of Trizivir, its new Aids drug, which contains Ziagen...Glaxo...yesterday confirmed patients had died as a result of "hypersensitive" reactions since Ziagen was launched in the US and Europe last year. There are as yet no reliable figures on the number of fatalities from the treatment but Glaxo admitted that about 4 per cent of patients had displayed symptoms such as fever and vomiting. It put the negative response to the drug at about two people in every 10,000 patients, which is 10 times higher than the figures for other drugs generally. The company said: "This is a very potent drug and clinical trials have indeed shown that it has a potential for side effects and patients have died from using it."”

“An uncommon but life-threatening syndrome of severe hepatic steatosis and lactic acidosis among patients infected with HIV-1 was first described in the early 1990s. By early 1994, at least 40 such cases had been reported to regulatory authorities, and an association with use of zidovudine and didanosine was established. An underlying mechanism involving impaired replication of mitochondrial DNA was proposed. Although stavudine (Zerit, Bristol-Myers Squibb, Princeton, New Jersey) is the second most widely prescribed antiretroviral nucleoside analogue, it has rarely been associated with the syndrome of severe hepatic steatosis and lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine.”

“8 subjects (10%) discontinued the study prematurely because of adverse events, all of which were considered by the investigator to be attributable to abacavir. None of these subjects were on 300 mg twice daily. Four subjects were withdrawn because of nausea, two receiving abacavir–ZDV therapy [200 mg three times daily (cohort I) and 400 mg three times daily (cohort II)] and two receiving abacavir alone [400 mg three times daily (cohort II) and 600 mg three times daily (cohort IV)]. One subject was withdrawn due to dizziness, photophobia, and palpitations (cohort IV). Three subjects, one on abacavir–ZDV (cohort I) and two on abacavir alone (cohort IV), were withdrawn within 4 weeks of dosing because of hypersensitivity reaction (erythematous generalized rash, low-grade fever, malaise and nausea). After a temporary interruption of study drugs due to hypersensitivity, subjects were rechallenged at least once. Rechallenge with abacavir resulted in rapid onset of hypersensitivity. There were no deaths among the study subjects. Four additional subjects experienced a serious adverse event but remained in the study through week 12. Amongst abacavir–ZDV subjects, one experienced headache (cohort I) and another reported depression [300 mg twice daily (cohort III)]. Amongst abacavir monotherapy subjects, one experienced leukopenia (cohort II) and another had a syncopal episode (cohort III). Five subjects (6%) experienced grade 3 or 4 laboratory abnormalities. Three cases of hematological abnormalities were reported: amongst subjects receiving ZDV monotherapy, one had leukopenia (grade 3, but grade 4 at one evaluation) and another had decreased hemoglobin count (grade 4); one subject receiving abacavir–ZDV therapy had decreased platelet count (grade 3). Two cases of clinical chemistry abnormalities were reported: one subject receiving ZDV monotherapy had elevated alanine aminotransferase levels (grade 3), and one subject receiving abacavir–ZDV therapy had hypoglycemia (grade 3).”

“The antiretroviral drugs currently licensed in the United Kingdom [June 1996] are zidovudine (azidothymidine [AZT]), zalcitabine (ddC) and didanosine (ddI). All three are nucleoside analogues...All are very toxic. Suppression of bone marrow elements can occur with any of the three, as can peripheral neuropathy [nerve damage].”

“The median times to a first modification of the dose, including a reduction in or discontinuation of the study drug, were 33, 39 and 27 weeks for subjects assigned to receive 750 mg of didanosine [a cousin of AZT, and the second AIDS drug ever approved], 500 mg of didanosine, and zidovudine, respectively. Severe anemia was uncommon in all groups and was less common in the group receiving 750 mg of didanosine than in the zidovudine group. Recipients of the 750-mg didanosine dose had less severe leukiopenia and granulocytopenia than recipients of zidovudine. Treatment with the 500-mg dose of didanosine was associated with less severe granulocytopenia than treatment with zidovudine. The rate of pancreatitis was higher in the 750-mg didanosine group than in either the zidovudine group or the 500-mg didanosine gropu. The number of casees of pancreatitis [pancreas failure] was higher in the 500-mg didanosine group than in the zidovudine group, but the difference was not statistically significant. Fatal pancreatitis developed in two subjects receiving 750 mg of didanosine. The 750-mg and 500-mg didanosine groups both had greater increases in unfractionated serum amylase concentrations than the zidovudine recipients. The rate at which peripheral neuropathy of grade 2 or worse developed did not differ significantly between the three treatment regimens.”

“D4T [Stavudine] is a structural analogue of the naturally occurring nucleoside thymidine [one of the four building blocks of DNA]…The dose-limiting toxicity in humans is peripheral neuropathy [damage to surface nerves resulting in numbness, pain and other abnormal sensations], which was not predicted by animal toxicology”

“Rifampicin is an important drug in the treatment of tuberculosis (TB) but has strong liver enzyme inducing capacity, resulting in drug–drug interactions with antiretroviral therapy…Adult HIV-infected patients treated concomitantly with [AIDS drugs] lopinavir/ritonavir and rifampicin were selected from the Dutch ATHENA cohort…Acute, premature termination of lopinavir/ritonavir and rifampicin was defined as stopping concomitant treatment within 4 weeks from the start…A total duration of combined use of rifampicin and lopinavir was less than 4 weeks in 12 patients, between 4 weeks and 4 months in 11 patients, and 4 months or longer in the remaining 11 patients…Overall, seven of 34 (21%) patients prematurely stopped the combination within 4 weeks because of acute adverse event…Concomitant use of lopinavir/ritonavir and rifampicin remains challenging.”

“Kaweesi has totally suspended bonking for the foreseeable future after suffering from a severe erectile dysfunction due to his body reacting badly to septrin [aka septra, bactrim] which was prescribed after dental surgery [for HIV-positive people it is often prescribed because of claims it can prevent PCP pneumonia]…Kaweesi, who has also suffered blisters and seen his skin peeling off [something like Stevens-Johnson Syndrome or Toxic Epidermal Necrosis (TEN)]”

“Several drugs in common use have well characterized HSRs [hyper-sensitivity reactions], as typified by ß-lactam antibiotics – the most frequent cause of cutaneous drug reactions. Reactions mostly affect the skin [typically exanthema, nonimmediate urticaria, Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis or acute generalized exanthematous pustulosis (AGEP)], but can manifest as DHS [drug hypersensitivity syndrome, with symptoms like fever, malaise and “internal organ involvement of varying severity”], most commonly involving the liver, lungs and/or kidneys. Serious systemic HSRs are also associated with anticonvulsants, sulfonamide antimicrobials [often given to HIV-positive people], dapsone [ditto] and allopurinol. Rechallenge after an initial reaction can cause a more intense and immediate reaction. Controlled rechallenge (drug provocation testing), either with the culprit drug or a pharmacologically related agent, is therefore contraindicated following most DHS, with the risk of a more severe reaction weighing heavily against any therapeutic benefit.”

“A 19-year-old man was diagnosed with HIV 3 months earlier, with a self-reported history of purple skin lesions that appeared 2 years before and spontaneously remitted. At diagnosis he had extensive nodal and mucocutaneos KS [Kaposi’s Sarcoma], with a CD4 cell count of 182 cells/ml (13%) and a viral load of 21 000 copies/ml. He started antiretroviral therapy with lamivudine, stavudine, indinavir and ritonavir…He experienced an initial flattening of the KS lesions after 52 days, and was hospitalized with fever, vomiting and diarrhoea. Based on the time between the initiation of HAARTand an increase in CD4 cell numbers at the onset of the symptoms (an increase of CD4 cell count from 182 to 322 cells/ml in 18 days, last viral load 1840 copies/ml), IRIS was diagnosed by his original attending physician, who prescribed prednisone 20 mg twice a day and the patient was discharged. After 2 weeks of prednisone, he experienced an explosive growth of mucocutaneous [internal skin] lesions, facial oedema [swelling] and haemorrhagic [bleeding] lesions in both eyes. He reported that he perceived the oral lesions growing in a matter of hours, and was referred to our institution. An emergency tracheotomy was performed, steroids were withdrawn and a first cycle of 2mg vincristine and 15 mg bleomycin was administered. He developed Streptococcus pneumoniae purulent otitis media and thrombocytopenia. He was discharged with a silver cannulae, oral amoxycillin and unchanged HAART. Three weeks later he was hospitalized with epistaxis and profuse bleeding of the exophytic lesion in the oral cavity. Antiretroviral therapy was stopped, platelet aphaeresis was transfused and 5 days later a second course of bleomycin and vincristine was administered. He was discharged with a marked remission of all KS lesions as well as of the lymphoedema. He resumed HAART 2 weeks later…In the present case, a life-threatening exacerbation of KS shortly after steroids were used to treat IRIS was seen. In other corticoid-related KS manifestations in the literature, the onset was not explosive nor life threatening, and all remitted by simply removing steroids. The potential additive effects of IRIS with steroid use in KS, contraindicates its use as an anti-inflammatory therapy”

“A four-year-old male child presented with a history of anorexia and fatigue for the last several weeks duration. His past medical history was remarkable for an ear infection at six months of age. He was then prescribed TMP-SMX for the treatment of the ear infection. The family noticed that the infant liked the taste of the liquid form of TMP-SMX. The parents continued to purchase the drug for the infant almost in lieu of daily fruit juice replacement. Thus his daily intake of TMP-SMX ranged between 6 to 12 mg/kg per day for TMP and 30 to 60 mg/kg per day for SMX since he was 6 months old…The diagnosis of pre B cell acute lymphoblastic leukemia (ALL) was confirmed…TMP impairs the function of the dihydrofolate reductase enzyme and inhibits the synthesis of folic acid. Folic acid deficiency particularly affects those hematopoietic cells with a rapid turnover. The chronic decreased levels of serum folic acid due to long-term exposure to TMP may cause megaloblastic anemia and thrombocytopenia.”

“The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations.”

“Cytomegalovirus (CMV) retinitis is one of the most devastating complications of the acquired immunodeficiency syndrome (AIDS) and the most common ocular opportunistic infection among patients with AIDS. It is a necrotizing, blinding form of retinitis…In the multivariate model, only steroid use was a statistically significant predictor of CMV retinitis”

“The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either…statins…or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate…35 patients who had received ritonavir/saquinavir-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups…T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in [the other three] groups, when measured after 6, 12, and 18 months of treatment.”

“PCP [Pneumocystis carinii pneumonia] accounted for 39 of 116 (33%) AIDS-defining illnesses. Kaplan–Meier survival curves did not demonstrate a statistically significant difference in the rate of disease progression for children who began PCP prophylaxis within 6 months of birth compared with those untreated [i.e. PCP treatment was of no value]”

“A total of 167 adverse events were recorded in 99 (54%) of the 183 patients for whom data on therapy [either for TB alone, or for TB and AIDS] were available. Adverse events led to cessation or interruption of either their TB or HIV therapy in 63 [34%]. The most common side effects noted were peripheral neuropathy [21%; damage to peripheral nerves], rash [17%], gastrointestinal [10%; e.g. nausea, vomiting, abdominal pain, diarrhea], hepatitis [6%; liver disease] and neurological events [7%; e.g. seizures, memory loss, optical nerve damage, paranoid psychosis]...Other adverse events [include] Arthralgia [joint pain]...Drug hypersensitivity excluding rash...Hyperuricaemia/gout...Pancreatits [inflammation of the pancreas]...anaemia...pigmentation...neutropenia...retro-orbital pain...and cholestasis”

“In addition to previous clinical and laboratory publications this work by Kwak and colleagues has provided a firm scientific rationale to support the use of statins as adjunct immunosuppressive agents in organ transplantation. [Statins are often used to counteract the increase of lipids induced by HAART, but consequently increase immune suppression in people who are already immune-suppressed]”

“myelosuppression [deficiency of white blood cell production] and neutropenia [deficiency of one type of white blood cells responsible for clearing bacteria and cellular debris] may result from any one of several medications commonly used in HIV-infected patients [including nucleoside analogs AZT, 3TC, ddI, ddC and d4T as well as anti-PCP therapies Trimethoprim, Pyrimethamine and Pentamidine]”

“In January 1998 a 26 year old man who was HIV positive started taking stavudine..., didanosine..., and nevirapine...because of a falling CD4 count (250x10^6/l), high viral load (81,747 copies/ml), and symptoms related to HIV. He was receiving no other treatment. He had no additional risk factors for pancreatitis. Response to treatment was good: the viral load decreased to undetectable levels, the CD4 count increased to 470x10^6/l, and the symptoms improved, enabling the patient to resume full time employment. In June 1999 the viral load increased to 1390 copies/ml despite the patient's adherence to treatment, so treatment was intensified with hydroxyurea 500 mg twice daily (Hydrea, Bristol-Myers Squibb). The viral load decreased to 237 copies/ml. The patient began to experience malaise and pain in the upper abdomen. This was attributed to the hydroxyurea, which was stopped after 42 days. The symptoms worsened, and three weeks later he was admitted to hospital with severe pain, vomiting, fever, tenderness of the upper abdomen, and guarding...Computed tomography showed changes consistent with pancreatitis. All drugs were stopped. The patient made an uneventful recovery with conservative treatment. He is no longer taking antiretroviral drugs”

“We report a case of sarcoidosis beginning after 2 months of interleukin-2 (IL-2) therapy in a patient with HIV who had undetectable plasmatic viral load under HAART and we discuss possible mechanisms...IL-2 [Interleukin-2] plays a pivotal role in the pathology of sarcoidosis [formation of nodules in the lungs, liver, lymph nodes and salivary glands].”

“RhuIL-10 [Recombinant Inter-Leukin 10] was generally well tolerated. [Out of 39 HIV-positive subjects] 2…required discontinuation due to thrombocytopenia [deficiency of platelets]. 1 patient…who had chronic hepatitis B and C infections discontinued drug because of elevated liver function tests…Fatigue, headache, nausea and dizziness occurred moer frequently in subjects receiving rhuIL-10 than…placebo (8/29 vs. 1/10, 8/29 vs. 2/10, 6/29 vs. 1/10 and 4/29 vs. 0/10 for each adverse event, respectively).”

“the potential benefit gained from an increase in the number of CD4 cells needs to be balanced against the toxic effects of the treatment. In the study by Davey et al, 54% of the patients receiving IL-2 [Interleukin-2] with HAART had serious adverse effects compared with 16% of patients receiving HAART alone. Studies demonstrating a clinical benefit from IL-2 therapy are needed before it is adopted as a complementary option in conjunction with antiretroviral therapy.”

“IL-2 [Interleukin-2] recipients experienced more adverse events than recipients of ART [standard antiretroviral therapy, not including IL-2] alone. The most common toxic effects experienced by IL-2-treated patients were constitutional symptoms of fever, fatigue, and myalgias of varying severity. Per protocol-defined guidelines, mild-to-moderate symptoms were managed by scheduled administration of alternating acetaminophen and ibuprofen, oral hydration, oral narcotics to control rigors, and rest. More serious or sustained symptoms were managed by omitting a scheduled dose, dosage reduction, or both, as required. Despite these measures, serious (at least grade 3) adverse events occurred in 20 (54%) of 37 evaluable IL-2 recipients and 7 (16%) of 43 ART recipients.”

“A higher proportion of those on combination therapies with and without PIs [Protease Inhibitors] reported taking vitamin and mineral supplements in the past 3 months compared with those in the monotherapy (41%), no treatment (31%) and HIV-negative (30%) groups. A significantly lower proportion of those on PIs reported injecting drugs (20% versus 50%) and drinking any alcohol (47% versus 64%) than the other groups combined [meaning that better health in people taking PIs could be, at least in part, due to factors other than the drugs]”

“Among severely ill patients, mortality was 3-fold higher when corticosteroids were given according to CDC guidelines. Our findings suggest that that the utility of adjunctive corticosteroids in severe PCP needs to be revisited.”

“We present a case of paradoxical clinical deterioration during antituberculosis therapy in an HIV-infected adult with pulmonary TB. The clinical course was characterized by marked cervical and mediastinal adenopathy accompanied by fever and weight loss during simultaneous treatment of TB and HIV disease”

“We recently treated a patient with intractable ulcerative colitis complicated with Pneumocystis carinii pneumonia in whom sulfamethoxazole/trimethoprim caused pneumonitis. The pneumonitis was difficult to differentiate from worsening of the infection or the appearance of another opportunistic infection.”

“The present study reveals a relationship between the occurrence of adverse reactions to TMP-SMZ [strong antibiotics often given to HIV-positive people to prevent pneumocystis carinii pneumonia] and the course of HIV infection. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS and death and with a more rapid decline in CD4+ cell counts...A low CD4+ cell count, repeated CD4+ cell counts below 200/mm3, T cell reactivity at baseline, and...the use of antiretroviral agents before the start of prophylaxis were also statistically associated with a more rapid progression to AIDS and death”

“the use of systemic corticosteroids in immunocompromised patients is generally to be avoided. Patient 3…did not demonstrate any contraindications to corticosteriod therapy. Unfortunately, it appears his disease was exacerbated [resulting in retinal detachment and complete blindness in both eyes] by the corticosteroid use”

“Glucocorticoids caused immunosuppression, provide selective growth advantage to various microorganisms including the fungi, and enhance replication or reactivation of latent viruses (e.g. EBV, CMV, Kaposi's sarcoma-associated herpes viruses)…A very strong linear correlation exists between saliva cortisol level and concentration of free cortisol in blood…High circulating levels of glucocorticoids suppress immune and inflammatory responses…Our study population consisted of 23 HIV-positive subjects (18 males and 5 females, ages 24-48 yr) and 14 HIV-seronegative controls matched for age, ethnicity and gender…12 of these HIV-infected subjects were asymptomatic…2…had pseudomembranous candidiasis…two had severe HIV-related periodontitis, and one patient had histologically confirmed oral Kaposi's sarcoma (KS). All the HIV-positive patients were from the intravenous drug use risk group…Kaposi's sarcoma (KS), a tumor which has become epidemic in HIV-infected patients, often presents with oral lesions. Corticosteroid therapy has been linked with increased risk of KS in both HIV-infected and non-infected patients…Another frequent HIV/AIDS-associated oral lesion is necrotizing ulcerative gingivitis (NUG). Prior to the AIDS era, NUG in the developed world was primarily a disease of young adults subjected to the stress of military life and/or college examinations. Such individuals usually have high salivary cortisol levels. In the developing world, it was exclusively a disease of malnourished children who generally had high blood levels of cortisol. We therefore conclude that increased levels of corticosteroids in blood and saliva may be of some relevance to the frequency and clinical progression of some common HIV/AIDS-associated oral lesions.”

“Drug reactions are common in patients infected with human immunodeficiency virus (HIV). Administration of trimethoprim-sulfamethoxazole (TMP-SMZ) is associated with adverse reactions in 40% to 80% of HIV-infected patients. However, pulmonary reactions have been rare...We report a patient who developed two episodes of acute pulmonary edema [fluid on the lungs] after administration of ibuprofen [although perhaps TMP-SMZ was involved]”

“Thirty-nine patients who have not had a transplant have been reported to have KS associated with corticosteroid therapy…The authors studied 10 patients with the appearance of KS during corticosteroid therapy (6 men, 4 women; age range, 42-79 years)…Most patients had received prednisone, one had received triamcinolone, and one had received betamethasone and methylprednisolone…The interval between initiation of steroid therapy and appearance of KS lesions ranged from 3 months to more than 36 months…4 patients experienced complete regression of the KS lesions: in one after steroid withdrawal, in one after steroid withdrawal and radiation therapy, in one with no change in steroid dosage, and in one with radiation therapy. 4 patients experience partial regression after reduction or withdrawal of steroids. In two patients there was no progression after reduction of the steroid dosage. One of the patients who had a partial regression…exhibited progression of the lesions after reinstitution of steroid therapy.”

“Both drug-induced eosinophilic pneumonias and interstitionephritides may occur after treatment with sulfonamides and penicillin. Reports about the glomerular [filtration portion of kidneys] diseases due to these drugs are rare [but one is reported in this paper]”

“This study monitored adverse drug reactions during treatment for tuberculosis [in Zambia] over an 18 month period (1 April 1990 to 31 October 1991) in 237 children with a clinical diagnosis of tuberculosis (125 boys and 112 girls; 88/237 (37%) infected with HIV-I) and 242 control children (149 boys and 93 girls; 26/242 (11%) infected with HIV-I). 22 (9%) of the 237 children with tuberculosis developed hypersensitivity skin reactions during the course of treatment…12 (55%) of the 22 children who reacted adversely to treatment developed the Stevens-Johnson syndrome. All 12 of these children with the Stevens-Johnson syndrome were infected with HIV [HIV antibody-positive, to be precise]. The mortality among these children who developed the Stevens-Johnson syndrome was 91% (11 of 12 died within three days of the onset of the reaction). No further reactions were observed in the 11 children who recovered from the cutaneous hypersensitivity reactions after thiacetazone was discontinued over a period of six months of further treatment of tuberculosis.”

“The rapid response of the infiltrate and peripheral blood eosinophilia to withdrawal of trimethoprim-sulfamethoxazole and corticosteroids is suggestive of drug-induced disease in this case”

“The [CDC] has recommended prophylaxis for [PCP] in patients with HIV infection who have had a previous episode of [PCP], have [low CD4 immune cell counts]...Unfortunately, 29-50% of patients with HIV infection develop adverse reactions to this regimen. The most common of these have been rash, fever, nausea, altered taste, pruritis [rash], leukopenia [depletion of leukocytes, white blood cells], thrombocytopenia [loss of platelets, blood clotting cells] and hepatitis. We now describe a patient who developed fever and acute hypoxemia mimicking early PCP as a complication of trimethoprim-sulfamethoxazole prophylaxis”

“We report on a patient who developed hypersensitivity pneumonitis induced by trimethoprim [bactrim]”

“a 23-year-old homosexual man with human immunodeficiency virus infection developed progressive exertional dyspnea [difficulty in breathing]...[after diagnosing pneumocystis carinii pneumonia] the patient was started on oral TMP/SMX [sulfa antibiotics]...after 7 days he developed patchy erethema and hives over his trunk and arms. These resolved after one day off medication. He did well until dyspnea recurred...and in response took another dose of his prescribed TMP/SMX. He quickly became flushed, diaphoretic, more dyspneic, nauseated and experienced vomiting and diarrhea. A bifrontal headache developed [which resolved after TMP/SMX was withdrawn again]...Re-exposure to TMP/SMX can indeed mimic progression of the underlying pulmonary infection”

“Adverse reactions to trimethoprim-sulfamethoxazole [Bactrim, Septra] are common in persons with [AIDS]. These reactions typically consist of fever, rash and/or neutropenia [depletion of neutrophils, white blood cells]...We observed transient hypotension [low blood pressure], fever, hypoxemia [lack of oxygen in the blood] and pulmonary infiltrates following reinstitution of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia [PCP] in 2 patients with AIDS. Differentiating this type of reaction...from sepsis or from worsening opportunistic pulmonary infection is important in the management of these patients [i.e. therapy can cause symptoms that are very similar to the disease]”

“Co-trimoxazole has been associated with severe damage to internal organs and neurological symptoms and signs...We report here a case of cerebromedullospinal disconnection association with lesions of the kidney, lung, and pancreas and cardiac arrhythmia after treatment with co-trimoxazole”

“The incidence of first severe anemia was assessed among HIV-uninfected infants in…MTCT [mother-to-child transmission] prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV [AZT]) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF)…A total of 1719 infants were analyzed- 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF and 2.5% of ZDV-FF infants [which is amazing because one of the most notorious side effects of ZDV [AZT] is anemia. Note that there was no comparison with a group whose mothers were not given any AIDS drugs during pregnancy]”

“High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death [This does not mean that AIDS drugs are absolved from responsibility. Some children might have been on only one or two AIDS drugs (notably AZT) which does not count as HAART or it might be that children with low hemoglobin to start with are less able to withstand the additional blood toxicity of HAART]”

“Macrocytosis, generally defined as a mean corpuscular volume [MCV] greater than 100 fL, is frequently encountered when a complete blood count is performed. The most common etiologies are alcoholism, vitamin B12 and folate deficiencies, and medications…Treatment of HIV with reverse transcriptase inhibitors (e.g., stavudine [Zerit], lamivudine [Epivir], zidovudine [Retrovir/AZT]) will cause macrocytosis because they interfere with DNA production, which may lead to megaloblastic changes. Most patients with HIV who are being treated with reverse transcriptase inhibitors will display macrocytosis without anemia. This indicates medication compliance by the patient, and no treatment is necessary [except that anemia is one of the leading side effects of these drugs, so this is clearly not true]”

“The most common side effects attributed to abacavir [a nucleoside analog AIDS drug] are gastrointestinal signs and symptoms (loss of appetite, nausea, vomiting, and diarrhoea), headache, malaise, and asthenia. These untoward events usually appear in the first few weeks of therapy, tend to resolve spontaneously, and are usually mild-to-moderate in severity [which could be because the body adapts to the drug or because patients lose patience and stop taking it]…The most serious adverse event caused by abacavir is the hypersensitivity reaction, a severe allergic reaction that has been estimated to occur in around 8% of persons who begin abacavir therapy, usually within the first 6 weeks of treatment. Its multiform clinical manifestations include fever, rash, gastrointestinal, or respiratory symptoms, and may lead to life-threatening hypotension, renal failure and death, especially in the event of rechallenge with abacavir after a prior episode of hypersensitivity…In our patient, a potentially life-threatening neutropenia occurred 4 weeks after the start of abacavir therapy and was associated with fever, skin rash, and anaemia. The neutrophil count started to increase and themajority of clinical signs and symptoms resolved within 3–4 days after stopping abacavir, whereas absolute neutrophil count and haemoglobin level became normal after 10 days. Consistent clinical manifestations, a positive HLA-B 5701 testing, and the rapid recovery of our patient suggest that these adverse events may be immune mediated, probably due to the secretion of drug-related antibodies.”

“The hemophagocytic syndrome is characterized by an association of fever, hepato-splenomegaly [liver and spleen enlargement] and hemophagocytosis in organs such as the bone marrow and a high ferritin level…We describe two cases of hemophagocytic syndrome occurring after highly active antiretroviral therapy (HAART) initiation. Both patients were antiretroviral therapy naive, starting HAART with a low CD4 count, and, within 1 week, developed a severe hemophagocytic syndrome revealing Hodgkin’s lymphoma in bone marrow biopsy [both developed severe pancytopenia, a major reduction in all major blood cell types]”

“Boehringer Ingelheim has identified 14 cases of intracranial hemorrhage (ICH) (bleeding into the brain), including 8 deaths, in 6,840 HIV-1 infected patients receiving APTIVUS [a protease inhibitor also known as Tipranavir] in clinical trials [note that it is estimated that only 1% to 10% of adverse reactions are reported, although this may be higher for patients participating in clinical trials]”

“A 42-year-old HIV patient was hospitalized in July 2003 after his HIV specialist doctor noted advanced anaemia in a routine blood count (haemoglobin 0.71 g/l, normal range 1.4–1.8) and elevated lactate dehydrogenase…In February 2003, a salvage regimen with two boosted protease inhibitors, lopinavir/ ritonavir and indinavir, was started…The review of the routine blood parameters during the past few weeks showed that both the anaemia and lactate dehydrogenase increase started after the failing antiretroviral therapy (ART) had been changed in February 2003.”

“A 59-year-old nurse of Korean origin from our HIV ward sustained a needle-stick injury with an HIV-contaminated needle. A potent PEP [post-exposure prophylaxis] regimen comprising ZDV[AZT]/3TC (Combivir) 300/150 mg twice a day (bid) and LPV/r (Kaletra [Lopinavir]) 400/100 mg bid was instituted 2 h after exposure. The following day, she experienced weakness and nausea, followed by acute deterioration of her condition. On admission, the patient was somnolent but rousable. She was unable to communicate appropriately but could open her eyes on command…Under initial therapy comprising vasopressors and fluid substitution her cardiovascular situation stabilized temporarily, before she developed acute renal [kidney] failure with anuria and hypoxaemic respiratory failure several hours after admission…The patient experienced a delayed recovery, suffering from sustained severe vertigo and weakness. Renal function also recovered after a polyuric phase of about 2 weeks’ duration. After 6 weeks of hospitalization, and a further 5 weeks in a neurological rehabilitation centre, she was finally discharged. At that time, she was still suffering from vertigo, concentration difficulties and neuropsychological cognition disorder. Other organ systems recovered completely and were unremarkable. Six months after the incident, she was still unable to resume her work. …Although the exact cause and mechanism of this incident remain unclear, the timely coincidence with PEP initiation suggests a primarily drug-induced cardiovascular failure leading to severe hypotension, shock and subsequent effects on pulmonary, renal and neurological function.”

“In this retrospective study, performed on 16 HIV-infected patients with congenital coagulation disorders [hemophilia]…the incidence rate of bleeding with a lopinavir–ritonavir-containing regimen was almost 4 times the rate with other protease inhibitor-containing regimens. Lopinavir–ritonavir also appeared to be associated with exceptionally severe haemorrhagic events.”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Didanosine appears associated with an increased risk of hyperlactataemia [elevated levels of lactic acid]”

“We report the case of a child who was diagnosed with a vertical HIV infection at the age of 11 months. Before diagnosis the boy had been repeatedly admitted with thrombocytopenia [lack of platelets that allow blood to clot], hepatosplenomegaly and lymphadenopathy…HAART was initiated with lamivudine (4 mg/kg twice a day), stavudine (1 mg/kg twice a day) and nelfinavir (55 mg/kg twice a day). A reduction in the size of lymph nodes, liver and spleen occurred over a period of 2 months. The HIV-RNA viral load was 1495 copies/ml 2 weeks after the initiation of HAART, and reached undetectable levels (detection limit 50 copies/ml) within 5 months…While on therapy the patient has been repeatedly admitted to our hospital with petechiae [blood blister] and platelet counts below 10 000/microliter. Intravenous gammaglobulin led to a prompt increase of the platelet count above 150 000/microliter, followed by a gradual decrease to counts below 10 000 within 4 weeks on all occasions. Thrombocytopenia has now persisted for more than 9 months despite [or perhaps because of] HAART.”

“73 (8.3%) of 880 [Swiss HIV] patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine, as compared with patients who received zidovudine[AZT]-based regimens…Hyperlactatemia was associated with lipoatrophy [fat loss], hyperlipidemia [high blood lipid levels], and hyperglycemia [high blood sugar levels]. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia”

“Severe lactic acidosis has been increasingly reported as a potentially fatal complication of HIV treatment…A 39-year-old HIV-positive woman was admitted…on February 2000 because of progressive dyspnoea [difficulty breathing], peripheral oedema [accumulation of fluid under the skin], ascites [accumulation of fluid within the abdominal cavity] and cyanosis [blue tinge to the skin due to lack of oxygen in the blood]. She was on her first anti-HIV combination regimen with stavudine, lamivudine and indinavir since January 1999…The patient was asymptomatic [at the time drugs were prescribed]…Anti-HIV therapy was well tolerated [whatever this means] with good virological (HIV-DNA <50 copies/ml) and immunological response (CD4: 326 cells/cubic mm) after 52 weeks…On December 1999 she developed mild dyspnoea and peripheral oedema, and she was started on frusemide [a diuretic] 12.6 mg daily…On February 2000, the patient was hospitalized because her condition had worsened…Highly active antiretroviral therapy was discontinued the same day…Over the following 16 h[ours], her clinical condition worsened dramatically and she developed severe acidosis [buildup of lactic acid in the blood]…An empirical approach with thiamine was started and, after a few hours, the patient had a dramatic improvement…All the metabolic abnormalities normalized within 7 days…It is noteworthy that similar events always took time to develop, occurring several months after starting antiretroviral medication…Several cases of lactic acidosis resolved spontaneously after stopping HIV treatment.”

“In 516 patient-years of observation, 2 patients experienced severe fulminant lactic acidosis (lactate >5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further 5 patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia”

“High-grade B-cell non-Hodgkin lymphoma (NHL) has been classified as an AIDS-defining illness (ADI) since 1985, following the description of NHL in a group of 90 HIV-1 seropositive men…HIV-associated NHL consequently accounted for up to 16% of all deaths attributable to AIDS [in 1994]…During [the 1990’s], potent therapies for the treatment of HIV infection have become available, and morbidity and mortality have plummeted. Despite this, the incidence of NHL remains largely unchanged-a finding confirmed by other studies [so, if NHL is caused by HIV, and HAART attacks HIV, why is this the case? Could it be that NHL is not caused by HIV, but by drugs, including antiretroviral drugs? Or, is it that HAART does not attack HIV, but simply acts as a potent, although toxic, antibiotic? Or, both?]”

“Further study is needed to characterize the association between indinavir and thrombosis [2.4 times the risk of blood clots inside blood vessels]…physicians should be alert for thrombosis in recently hospitalized HIV-infected patients, those with AIDS-defining opportunistic illnesses and those receiving indinavir [a Protease Inhibitor] or megestrol acetate.”

“In HIV-infected individuals, serum parameters of iron status can resemble those seen in chronic disease anemia, associated with immunologically altered iron metabolism…Frequent findings are: elevated concentrations of serum ferritin, decreased values of serum iron; decreased levels of total transferrin [there is no mention of the possibility that the increased iron may be from blood cells destroyed by nucleoside analogs or other anemia-inducing drugs]”

“Hydroxyurea has become an important drug in the treatment of HIV disease...One of the side effects...is [bone] marrow suppression, which is seen commonly as pancytopenia [deficiency in all types of blood cells], although different cell lineages can be affected individually. Conventional thinking is that stopping hydroxyurea administration will result in quick reconstitution of the suppressed cell lines. We describe two cases of prolonged hydroxyurea-induced marrow suppression in HIV-infected patients...Our patients became transfusion dependent [one for 2-1/2 months, one longer]”

“Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC [a nucleoside analog similar to AZT]) were conducted in F344/N rats and B6C3F1 mice…AZT and ddC produced dose-related, poorly regenerative, macrocytic anemias as evidenced by decreases in erythrocyte counts, hematocrits, and hemoglobin concentrations and increases in mean corpuscular hemoglobin and mean corpuscular volume. Bone marrow samples in rats treated with AZT were hyperplastic whereas those in mice treated with AZT and rats and mice treated with ddC were hypoplastic. The hematologic toxicity of AZT was more severe than that of ddC. Generally, toxic effects of either chemical were greater in mice than in rats and more pronounced in female than in male animals. After 30 days without dosing, hematologic effects either resolved or dramatically improved…These studies demonstrated the early and progressive time course of toxicity of AZT and ddC”

“d4T [a nucleoside analog] significantly inhibited erythroid [red blood cell] progenitor cell colonies [the cells in the bone marrow that produce red blood cells]”

“There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density…Our findings demonstrate for the first time that tenofovir treatment of primary osteoblasts [bone producing cells] results in gene expression changes that implicate loss of osteoblast function in tenofovir-associated bone mineral density loss.”

“The 214 participants were followed for a mean [of] 2.4 years. With continuous ART [anti-retroviral therapy], BMD [bone mineral density] declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART…In the parent study, 10 of 2753 participants in the VS [continuous ARV] group and two of 2720 in the DC [intermittent ART] group reported serious fractures”

“High prevalence of osteopenia and osteoporosis has been recently observed in HIV-infected patients. The pathogenesis of these bone metabolism disorders in HIV infection has not been fully elucidated, even though multiple factors seem to be involved. Osteopenia was initially attributed to highly active antiretroviral therapy (HAART), especially regimens containing protease inhibitors; however, further studies did not confirm this relationship. Then, HIV infection per se was postulated as a possible cause [despite this problem arising after protease inhibitors were approved]…We report of [sic] two AIDS patients who suffered from vertebral fractures [broken back] just a few months after HAART introduction.”

“Among men, the following factors significantly associated with the diagnosis of bone mass loss in the univariable model were included in the multivariable analysis: age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load <500 copies/ ml, log-based plasma viral load, tobacco consumption, physical activity, cumulative exposure to antiretroviral drug class, BMI [body mass index] <20.6 kg/m^2 and lipodystrophy. Independent factors associated with the diagnosis of osteoporosis were older age, homosexual HIV transmission, low BMI and HIV plasma viral load <500 copies/ml. Only older age and lower BMI were marginally associated with osteopenia. In women, all bone disorders were pooled without distinction between osteopenia and osteoporosis because of the lower number of observations in each subgroup. Factors analysed in the multivariable model were menopausal status, age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load <500 copies/ml, log-based plasma viral load zenith, CD4 lymphocyte count nadir, alcohol consumption, calcium intake >1 g/day, physical activity, cumulative exposure to antiretroviral drug class and lipodystrophy. Older age and low CD4 cell count nadir were identified as factors associated with reduced BMD [bone mineral density]. To explore further whether the association between low HIV plasma RNA and osteoporosis in men was related to antiretroviral exposure, the effect of cumulative exposure to HAART was analysed without adjustment for HIV plasma RNA. Three different multivariable models were developed but in none was the treatment variable effect significant: cumulative exposure to any antiretroviral drug (OR, 1.01), cumulative exposure to HAART (OR, 1.02), and naive versus drug experienced status (OR, 0.28) [note that although this was not statistically significant, probably because of small numbers included who had never taken any drugs, this does indicate a possible massive (more than 3 times greater) risk with taking any AIDS drugs]”

“Although early data suggested that protease inhibitors might have a deleterious effect on bone metabolism, recent results do not support these findings [cleverly, this study studied whether protease inhibitors were more likely than other AIDS drugs to cause bone disease, there were few if any patients in the study not taking drugs in other classes]. Likewise, preliminary warnings have appeared with respect to tenofovir, suggesting an increased loss of BMD [bone mineral density] with the use of this nucleotide, in comparison with other nucleosides. However, other clinical studies with a long follow-up did not reveal changes in BMD or an increased incidence of bone fractures in patients receiving a tenofovir-containing regimen. [Again, this does not show that Tenofovir doesn't cause bone disease, just that it's not significantly different than other drugs to do so]”

“Among HIV-infected patients receiving antiretroviral therapy (ART), reduced BMD [bone mineral density] has been reported with increasing frequency…We conducted a systematic review and six meta-analyses of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART[antiretroviral therapy]-treated versus ART-naive [untreated]; and PI[protease inhibitor]-treated versus PI-untreated individuals…ART-treated subjects had a higher prevalence of reduced BMD compared with ART-naive subjects. In addition, for the seven studies that included appropriate data, the odds of osteoporosis was increased 2.4 times in ART-treated subjects compared with ART-naive subjects. None of the studies adjusted for potentially important confounding factors, such as age or the duration of HIV infection [which is to some extent a measure of the total amount of ART consumed]”

“Osteonecrosis [bone decay] was diagnosed in 104 subjects [out of 56,393], corresponding to an incidence rate of 4.5/10 000 person-years and affected the hip in 83, the knee in 14 and other joints in 16 patients. Of these patients, 63 received analgesics and 52 were treated surgically…The incidence of osteonecrosis was also higher among subjects exposed to cART [combination antiretroviral therapy]. The adjusted RR [risk ratio] ranged from 2.6 among patients treated with cART for < 12 months (compared with patients unexposed to cART), to 5.1 among patients treated for 60 months.”

“Bone disorders in HIV-1 patients treated with highly active antiretroviral therapy (HAART) are an emerging issue…After approximately 27 months of treatment with indinavir (800 mg three times a day), zidovudine [AZT] and lamivudine [3TC], a 56-year-old HIV-1-infected bisexual man noticed thickenings on almost all fingers of his hands. He also noted several small protrusions at the costosternal [breastbone] junctions…After the introduction of indinavir [a protease inhibitor] in June 1998, the patient experienced myalgia [muscle pain], arthralgia [joint pain], dry skin, body hair loss, and ingrown toenails developed. The patient has also been taking trimethoprim–sulfamethoxazole…On examination in November 2000, a hand X-ray revealed periostal [near the bone] reactions in the diaphyseal [shaft] regions of all proximal phalanges, the middle phalanges [finger bones] of both index fingers, and navicular bones. Osteosclerosis [bone thinning] was present throughout the spine, this was now also apparent in the lumbar region. Radiographic evidence of osteosclerosis [bone thinning] was also observed in the skull, and a marked periostal reaction was present in the middle part of both radial bones…In December 2000, indinavir was replaced with nelfinavir, nucleoside analogues were not changed, but the patient refused to stop taking multivitamins [which he had been taking for 20 years]. Four months after indinavir therapy was discontinued, an X-ray showed a strikingly reduced periostal reaction on the patient's fingers…We have presented the first patient with osteosclerosis and new bone formation during indinavir therapy…The concomitant long-term use of indinavir with vitamin A, even at the recommended daily dietary allowance, should be discouraged [note that the doctors have no evidence that stopping Vitamin A would have reduced this problem]”

“Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and 5 naive to any antiretroviral treatment (untreated). 6 HAART-treated children showed clinical evidence of lipodystrophy [abnormal fat redistribution]...HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children.”

“Bone density...was reduced significantly in the HIV+ lipodystrophy versus HIV- control groups...and HIV+ non-lipodystrophy groups...PI [Protease Inhibitor] and NRTI [Nucleoside Analog] use were more prevalent among those diagnosed with lipodystrophy [Table 1 shows that, comparing HIV+ with lipodystrophy against HIV+ without, current NRTI use/duration of use was 100%/67 months vs. 60%/26 months and PI use/duration of use was 90%/35 months vs. 45%/11 months]”

“Prior to the introduction of long-term highly active antiretroviral therapy, healthy HIV-infected adults generally had normal bone mineral density that was stable over time...The present study has confirmed previous studies that found osteopenia [loss of bone mass] to be common in HIV-infected adult males receiving antiretroviral therapy even after adjustment for age. This osteopenia may result from mitochondrial toxicity of nucleoside analogues [which also may be the cause of excessive, sometimes fatal, levels of lactic acid]”

“We describe 5 patients whose symptoms of osteonecrosis [bone disintegration] developed with viral suppression and improvement in CD4 lymphocyte counts as a result of antiretroviral therapy. In addition, we review previously reported cases…We conclude that osteonecrosis is an emerging manifestation of HIV infection and that it may be either a consequence of immunologic and virologic improvement resulting from antiretroviral therapy or a complication caused by the drugs themselves.”

“We report on six patients (out of a cohort of 508 HIV-infected patients, including 280 on triple antiretroviral treatment) who were diagnosed with bilateral avascular necrosis of the femoral head, all between 1998 and January 2000...Four of the six patients had to undergo hip replacement surgery (bilateral in three cases). Of note was the fact that no case of osteonecrosis had been diagnosed in our cohort between 1992 and 1998. As shown in Table 1, all six patients had long exposure to antiretroviral treatments, including protease inhibitors; five out of six had signs of fat redistribution. When on therapy including a protease inhibitor, all patients had an elevated level of plasma triglycerides or cholesterol, and three had developed diabetes linked to insulin resistance...osteonecrosis may be more frequent in HIV-infected individuals, and two cases have already been reported in patients on highly active antiretroviral therapy In our cohort, osteonecrosis involved 2% of all treated patients and approximately 10% of patients had clinical features of lipodystrophy.”

“Osteopenia and osteoporosis [bone weakening disorders] are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution…HIV-infected individuals receiving PI-based HAART are more likely to have significant bone demineralization…which may increase the risk of fracture”

“Risk factors for death in patients diagnosed with non-Hodgkin’s lymphoma in the era of combination antiretroviral therapy…[risk related to status of combination Anti-Retroviral Therapy] No: 1 [baseline]; Yes for <90 days: 1.42 [times greater risk than those not using this therapy]; Yes for ³90 days: 1.98 [times greater risk than those not using this therapy]…Patients who developed NHL while not on cART had better survival, particularly when compared with patients who developed NHL after receiving cART for 90 days or more.”

“Among 86 322 patients included in the analysis, 132 had a diagnosis of anal cancer…102 occurred in the recent cART [combination Anti-Retroviral Therapy] period (1999– 2004)…The median CD4 cell count at anal cancer diagnosis increased with time from 188 cells/µl in the precART period to 288 cells/µl in the recent cART period. Nearly one-quarter of the patients had not received cART before the onset of anal cancer [i.e. more than three-quarters had received AIDS drugs]…In the precART, the early cART and the three sub-periods of the recent cART era (1999–2000, 2000–2001 and 2002–2003), the incidences of anal cancer were 10.5, 18.4, 43.1, 36.3 and 39.3 per 100 000 person-years, respectively.”

“Dramatic declines in KS [Kaposis Sarcoma] and NHL [Non-Hodgkins Lymphoma] were temporally related to improving therapies, especially introduction of HAART, but those with AIDS remain at marked risk. Among non-AIDS-related cancers, a recent increase in Hodgkin lymphoma was observed…Risk of Hodgkin Lymphoma increased substantially over the 1990-2002 period [8.1 times higher than the general population in 1990-5 and 13.6 times higher in 1996-2002]…[Table 2 shows that the risk of all non-AIDS associated cancers was double (compared to the general population) in 1980-9, 1.8 times higher in 1990-5 and 1.7 times higher in 1996-2002. Why would the risk of non-AIDS cancers be higher?]”

“With the advent of HAART there has been a dramatic decline in the incidence of Kaposi's Sarcoma [this may be a false association as many other things have changed, including usage patterns of nitrite inhalants]. However, the existence of B cell related lymphomas has not declined to the same extent…Bonnet et al noted that malignancies were the cause of death in 28% of HIV infected patients who died in 2000. Of 964 deaths, solid cancers accounted for 103 cases and included 50 lung, 19 hepatocellular [liver], 9 digestive and 6 anal cancers. The authors also reported 17 non-HIV-related hematological [blood] cancers.”

“We describe a patient who developed BL [Buschke-Loewenstein] tumour transformation of a long-standing perianal wart after sustained virological and immunological control of this chronic HIV infection [long-term use of AIDS drugs resulting in low 'viral load' and higher CD4 cell counts]…the perianal mass was now 15x10 cm [~6x4 inches] and was eroding both buttocks…A palliative colostomy was formed…He developed bacterial superinfection of the lesion and died 6 weeks later.”

“In HAART era, incidence rates of Kaposi’s sarcoma and cervical cancer have decreased, but NHL [non-Hodgkins lymphoma] remains the same. Incidence rates of five non-AIDS cancers (lung, head/neck, Hodgkin’s, anorectal, melanoma) in HIV-infected persons are significantly higher than in the general population…Recommendations: Smoking cessation counseling; Surveillance of cancers in HIV-infected persons with risk factor data. [stopping HAART was not on the list]”

“The five non-AIDS-defining cancers were lung, head/neck, Hodgkins disease, anorectal, [and] melanoma. Among the HOPS cohort…incidence of [these] four cancers was significantly greater than expected compared with the general popuation: lung (Relative Risk = 2.13), Hodgkins disease (RR = 4.58), anorectal (RR = 10.13), and melanoma (RR = 2.99). Among Chicago clinic patients, all five cancers were significantly increased in the multivariate analysis: lung (RR = 3.63), Hodgkins disease (RR = 77.43), anorectal (RR = 5.03), melanoma (RR = 4.10), head/neck (RR = 9.96)”

“As HIV-infected men experience longer lives in the era of highly active antiretroviral therapy (HAART), a higher incidence of prostate cancer may become more apparent [or HIV drugs could be causing prostate cancer]. Three cases of prostate cancer were identified in the past 18 months among 155 HIV-infected men over the age of 40 years in our clinic…our data suggest that it exceeds the annual national rate of 50–100 cases of prostate cancer per 100 000 persons. [All three patients were taking 3 or 4 AIDS drugs]”

“[from a news report on this article] During 2 years of follow-up, 51% of those undergoing HAART developed AIN-3 [anal intraepithelial neoplasia (cancer)] compared with 31% of those not receiving HAART. Thus, the prevalence and incidence of AIN-3 were clearly higher in men who received HAART, even after correction for baseline immune function, and the use of HAART did not reduce the incidence of AIN-3 during follow-up.”

“Among 71 HAART-treated women the prevalence of CIN [cervical intraepithelial neoplasia] before HAART was 55%. After a median of 10 months after starting HAART the prevalence had increased to 62% (P 0.20)”

“To our knowledge . . . cases of lymphoma that appear during the first weeks of therapy have not been published, although this possibility has been mentioned mainly in meetings. We report here three patients who developed rapidly growing lymphomas of different cell lineages within the first 2 months of the initiation of HAART . . . Several arguments strongly suggest that the relationship between the flare up of the lymphomas and HAART initiation is not casual. First, there is a strict temporal relationship between them. Second, the subsequent control of HIV replication and immune recovery induced by therapy should have mitigated, rather than accelerated, the appearance of the lymphoma. Third, bouts of another malignancy, Kaposi's sarcoma, which have been related to immune recovery after similar periods of HAART, have been reported. Fourth, the clinical presentation of the lymphomas in the three patients was remarkably abrupt, with the appearance of large, rapidly growing lymphomatous masses, despite the fact that both the clinical and radiological evaluation of these patients a few weeks earlier had failed to detect any manifestation of the malignancy. Fifth, although their observations have not been published, several authors have also suspected a relationship between the onset of HAART and the appearance of lymphomas in some patients. Finally, the incidence of lymphoma arising shortly after the onset of HAART seems to be higher than expected. In a study on a large cohort of patients that evaluated the development of opportunistic illnesses after the initiation of HAART, lymphomas were diagnosed within the first 3 months of treatment in three out of 14 patients (21%). The data from our institution are still more significant: 3 of the 5 patients in whom lymphoma was diagnosed while receiving HAART developed the malignancy within the first 2 months of therapy, a rate considerably higher than expected for such a short period.”

“In the period 1981 through 1995, a trend of increase was observed in the incidence of ICC [invasive cervical cancer] and other AIDS-defining diseases; this trend has continued only for ICC, whereas the incidence of other AIDS-defining diseases has decreased since 1996. Compared with 1981 through 1995, the RH[relative hazard] of ICC for 1996 through 1998 was 7.41; when adjusting for age at HIV seroconversion, the RH decreased to 4.75.”

“We used a triple combination regimen, including nevirapine, for prophylaxis after occupational or sexual exposure to HIV-1 infection. Of 57 individuals who started therapy, only 41 returned for follow-up. Five had a grade three or four drug-induced hepatitis, two of whom also had a rash. This high rate of major adverse events raises concerns over the safety of such a regimen for its use in this population.”

“High-grade B-cell non-Hodgkin lymphoma (NHL) has been classified as an AIDS-defining illness (ADI) since 1985, following the description of NHL in a group of 90 HIV-1 seropositive men…HIV-associated NHL consequently accounted for up to 16% of all deaths attributable to AIDS [in 1994]…During [the 1990’s], potent therapies for the treatment of HIV infection have become available, and morbidity and mortality have plummeted. Despite this, the incidence of NHL remains largely unchanged-a finding confirmed by other studies [so, if NHL is caused by HIV, and HAART attacks HIV, why is this the case? Could it be that NHL is not caused by HIV, but by drugs, including antiretroviral drugs? Or, is it that HAART does not attack HIV, but simply acts as a potent, although toxic, antibiotic? Or, both?]”

“HIV-infected individuals have an increased risk of CVE [cerebrovascular events] with and without proven risk factors. The risk is associated with IDU [intravenous drug use], low CD4 count [which implies more exposure to AIDS drugs] and exposure to abacavir, but not with HAART [which may have been adjusted out because low CD4 counts are correlated with HAART use].”

“The FDA said, “some patients using Invirase and Norvir may be at an increased risk for heart abnormalities leading to irregular heart rhythms.”…Invirase falls into a class of drugs known as protease inhibitors [which are known to cause heart problems by themselves]”

“Recent exposure to abacavir or didanosine was associated with an increased risk of MI [Myocardial Infarction=Heart Attack]…Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI [32,728 out of 33,308 people (98%) in the trial were taking at least one AIDS drug so it is not possible to exclude cardiovascular risk from drugs not listed above. The analysis was thus comparison of risk between drugs, as opposed to drugs versus no drugs, which would be more realistic. It is possible that all ARVs have a cardiovascular risk so this study would only show those with the highest risk]”

“Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir [a nucleoside analog] was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir- treated patients.”

“Antiretroviral-treated patients had a higher median IMT [Intima-Media Thickness, “a validated measure of atherosclerosis”] than the untreated patients. Furthermore, among all HIV-infected participants, increasing duration of HAART, protease inhibitor use, and nucleoside analogue use were each associated with thicker IMT. These relationships remained significant after adjustment for traditional cardiac risk factors and the duration of HIV diagnosis”

“In a large group of vertically HIV-infected children and youth with extensive antiretroviral therapy exposure, height, weight, and total and limb fat were lower than in controls. There was a high prevalence of lipid abnormalities among those on protease inhibitors and evidence of developing insulin resistance, factors that may accelerate lifetime risk for cardiovascular disease.”

“[In a supplement sponsored by a drug company with several heart drugs in their pipeline…] Given their known propensity to induce dyslipidemia [fat-related abnormalities] and insulin resistance [a precursor to diabetes], PI [protease inhibitors] are primarily implicated in the possible cardiovascular risk. NRTI [nucleoside reverse transcriptase inhibitors such as AZT] may, however, also play a role in CAD [coronary artery disease] because of their potential role in the development of insulin resistance. Several studies have investigated a possible link between ART and the development of CAD and MI in HIV-infected patients…Overall, the data from those studies indicate a probable association between PI use, the duration of PI use, and increased cardiovascular risk…To confirm this association, large, adequately powered studies that rigorously characterize and confirm adverse events with the ability to control for conventional risk factors are required. One such study, the DAD study, has been reported. Initiated in 1999, the DAD study…enrolled 23,437 patients and followed their progress up until February 2005. The primary outcome of the study was MI [myocardial infarction, i.e. heart attack]…The full data from this study were recently published. The patient population in the DAD study was young, with a median age of 39 years, and approximately a quarter of patients were women…Incidence rates of MI between study initiation in 1999 and last follow-up in 2005 were relatively stable, with an incidence of approximately 3.7 per 1000 person-years of follow-up. A linear increase in the incidence of MI was seen with longer duration of exposure to combination therapy with antiretroviral drugs. The relative rate per year of exposure after adjustment for other factors was 1.16 per year of exposure. A linear trend of increasing MI was also seen with increasing exposure to PI. With NNRTI [non-nucleoside reverse transcriptase inhibitors] there was no clear pattern of risk association. There was, however, an increased risk of 16% per year of additional PI exposure in NNRTI-treated patients. The association between exposure to PI and an increased risk of MI was confirmed when patients treated with PI only (i.e. those naive to [never having taken] other antiretroviral drugs) were analyzed; the risk of MI in these patients was 1.15.”

“After adjustment for age, race, family history, smoking, high-density lipoprotein-C, low-density lipoprotein-C and hypertension, HIV infection and long-term HAART use increased the odds for presence of CAC [coronary artery calcification]”

“We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus…345 patients had a myocardial infarction [heart attack] during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16, whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05. Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 and 1.00, respectively…Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.”

“This study will use the NIH-sponsored Women and Infants Transmission Study (WITS) and the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2) HIV-infected pediatric cohorts to determine how left ventricular (LV) function (particularly fractional shortening and contractility) and structure (particularly wall thickness and mass), are affected by cumulative intensity of HAART exposure.”

“A 62-year-old Japanese woman, who consulted a hospital because of dyspnoea and dry cough, was presumptively diagnosed as having Pneumocystis pneumonia based on history, examinations, chest X-ray and a computed tomography scan…HIV-1 antibody was found to be positive…After treatment for Pneumocystis pneumonia, antiretroviral therapy was started, with stavudine, lamivudine, and lopinavir– ritonavir (400/100 mg twice a day) in December 2003. On the fourth day of antiviral treatment, the patient suddenly became dizzy; a heart rate of 40 bpm [brachycardia; abnormally slow heart rate] and blood pressure of 71/51 mmHg were documented…Lopinavir–ritonavir was switched to nelfinavir, and a normal sinus rhythm was restored within 14 [hours].”

“A 62-year-old Japanese woman, who consulted a hospital because of dyspnoea and dry cough, was presumptively diagnosed as having Pneumocystis pneumonia…As HIV-1 antibody was found to be positive, she was referred to our hospital for a further evaluation…She had a past history of persecutory delusions and herpes zoster. She did not have any past history of cardiac problems. On admission, her blood pressurewas 114/62 mmHg and her heart rate was 78 bpm…Her CD4 cell count was 9 cells/ml and her HIV-1 load was 28 000 copies/ml. After treatment for Pneumocystis pneumonia, antiretroviral therapy was started, with stavudine, lamivudine, and lopinavir–ritonavir… On the fourth day of antiviral treatment, the patient suddenly became dizzy; a heart rate of 40 bpm and blood pressure of 71/51 mmHg were documented. An electrocardiogram showed atrial flutter of 2-to-1 conduction and sinus arrest with an escape rhythm occurring repeatedly…Lopinavir–ritonavir was switched to nelfinavir, and a normal sinus rhythm was restored within 14 h…Her heart rate has never dropped below 60 bpm thereafter and is in normal sinus rhythm currently”

“HAART may substantially increase the risk of cardiovascular mortality compared with non-infected individuals or with people infected with HIV who are not yet taking HAART. HAART is associated with known cardiovascular risk factors such as increased plasma concentrations of triglycerides, total cholesterol, possibly hypertension, and increased insulin resistance. In addition, HAART induces endothelial dysfunction, which is known to increase the risk of coronary heart disease.”

“Some authors have suggested an increased incidence of cardiovascular disease in patients on HAART”

“AIDS drug cocktails may double the risk of heart attacks, a risk comparable with smoking cigarettes, University of Copenhagen researcher Dr. Jens Lundgren said at the 12th Conference on Retroviruses and Opportunistic Infections in Boston. Lundgren's study reported 277 heart attacks among 23,441 AIDS patients whose median age was 39. "You wouldn't expect myocardial infarcts [heart attacks] in that young a population," Lundgren said at a news conference.”

“Drug-induced long QT syndrome results almost entirely through I(Kr) suppression to cause the potentially fatal cardiac arrythmia torsade de pointes. Unintentional blockade of HERG channels has emerged as an unanticipated side-effect of many pharmacological agents and is an obstacle in drug development. Here, we report a previously unrecognised association between QT interval prolongation or torsade de pointes, or both, and protease inhibitors, and investigate the effects of these drugs on HERG channel and native I(Kr) function in vitro…By December 2002, the FDA's adverse event reporting system had received voluntary notification of a total of 23 patients with QT prolongation in whom a protease inhibitor was listed as a suspect medication. Ten patients, including the patient reported here, had QT interval prolongation and 14 had torsade de pointes. Ten of 24 patients were receiving nelfinavir alone. The remaining patients were receiving dual protease inhibitor treatment…In 13 cases reported to the FDA [more than half], and the case we describe, protease inhibitors were thought by the attending physicians to be the most probable drug responsible for QT prolongation.”

“Our results point to a duration-related effect relationship [more drugs, more disease] between PI [Protease Inhibitor] and MI [Myocardial infarction; heart attack], with a higher MI incidence rate among men exposed to PI for 18 months or more.”

“Taken in aggregate, the weight of the evidence suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk for the development of premature atherosclerotic complications [heart disease, potentially fatal].”

“we conducted a collaborative, observational study of 11 previously established cohorts comprising 23,468 HIV-1–infected patients followed at 188 clinics in 21 countries in Europe, the United States, and Australia…A total of 126 patients had a myocardial infarction during follow-up (incidence, 3.5 events per 1000 person-years).…36 of the events (29%) were fatal…The incidence of myocardial infarction increased with increasing exposure to combination antiretroviral therapy. The patients with no exposure to therapy had a lower incidence of myocardial infarction than for any of the treated groups…the relative rate was 1.22 per additional year of exposure to combination antiretroviral therapy; it was 1.26 after adjustment for demographic risk factors, including age, which increased with increasing duration of therapy [i.e. every year of therapy with protease inhibitors increased the risk of a heart attack another 22% (26% after adjustment for confounding factors)]…None of the markers of HIV-1 disease were associated with myocardial infarction in the adjusted model. Including these variables in the model did not modify the association between duration of exposure to combination antiretroviral therapy and myocardial infarction.”

“Of the 5082 individuals who have ever received ART [anti-retroviral therapy], 63 (< 1%) were captured in the Cardiac Registry. There were 97 events: 70 (72%) since 1999. The age-adjusted [cardiac] event rate per 1000 HIV-positive individuals on ART increased significantly over time whereas that for the general BC [British Columbia, Canada] population did not increase over time. In multivariate analysis, age at baseline per 10 year increase, and months on ART remained significant.”

“Simon Mallal, MBBS, of Royal Perth Hospital in Perth, Australia, proposed an interesting hypothesis: that HIV infection yields protective benefits against cardiovascular disease (CVD) which HAART effectively abrogates. Following this line of reasoning, any strategy that limits total exposure to HAART (eg, delayed therapy) would be beneficial in terms of cardiovascular outcomes [conveniently for drug proponents, this would mean that HAART drugs aren’t bad for your heart, they just erase the goodness that HIV does for you!]”

“considering the toxic effect of the drugs on the metabolism alteration of the myocardium [lining of the heart], cardiologic [heart] analysis has to be included at least once per year.”

“The clinical data suggest that HIV protease inhibitors may promote accelerated atherosclerosis, and the current data provide one possible mechanism for this acceleration. Our studies demonstrate that three different HIV protease inhibitors, ritonavir, indinavir, and amprenavir, can increase the level of CD36 protein and the level of cholesteryl ester in THP-1 macrophages and human PBMCs.”

“We describe a case of severe and premature vascular disease, occurring in a young [37 year old] female patient, multiexperienced for HAART [having taken several different AIDS drugs], who is part of a cohort of patients followed for drug-induced toxicity. After 6 years of treatment she suffered a bilateral carotid stenosis [narrowing of one of the carotid arteries]; the only [other] risk factors were cigarette smoking and hypercholesterolemia…[The woman] was started on antiretroviral therapy with nucleoside reverse transcriptase inhibitors in 1993. Since 1998 the therapy was enhanced first with non-nucleoside reverse transcriptase inhibitors and then with protease inhibitors. In June 1999, as a result of unsatisfactory immunovirological control, a mega-HAART regimen with stavudine, abacavir, lamivudine, ritonavir and indinavir was introduced [resulting in a number of serious side effects, and eventually] a total obstruction of the right carotid artery, as well as the presence of soft lipidic plaque causing stenosis of the left carotid bifurcation…We must therefore consider the possibility that antiretroviral treatment may have contributed to the occurrence of vascular pathology.”

“The use of PIs [Protease Inhibitors] is associated with coronary artery calcification, atherogenic lipid changes [clogged arteries], and increased erythrocyte volume [larger red blood cells] in individuals infected with HIV-1.”

“Dr. Egger estimates that the more severe forms of lipodystrophy that develop as a result of highly active antiretroviral therapy (HAART) can increase the risk of coronary artery disease by three to four times.”

“[This] retrospective analysis of a cohort of 4993 HIV infected patients treated at our hospital between January, 1 1983 and December, 31 1998 [found] 29 patients with MI [myocardial infarctions/heart attacks] were diagnosed between 1983 and 1998. The incidence of MI per 1000 patient-years increased from 0.86 (1983-86), 1.14 (1987-90), 0.59 (1991-94) to 3.41 (1995-98) respectively. Age >40, previous HAART therapy, homo-, or bisexual mode of HIV transmission and previous AIDS diagnosis were significantly associated with MI in univariate analysis. Age >40 and previous HAART therapy remained significantly associated with MI in a multiple regression model…The incidence of MI in HIV infected patients increased in our cohort after the introduction of HAART.”

“A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD [coronary heart disease].”

“A 37-year-old previously healthy homosexual caucasian man became HIV positive in 1986. He started zidovudine [AZT] monotherapy in 1988…Didanosine (Videx) was added in April 1995 and lamuvidine (Epivir) in May 1996. Two months later…treatment with indinavir (Crixivane) was initiated. His drug tolerance, general health and compliance were excellent, and his viral load mainly remained below 50 copies/ml…The patient was never treated with anabolic steroids and there was no drug abuse. He had smoked 10-20 cigarettes per day for at least 12 years…At his last regular check up, 24 months after starting HAART, nothing unusual was found…Three days later he fainted while walking in the street. Electrocardiogram showed ventricular fibrillation. Cardiovascular resuscitation was unsuccessful and he died.”

“highly active antiretroviral therapy [HAART], which includes two nucleoside reverse-transcriptase inhibitors and a protease inhibitor, has been associated with an increased risk of potential cardiovascular complications that was related to the length of protease-inhibitor treatment and the type of protease inhibitor used. In approximately 60% of patients who were treated with this type of therapy, complications such as lipodystrophy, insulin resistance, and high cholesterol and triglyceride levels developed. In 10% to 20% of patients these complications were severe. There is also anecdotal information suggesting that the risk of angina and myocardial infarction is increased with high active antiretroviral therapy.”

“[Table 2 of this paper classifies possible factors behind a significant decline in HIV seropositivity in Zimbabwe. "Likely" causes of the decline were A) Fear induced by seeing people dying from AIDS and B) Poverty reducing the amount of prostitution. “Plausible” causes were condoms and various categories of awareness raising. “Unlikely” to be a cause were couselling, testing, injection safety, STD treatment, maternal ARV treatment (PMTCT) and Antiretroviral treatment in general]”

“hospitalization rates for men in this age group [45 or over] increased from 7.7 per 10,000 in 1997 to 14.8 in 2007; rates for women in this age group increased from 1.9 per 10,000 in 1997 to 4.9 in 2007. [If AIDS drugs were effective hospitalization rates (per person) would surely be decreasing]”

“By Dec 31, 2008, 23 699 patients (12%) of the 196 368 new patients who initiated ART in Malawi were known to have died. Although nearly two-thirds of deaths happened within 3 months after starting ART, an increasing proportion of patients are dying later. A further 24 409 patients (12%) were classifi ed as “lost to follow-up”, meaning that they have not returned to clinic for 3 months or longer. Operational research has shown that 50% of patients lost to follow-up have died.”

“Whether previous U.N. initiatives are responsible for the epidemic’s downturn is uncertain. Some experts said the drop in HIV may simply be a result of the virus burning itself out, rather than the result of any health interventions. Ties Boerma, a WHO statistics expert, said countries whose HIV prevalence declined dramatically, like Zimbabwe, were not always those that got the most AIDS money. The report also noted that where treatment is available, rates of HIV are either stable or rising.”

“Risk factors for death in patients diagnosed with non-Hodgkin’s lymphoma in the era of combination antiretroviral therapy…[risk related to status of combination Anti-Retroviral Therapy] No: 1 [baseline]; Yes for <90 days: 1.42 [times greater risk than those not using this therapy]; Yes for ³90 days: 1.98 [times greater risk than those not using this therapy]…Patients who developed NHL while not on cART had better survival, particularly when compared with patients who developed NHL after receiving cART for 90 days or more.”

“An HIV-1 antibody positive, 25-year-old female patient initiated ART in April 2007 under the care of a South African outpatient HIV clinic. After 3 months of ART, she reported cough, haemoptysis [coughing up blood], vomiting, diarrhoea and abdominal pain, and subsequently ceased to pass stools for over a week…The patient responded clinically to oral fluconazole and anti-emetic medication, and was discharged from the hospital. The initial symptoms recurred 2 weeks after discharge; this time the presentation was dominated by vomiting, with diarrhoea being less prominent. Despite aggressive correction of fluid and electrolyte disturbance and attempts to identify a cause, the patient died. Corticosteroids had not been given at any time and ART had been given uninterrupted for 5 months.”

“During the study period, 2878 patients were enrolled in the programme. At the time data were censored, 2423 (84%) patients had started ART, and their baseline characteristics showed that most had advanced immunodeficiency [<200 CD4 cells/µl]…Individuals were followed up for up to 5 years, and a total of 3155 person-years of follow-up accrued during ART [an average of just over one year per participant]…The mortality rate during the 1-month period prior to starting ART [anti-retroviral therapy] was very high [26.6 deaths/100 person-years]. The rate during months 0–4 of ART was also high (16.3 deaths/100 person-years) but decreased steeply thereafter, reaching a rate of 4.4 deaths/100 person-years during 8–12 months of treatment. Mortality rates in the second, third and fourth years of ART were 2.6, 0.7 and 0.4 deaths/100 person-years, respectively [this can be explained by assuming that the drugs take some time to work, that only sick people were enrolled and the drugs quickly killed the most susceptible or that the death rate on drugs was reduced through increasing non-compliance as participants recognized the toxicity of the drugs]”

“Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months…leading causes of death appear to be tuberculosis [AIDS], acute sepsis, cryptococcal meningitis [AIDS], malignancy [some cancers are AIDS-defining} and wasting syndrome [AIDS]…Symptomatic disease (WHO stages 3 and 4) was associated with mortality in some but not all studies…Low body mass index and anaemia were independently associated with mortality in some studies. Anaemia may be associated with a variety of conditions such as extrapulmonary tuberculosis (TB), gastrointestinal Kaposi’s sarcoma and severe malnutrition”]

“Without proper treatment for TB, about 90% of people living with HIV die within two to three months of becoming sick with TB, even if they are receiving anti-retroviral treatment [because they are receiving anti-retroviral treatment?]”

“A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana's National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [i.e. not considered in the analysis]. In addition, a significantly increased risk of death after HAART among men would have been missed had patients not been traced…Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced…[there was a] very short survival after HAART initiation among patients initially categorized as lost but who were eventually confirmed dead (i.e., 42 days)…in this study, nearly 60% of all deaths within the first year would not have been detected unless patient tracing was performed…The finding of substantial death rates among patients who are lost to follow-up also suggests that death rates after HAART initiation in the developing world may be higher than previously suspected.”

“Studies of antiretroviral therapy (ART) programs in Africa have shown high initial mortality…The aim of the present study was to assess mortality and to identify predictors of mortality in HIV-infected patients starting ART in a rural hospital in Tanzania.…This was a cohort study of 320 treatment-naïve adults who started ART between October 2003 and November 2006…Mortality was found to be high, with the majority of deaths occurring within 3 months of starting ART.”

“The incidence of mortality decreased over time in HIV-infected patients, although it has remained approximately five times higher than that for the age-matched general population. AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time, whereas liver diseases and non-AIDS-defining infections significantly increased over time. Infections in general (33 times higher), liver diseases (11 times higher) and non-Hodgkin lymphoma (5 times higher) were overrepresented as causes of death in the HIV-infected cohort compared with the age-matched general population.”

“[Harold] Jaffe said AIDS mortality rates in the United States are “twice that of any nation in the European Union and are 10 times that of the United Kingdom.” “We have known for a long time that the rates in the United States are higher than those in Europe,” Robert Janssen, director of HIV/AIDS prevention at the CDC, told United Press International. “There are major differences between the epidemics in the U.S. and in Europe, so it is difficult to understand why there are such differences.” [like more aggressive AIDS drug promotion in the U.S.?]”

“This is a disease that science is keeping up with [no vaccine, no cure, no non-toxic drugs] but you have to keep fighting to keep up with it because treatment is life-long and in combination. Life-long treatment is…almost invariably associated with problems of side effects or problems with drug resistance”

“Of the 1735 patients who initiated HAART, 186 patients died and 37 were lost to follow-up during 1955 person years of follow-up. Out of these patients, 103 (46.1%) died within 3 months after HAART initiation.”

“Within a community-based programme in Cape Town, the mortality rate among referred individuals eligible to start ART is extremely high, exceeding 30 deaths per 100 person-years. Moreover, during 3 years follow-up of this cohort, 87% of mortality occurred in the interval just before treatment initiation or during the first 16 weeks of ART. Collectively, these data indicate that patients are arriving with disease that is too far advanced [or maybe the drugs are killing them]”

“United Nations Special Envoy for HIV/AIDS in Africa Stephen Lewis expressed concern on Tuesday over Malawi's rising number of deaths among people receiving HIV/AIDS treatment in the country. Lewis was speaking at the end of his three-day visit to the impoverished southern African country when he was briefed by Malawian government officials that the country was grappling with an 11% death rate of people who were receiving free antiretroviral (ARV) drugs in public hospitals. Malawi has managed to increase the number of people receiving free ARVs from about 4,000 two years ago to 70,000 at present. Lewis expressed concern over the high death rate of those people on free ARVs but added that all African countries were faced with the similar problem that must be addressed as quickly as possible. "Malawi and other countries on the continent are lacking capacity to determine immunity levels of those people on treatment and this is leading to increased deaths of people on treatment," he observed. The UN special envoy added that poor nutrition was emerging as the single greatest threat to quality life for HIV positive people who were on ARV treatment in Malawi and most sub-Saharan African countries. He said the United Nations through the World Food Program (WFP) would continue to support governments to provide supplementary food to people on antiretroviral therapy. [meaning that any improvement in the health of people on ARVs could be because of the supplementary food, combined with the economic benefits of people who sell their drugs on the black market]”

“Between 1999 and 2004, the percentage of deaths due to non–HIV-related causes increased by 32.8% (from 19.8% to 26.3%). The age-adjusted mortality rate decreased by 49.6 deaths per 10 000 persons with AIDS annually for HIV-related causes but only by 7.5 deaths per 10 000 persons with AIDS annually for non–HIV-related causes. Of deaths due to non–HIV-related causes, 76% could be attributed to substance abuse, cardiovascular disease [which can be caused by AIDS drugs], or a non–AIDS-defining type of cancer [which can be caused by AIDS drugs]. Compared with men who have sex with men, injection drug users had a statistically significantly increased risk for death due to HIV-related causes [implying that 'HIV-related causes' are really 'drug-related causes'] and non–HIV-related causes.”

“The results of this collaborative study, which involved…over 20 000 patients with HIV-1 from Europe and North America, show that the virological response after starting HAART has improved steadily since 1996. However, there was no corresponding decrease in the rates of AIDS, or death, up to 1 year of follow-up. Conversely, there was some evidence for an increase in the rate of AIDS in the most recent period.”

“The risk of an OI [opportunistic infection] during cohort follow- up was higher in children who were older, were Hispanic or non-Hispanic black, were in CDC category C [more severe disease], had a CD4 percentage of less than 15%, had a higher HIV-1 viral load at enrollment, initiated HAART [AIDS drugs] at an older age, and were treated with at least 3 different ART regimens before HAART initiation or at least 3 different HAART regimens before enrollment in [this trial].”

“There are no study results demonstrating the effect of APTIVUS [tipranavir]/ritonavir on clinical progression of HIV-1.”

“The results [of the introduction of antiretroviral drugs] have been exciting with improvement in the quality of life for many. In a randomly selected sample of 100 patients, 88% had undetectable viral load…the CD4+ cell counts went up in most patients…We decided to analyse the cause of death in those patients who died while on treatment…We analysed data from the first 15 months of ARV's…55 died (documented deaths) [approximately] 5% of total no. of patients. 40 patients were lost to follow up…[Leading cause of death was] Advanced RVD [Retroviral disease] (27%)…Median time on ARV's (1 month). Could have been immune reconstitution inflammatory syndrome [i.e. caused by the drugs]…TB (22%) [also often a result of initiating AIDS therapy]…Chronic diarrhoea (12%) [also a result of some AIDS drugs]…Lactic acidosis - Four of the patients [also a drug side effect]”

“ART [anti-retroviral therapy] is needed prior to AIDS [which means that if AIDS drugs can cause AIDS-defining illness, they can cause AIDS. In addition, by 2003, 71% of new US AIDS cases were in people diagnosed with no AIDS-defining illness]”

“That skeletal fellow reading a magazine, skin pulled taut over his skull, folds of denim covering his wasted legs, is actually one of our big successes. He is perfectly well, at least as far as his HIV infection goes. Ten years ago he was dying of AIDS; now he is living with it — or, more accurately, living almost without it, his immune system normal, no trace of virus detectable in his blood. It is the lifesaving drugs that have transformed his appearance like this, leaching the fat from his body even as they clear the virus from his blood…we have patients scattered at every possible point: men and women who cruise on their medications with no problems at all, and those who never stabilize on them and die of AIDS; those who never take them properly and slowly deteriorate and those who never take them properly and still do fine; those who refuse them until it is too late, and those who never need them at all; those who leave AIDS far behind only to die from lung cancer or breast cancer or liver failure, and those few who are killed by the medications themselves…It is all too cold, too mathematical, too scary to dump on the head of a sick, frightened person. So we simplify. “We have good treatments now,” we say. “You should do fine.””

“Clinical research has shown beyond doubt that well-administered ARV [antiretroviral drug] treatment drastically cuts the mortality rate associated with AIDS. And yet, if all the people of Nomvalo [Transkei, South Africa] have to go by is the empirical evidence embodied in the health of their neighbours, they may not see this. The young women who all tested positive one Saturday in March [2006] may be years away from getting sick. The ones on ARVs, in contrast, have all been ill, are all at various stages on a slow and uneven path to recovery, and are probably more likely to fall ill in the next while than those in whom the virus is still latent”

“Health officials say they are trying to improve nutrition amongst AIDS patients [meaning that stories of dramatic improvements among people being prescribed antiretroviral drugs in third world countries may at least partly be due to improved nutrition]”

“Highly active antiretroviral therapy (HAART) started shortly after birth resulted in reversion of human immunodeficiency virus (HIV) plasma viremia, proviral DNA in PBMC, viral culture, and serum HIV antibodies to negative. Discontinuation of HAART 2 years after apparent HIV eradication, however, was followed by virus replication, CD4 decline, and destruction of HIV-specific lymphocytes, epitomizing the impossibility of HIV eradication.”

“We conducted a pilot study to assess the effect of atorvastatin [a statin believed to have anti-viral activity] on HIV replication…Paradoxically, baseline serum cholesterol, but not atorvastatin, influenced viral rebound at week 4.”

“Between September 2002 and February 2005, 758 individuals were referred for ART…Following referral to the ART service, the standard schedule of visits was as follows: screening visit (week 0), blood tests for plasma HIV load and blood CD4 lymphocyte count (week 2), treatment initiation (week 4) and treatment follow up (weeks 8, 12 and 20, and 16-weekly thereafter). At the screening visit, a treatment readiness evaluation was completed and a 4-week supply of co-trimoxazole was dispensed, with pill counts at 14 and 28 days to assess adherence.…68 (9.5%) patients died following enrolment into the programme, with an all-cause mortality rate of 12.1 deaths/100 person-years. The baseline pretreatment mortality rate (during the first 30 days of entry to the programme) was very high but the overall rate decreased markedly during follow up. 44 (65%) of the deaths occurred within the first 90 days from enrolment. Among those who received ART, the mortality rate during the first month of treatment was 2.03-fold lower than the baseline rate. The mortality rate continued to decrease during ART, and after 6–9 months the rate was 13.2-fold lower than the baseline rate. The survival probability among treated patients at 1 year was 0.929. Deaths among patients who did not start ART was very high and 31 patients died before they were able to start ART. [Note that the decision to not start AIDS drugs was not made randomly and could have been associated with much more severe illness. Deaths in the first month could have been associated with co-trimoxazole therapy and declining death rates could be associated with declining adherence]”

“The persistence of latently infected, resting CD4+ T cells is considered to be a major obstacle in preventing the eradication of HIV-1 even in patients who have received effective antiviral therapy for an average duration of 5 years…Here, we demonstrate the persistence of replication-competent virus in CD4+ T cells in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years that rendered them consistently aviremic throughout that time [i.e. the virus may be undetected in the serum, but it's present in the immune cells]”

“[Table 2 shows that the CD4 count in 20 Treated Patients was lowest (median 338) compared to Never Treated (’Naive’) patients (391) and STI (Structured Treated Interruption, i.e. probably not taking drugs right now but did in the past) Patients (717). Plasma HIV-RNA was highest in the untreated group (median 4.8) but only slightly lower in the treated group (4.4) and significantly lower in the STI group (3.2). HIV1-DNA (integrated into the nucleus of CD4 cells) was highest in the treated group (3.3) and lower in the untreated group (3.0) and STI group (2.9)]”

“the cumulative risk of acquiring an AIDS defining event does not increase if HAART is postponed until a CD4T lymphocyte cell count of 200 million/l is reached.”

“The majority of children [in a chart review at Tygerberg Academic Hospital, South Africa] were in stage B [mild symptoms, such as anemia, diarrhea, heart problems, hepatitis or persistent fever] at the beginning and end of the period of observation. Clinical progression from N [no symptoms] and A [mild symptoms] to B [moderate symptoms] and from B to C [AIDS] occurred within the follow-up period [despite the use of AIDS monotherapy and dual therapy and, rarely, HAART].”

“As the HAART era progressed the holes in the HAART armor because more apparent. Although patients were not having as many opportunistic infections, there was still a relatively high incidence of certain HIV associated malignancies…deaths related to end stage liver disease [almost certainly caused by the drugs] were more common than deaths from opportunistic infections…Hospitalizations for lactic acidosis, reconstitution syndromes [which are opportunistic infections occurring shortly after starting AIDS drugs] and late stage complications related to HAART were becoming more apparent. Some authors also noted an increase in mortality and hospital admission rate as the HAART era progressed.”

“the lives of some HIV-positive teens have not improved with HAART. Lightfoot and colleagues found that the post-HAART group was in worse health, more likely to have been sexually abused and to be clinically distressed than the pre-HAART group.”

“No trials exist which directly demonstrate the clinical benefit of regimens containing commonly used drugs such as efavirenz, abacavir and nelfinavir, because they have been licensed after changes in the drug approval process, which meant that evidence from trials with clinical endpoints was no longer required. Indeed, even for d4T, approved before 1997, there is no such clinical evidence. We therefore conducted an analysis to test the assumption which is implicitly made in both clinical and research settings, namely that the risk of a clinical AIDS event or death for a patient on CART [combination anti-retroviral therapy] with a given HIV RNA ['viral load'] and CD4 cell count is the same, regardless of which specific drugs are being used in the current regimen…Reassuringly, we found that rates of disease and death for a given latest (i.e. the most recent measurement) HIV RNA/CD4 cell count do not appear to differ between drugs for which there is some direct evidence of clinical efficacy (zidovudine, didanosine, lamivudine, indinavir, ritonavir, saquinavir), and those newer drugs which are currently widely used, for which there is no such evidence…It has been suggested that antiretroviral drugs might have adverse or perhaps even positive effects on risk of AIDS and/or death, which are not mediated by the effect of the drugs on HIV-RNA and CD4 cell count…However, our results suggest that for a given CD4 cell count, HIV-RNA and time from start of the drug (plus the other factors that we adjusted for in our model) the risk of AIDS or death is the same, regardless of the specific antiretroviral drug being used. It is important to note that these results do not suggest that the regimens assessed have equal clinical efficacy. Several published randomized clinical trials have shown that different regimens have different capacities to decrease the HIV-RNA and raise the CD4 cell count and this will lead to a difference in clinical efficacy for different drug regimens. Complete reliance on the ability of surrogate endpoints to evaluate treatment effect has led to adverse clinical outcome in other disease areas; one example being antiarrhythmia drugs. Therefore it is imperative to revisit and validate historical assumptions on a regular basis, especially in the case of new drug regimens. To be an ideal surrogate, two basic conditions should be satisfied, namely that the surrogate marker is a correlate of the clinical outcome being the only causal pathway of the disease process, and that the intervention’s entire effect on the clinical outcome is mediated through its effect on the surrogate…However, the above-mentioned references suggest that also in the field of HIV, it is necessary to validate surrogate markers against effect markers regularly to evaluate the true treatment effect of drugs and the predictive ability of surrogate markers on clinical progression. The relevance of these type of analyses is evident, knowing that complete reliance have been made on the virologic and immunologic markers to measure treatment effect of drugs released after 1997, even though the relative proportion of non-AIDS-related death has increased during the period of combination and highly active antiretroviral therapy, and treatment effects and regimens have changed dramatically since the release of these newer drugs”

“Whether treatment of acute HIV infection results in long-term virologic [decreased 'viral load'], immunologic [increased CD4 cell counts], or clinical benefit is unknown”

“"A 33-year-old man was diagnosed with HIV-1 infection after a suicide attempt. This infection was acquired through homosexual contact. 3 years later he started therapy with zidovudine, lamivudine, and saquinavir because of falling CD4-positive cell counts, but he opted to discontinue treatment after a few months. A year later, he developed skin nodules on his left thigh and was diagnosed with Kaposi’s sarcoma, an AIDS-defining illness. His CD4-positive cell count was 389 cells per µL. He refused treatment for both his HIV infection and skin lesions. After 5 years, the Kaposi’s sarcoma progressed to include most of the upper left leg in a circumferential manner, with large nodules and infiltrated plaques, and prominent lymphoedema. Antiretroviral treatment was resumed with lamivudine, zidovudine, and nevirapine. Despite declining and eventually undetectable viral load measurements (<50 copies per mL) and a CD4-positive cell count of around 700 cells per µL the skin tumours progressed. He received six cycles of chemotherapy with doxorubicin (15 mg/m2) and three cycles of the liposomal preparation (20 mg/m2), without benefit. Radiotherapy with 10 MV photons (total dose of 22 Gy in 11 fractions) resulted in moderate perianal and groin radiodermatitis and proctitis. Further treatment with thalidomide or paclitaxel is currently being considered."

Sanders CJ et al. Kaposi's sarcoma. Lancet. 2004 Oct 23; 364(9444): 1549–52.”

“To date, no reported study has compared the mortality rate in HIV-seropositive persons receiving HAART to that in HIV-seronegative persons who were in the same risk category (e.g., injection drug use). The purpose of such a comparison would be to demonstrate the degree to which survival rates in persons receiving HAART approximate uninfected populations with similar background mortality rates…[In this study] Survival of HIV-seropositive participants receiving HAART approximated that of HIV-seronegative participants only when therapy was given at CD4 cell counts >350 cells/microliter. These data, restricted to IDUs [injection drug users], suggest initiating or switching to HAART at higher CD4 cell levels than are currently recommended [or that HAART can be tolerated by the healthy, but not by the sick]”

“Logistic regression analysis showed that CD4+ cell percentage and viral load were independently associated with the risk of hospitalization, even after adjusting for HAART use, PCP prophylaxis, year, site, sex, and ethnicity. Linear regression showed that use of HAART, CD4+ cell percentage, year, and PCP [pneumocystis carinii pneumonia] prophylaxis were independently associated with viral load.”

“The primary end point was the proportion achieving an HIV RNA level of less than 400 copies/mL at week 48 [i.e. the trial did not show that health was improved]”

“A total of 426 HIV-related admissions [to an intensive care unit in Paris from January 1995 through June 1999] were included. Sepsis increased from 16.3% to 22.6% from the pre- to the post-HAART era, whereas AIDS-related admissions decreased from 57.7% to 37%. No significant difference in ICU utilization was found…In-ICU mortality was 23%, without significant difference between the study periods. By multivariate analysis…long-term survival [was significantly associated] with admission in the HAART era [but not actual usage of HAART] and AIDS at ICU admission.”

“the cumulative proportion of persistent undetectable HIV viral load below 500 copies/ml was significantly higher in the antiretroviral naive patients [those who had never taken AIDS drugs before] than in the non-naive ones…In multivariate analysis, being naive of antiretroviral treatment and having a low viral load, at the time of HAART introduction, were significantly correlated with a sustained undetectable HIV viral load.”

“28 patients (52%) received HAART at some time before admission to the ICU. Of the 25 patients who never received HAART, 15 patients (60%) fulfilled the criteria for receiving this treatment (CD4+ lymphocyte count <200 cells/microliter) or fulfilled the criteria for AIDS-defining illness. In comparison, in 1991 to 1992 only 22 patients had received any antiretroviral therapy, and 15 patients received anti-PCP treatment. There was no difference in the outcomes of patients receiving these medications and those who were not…[when conceiving this study] We speculated that the reduced incidence of progression to AIDS and opportunistic infections in the general population would be reflected in the reduced utilization of ICU services, that patients who were admitted to the ICU were likely either to not know their HIV serostatus or to not have used HAART, and that the reasons for ICU admission would be similar to those from earlier in the AIDS epidemic. In this analysis, all of these hypotheses were shown to be incorrect. In fact, intensive care utilization increased over the 10 years, all patients knew they were HIV seropositive, most had used HAART, and the types of disorders they developed and their outcomes were quite different than those seen earlier in the epidemic…We also found that two thirds of our ICU admissions were for non- AIDS–associated diagnoses. This reflects surveys indicating that these diagnoses (especially complications of hepatitis C) are now the most common causes of death in HIV-infected persons…As in other studies, we found that survival was not influenced by demographic characteristics or CD4 lymphocyte count. In addition, patients with non-AIDS–associated diagnoses were equally likely to survive. In contrast with the SFGH [San Francisco General Hospital] investigators, who found that patients receiving HAART had better ICU outcomes than those who did not, we found no survival advantage in patients using HAART. However, it was not possible to reliably assess adherence to treatment, so we cannot assess the impact of HAART on survival with certainty.”

“Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz.”

“there is currently no evidence from these studies to suggest that therapy during PHI [Primary HIV Infection – the flu-like illness and/or rash that is believed to occur shortly after HIV infection] results in a reduction in clinical progression compared with use of effective therapy in later disease, nor are there comparative data to suggest that short-term use of HAART during PHI can alter future disease progression. ”

“this IAPAC Monthly article considers the thousands who can and usually do get potent antiretrovirals but die anyway…A few examples: [1] At a major teaching hospital in Texas, Pneumocystis carinii pneumonia (PCP) accounted for an equivalent proportion of deaths before HAART in 1995 (21 of 112, or 19 percent) and well into the HAART era in 1999-2000 (15 of 88, or 17 percent, P = 0.76). [2] An analysis of 66 deaths in France’s Aquitaine cohort in 1998 and 1999 blamed 11 of them (17 percent) on treatment-induced toxicities. [3] In British Columbia, where access to antiretrovirals is universal and free, only pretreatment CD4 count and intermittent therapy predicted death in a study of 1,282 people beginning their first antiretrovirals between August 1996 and December 1999.”

“Compared with HAART-naive women, those using HAART had a [1.38 times] higher probability of more than three primary care visits per 6 months, a lower probability of more than one emergency room visit per 6 months, and a lower probability of more than one hospitalization per 6 months. Compared with HAART-naive women, women who had discontinued HAART had a higher frequency of primary care visits but did not demonstrate a significant change in emergency room or hospital use [note that because this was an observational study, there were significant socio-economic and lifestyle differences among the groups]. Non-HAART users who were HIV+ without AIDS were less likely to be employed, more likely to be black and had higher CD4 cell counts and lower viral load. There is no information on IV drug use or other health risk factors, no on how many of the emergency room visits were HIV/AIDS related, how many were health risk related (e.g. IV-drug related problems) and how many were for other reasons entirely (e.g. bone fractures)]”

“A significant decrease in CD4 and CD8 and in total lymphocyte counts was only seen in subjects receiving ddI standard dose + TDF[Tenofovir]-containing regimens, despite the maintenance of viral suppression. More than 50% of these patients showed a decline of more than 100 CD4 cells at 48 weeks.”

“Extending the model to include current antiretroviral status suggested that use of combination therapy [rather than no therapy or monotherapy] was associated with high [!] rates of disease progression (hazard ratios compared with treatment naive: 1.54 for AIDS, 1.14 for death), confirming the presence of treatment indication bias [i.e. sicker people are treated] [but, hold on, this data is also compatible with the therapy causing AIDS and death!]”

“For pre-treated patients [those who were taking anti-retroviral therapy for more than a year before the study] the risk of progression to AIDS was 1.91 times larger than for patients who had no or less than 1 year of previous treatment [and the risk of death was 2.18 times larger]…Non-HIV-related mortality was 2 to 3 times higher than in the general population. Part of this excess can be explained by the 7 proven and approximately 25 possibly-related causes of death”

“The incidence of OI [opportunistic infections (e.g. AIDS-defining conditions)] after the initiation of HAART in advanced AIDS patients with very low CD4 cell counts is high. Tuberculosis is the most common OI in an area with a high prevalence of tuberculosis”

“By contrast with the pre-HAART era, when most deaths were associated with recent AIDS-defining events, the situation has become more complex in the era of HAART. The current definition of AIDS is no longer a near-complete marker for overall progression. Infectious complications such as sepsis, pneumonia, or meningitis, and cancers such as Hodgkin’s disease are not included in the definition of AIDS. Unfortunately, these conditions and adverse events associated with antiretroviral therapy are not recorded in a standardised fashion. There is a need for complete and standardised information on all events that affect patients infected with HIV-1, and on causes of death, whether or not they are directly related to HIV-1 infection [or, presumably, to the therapy]”

“Baseline CD4 count was the strongest predictor of subsequent clinical progression [i.e. a woman’s immune status is more important than taking drugs]…By the end of the study, only 52% of the participants were on highly active antiretroviral therapy (HAART)…Despite underutilization of HAART in this multicenter cohort of urban women, opportunistic infections were uncommon, despite CD4 declines…As with changes in CD4, treatment effect was more pronounced for those with lower baseline CD4 counts. For those with baseline CD4 counts between 200-500 cells/cubic-mm, the OR associated with ART versus no therapy was 0.66, a 34% reduction in odds of progression; for HAART, the OR was 0.42, a 58% reduction [but the authors omit to quote the data (shown in Table 6 of the paper) for those with baseline CD4 over 500. This shows a 1.84 times greater risk of progression to AIDS with ART and a 1.58 times greater risk with HAART]…Women who were on ART at the start of this study had increased rates of disease progression, which may reflect confounding by indication; i.e., anti-HIV medication was prescribed because the women were ill [or perhaps the use of ART really did make the women sicker, not healthier]”

“Several patterns of response after initiation of highly active antiretroviral treatment (HAART) have been observed in persons with HIV infection. Apart from treatment success and failure a minority of patients will present a so-called ‘paradoxical response’, defined as a discrepancy between the plasma viral load (pVL) and the CD4 count. The first situation occurs in 7–15% of the patients. The CD4 count rises despite a persistently detectable pVL, which might be explained by the selection of mutant virus with decreased fitness compared with wild-type virus. Furthermore, protease inhibitors (PI) seem to inhibit lymphocyte apoptosis independently of their antiviral effect. The second type of paradoxical response is where the CD4 count does not rise despite a fully suppressed viral growth has been far less studied. This phenomenon seems to occur in 5–15% of the patients treated with HAART.”

“a minority of patients will present a so-called ‘paradoxical response’, defined as a discrepancy between the plasma viral load (pVL) and the CD4 count. The first situation occurs in 7–15% of the patients. The CD4 count rises despite a persistently detectable pVL…The second type of paradoxical response is where the CD4 count does not rise despite a fully suppressed viral growth…This phenomenon seems to occur in 5–15% of the patients treated with HAART…[In this study] A low CD4 count response [i.e. only a small increase in CD4 count numbers] was observed in 225 persons (29%).”

“The WHO [World Health Organization] and the [Durban] Declaration [a catechism signed by 5,000 scientists] report in 2000 34.3 million ‘living with HIV’, and the WHO reports 471,451 AIDS cases for 2000 (obtained by subtracting the WHO’s cumulative total of 1999 from that of 2000. Thus, even if we assume that all AIDS cases were fatal in 2000, the resulting global mortality rate of HIV-positives would only be 1.4% - and thus 4 to 6 times lower than the 6.7%-8.8% mortality rate of HIV-positives treated with anti-HIV drugs in the US and Canada. Therefore the claims that anti-HIV drugs reduce the mortality of, and delay progression to AIDS are at odds with the AIDS facts reported by the Durban Declaration and the WHO.”

“Although the feasibility of prophylaxis [AIDS drugs] after non-occupational exposure to HIV has been demonstrated, there are no data measuring the efficacy or effectiveness of PEP in the nonoccupational setting, although this therapy is being offered in various communities…the cost of prophylaxis after nonoccupational exposures is high, and adverse effects are relatively common and can rarely be fatal.”

“During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI [body mass index], CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change [but, these last two measurements should have improved if the therapy was being effective].”

“After 1997, six (18.2%) patients died of liver failure. Two died of antiretroviral drug hepatotoxity, one of whom was coinfected with HCV [Hepatitis C Virus]. Four patients died due to a complication of cirrhosis…The frequency of deaths due to liver failure increased significantly after 1997. The frequency of other causes of death [i.e. not AIDS or liver failure] decreased after January 1997 [this means that the benefits of antiretroviral therapy do not explain all the reduction of mortality. In fact, some of the 'AIDS' death reduction may also be due to other causes, such as the trend since 1993 to diagnose healthy people with AIDS. Healthier people will obviously tolerate antiretroviral therapy longer, and naturally the risk of them dying from AIDS would be lower, even if antiretroviral drugs were completely ineffective.]”

“From April 1996 through December 2000, a total of 501 antiretroviral-naive [never taken AIDS drugs] HIV-seropositive patients who initiated HAART were recruited…at the Hospital Ramón y Cajal [Madrid, Spain]…After 24 months of follow-up, 42 (16.5%) of 255 patients were considered to have a discordant immune response [low CD4 cell counts with low viral load or high CD4 cell counts with high viral load]…Clinical progression of HIV disease was uncommon among the patients included in the analysis. Overall, 4 patients (1.6%) died of HIV infection-related complications, and 44 patients (17.3%) developed HIV infection-related clinical events…Most events (29 [65%] of 44 events) occurred within the first year after initiation of HAART. Overall, clinical events were not more frequent among patients with a discordant immune response than among patients with a good immunologic response.”

“those who initiate treatment at a later stage had an unmeasured survival benefit before HAART was started [i.e. it could be that the longer you wait before starting HAART the better, implying that if you never start, you would live the longest]…Of the 25 deaths in women without AIDS at HAART initiation, 14 (56.0%) were unrelated to AIDS [in this group with high recreational drug use, quite possibly illicit- or AIDS-drug related]…A history of no exposure to antiretroviral treatment before HAART initiation was not significantly associated

with death in the women who were AIDS free (RH, 0.78)…at HAART initiation. [actually, this means that women were only 78% as likely to die if they had never taken any antiretroviral drugs before starting HAART]”

“[The objective of this study was to] determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999…89 cases of lymphoma were identified. 72 cases (81%) occurred in HIV-positive patients (67 NHL, 5 HD), and 17 cases (19%) in HIV-negative patients (9 NHL, 8 HD). The incidence of NHL in the HIV-positive cohort was significantly increased [by a factor of 84 over the general population] in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART) [the authors do not consider the possibility that nucleoside analogs are the cause, and that HAART merely reduced the amount of these drugs and their side effects, in favour of more Protease Inhibitors and their different side effects, such as lipodystrophy, heart disease etc.]”

“The proportion of patients who have died following an AIDS diagnosis has declined from 93% in the first period [1994-5] to 73% in the last period [1998-2001]…by the last period, 93% of patients who died had used 3 or more antiretroviral drugs…[among non-HIV related deaths there was] an increase in the proportion of deaths due to liver related problems (hepatitis, liver cancer and liver failure) [almost certainly due to AIDS drugs]. This increased from 12 (19%) of the other causes in 1994 to 16 (25%) in 2000/2001…In recent years the most common other causes of death were complications to hepatitis and myocardial infarctions [haart attacks], these groups contained 11 (17%) and 7 (11%) of the 65 subjects who died from other causes since January 2000.”

“We report a patient in whom HAART made TB treatment very difficult, and discuss whether…it would be wiser to treat TB first and defer HAART…The paradoxical worsening of TB is not a new entity, but since the introduction of HAART it has turned into a common clinical problem…As a general rule there is a closer temporal relationship with the beginning of HAART than with the beginning of TB treatment…In our patient the diagnosis of the paradoxical worsening of TB was clear. HAART was started twice, and both times a paradoxical worsening of TB could only be controlled by the discontinuation of HAART…We think that HAART poses many more problems than it can resolve for TB patients. Clinicians are aware of this, and in spite of the guidelines, they seldom begin both treatments simultaneously.”

“We found (see Table 3 and Fig. 2) that interruptions of HAART did not significantly increase the risk of HIV-associated morbidity and mortality, except for a statistically marginally increased risk for a CDC stage C event after the first interruption.”

“We found that in vitro treatment of PBMC [peripheral blood mononuclear cells] from healthy donors with either IDV [Protease inhibitor Indinavir] or SQV [Protease inhibitor Saquinavir] is associated with a loss in mitochondrial membrane potential. However, the mechanisms by which SQV and IDV induced mitochondrial damage remain to be clarified. We also noted that in vitro treatment of healthy donor PBMC with the combination of IDV (5 mcM; cell death, 15.7%) and SQV (5 mcM; cell death, 13.9%) is additive and induced cell death in 36.8% of the cells, which was similar to that observed with 10 mcM drugs used individually. Thus, the concentrations used in vitro to assess toxicity in this study reflect pharmacologic concentrations [in other words, at realistic concentrations, protease inhibitors can kill the cells that HIV supposedly targets]”

“HIV-1 DNA [HIV ‘integrated’ into cell nuclei] in peripheral blood mononuclear cells (PBMC) was quantified in 31 children who received efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors for 2 years and in whom undetectable plasma HIV-1 RNA [believed to be the genetic material found in HIV particles outside cells] levels (<50 copies/mL) were sustained…despite prolonged maintenance of undetectable levels of plasma HIV-1 RNA, HIV-1 DNA remains detectable in PBMC of children”

“a subset of non-T cells with NK [Natural Killer] markers are persistently infected [even after 1-2 years of HAART]”

“where highly active antiretroviral therapy is available its combination with the treatment of active tuberculosis is difficult for several reasons: overlapping toxicity profiles of some antituberculosis and antiretroviral drugs, drug interactions, and non-adherence to complicated [as well as painful and debilitating, if not fatal] treatment regimens. An important problem is the possibility of paradoxical reactions. Such reactions include the transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis within days to weeks after starting antiretroviral treatment. These reactions may be particularly severe when highly active antiretroviral therapy is started soon after the start of treatment for active tuberculosis. The explanation for these reactions is probably the restoration of the immunity towards mycobacterial antigens [in other words, we only get sick because we have an immune system]. Even in patients with low CD4+ lymphocyte counts, it is recommended to delay highly active antiretroviral therapy until the first two months of treatment for tuberculosis have been completed.”

“These results indicate that HAART has little effect on ASIL [Anal Squamous Intraepithelial Lesions] or HPV [Human Papillomavirus] in the first 6 months after HAART initiation”

“Conclusions: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease [but, is this strong conclusion warranted?]…The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus non-leukoreduced red blood cell transfusion in HIV-infected patients [note that this was not a trial of HAART versus placebo] who required a first transfusion for anemia [quite possibly due as a side effect of prior use of AZT and similar agents]…patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively [i.e. the study was turned into a HAART versus non-HAART study after the fact, and the actual use of HAART drugs was not monitored]…The proportion of patients receiving HAART changed significantly over the course of VATS…In January 1996, only 1% of 83 active patients were taking HAART. This proportion increased to 52% on 1 January 1997, 69% on 1 January 1998, and 79% on 1 January 1999. At the time of enrollment, 31% of patients were taking no antiretroviral medication, 44% were taking antiretroviral medication other than HAART, and 24% were taking HAART. Most of the HAART regimens contained an HIV protease inhibitor…There were 110 deaths during 466.2 post-HAART person-years (mortality rate, 0.24 case/person-year) and 179 deaths during 202.4 pre-HAART person-years (mortality rate, 0.88 case/person-year), for a crude mortality rate ratio of 0.26 [0.30 after adjustments]”

“The drugs are imperfect: Experts say they only extend life, on average, 1.8 years for people with AIDS, and have many severe side effects. Some people live longer, others shorter, on the drugs. About 10 percent of AIDS deaths now are due to protease inhibitor-induced heart disease...Half the people who try the medications do not respond to them and the side effects, such increased cholesterol levels and diabetes, may be so severe that the risk of taking the drug outweighs their benefits.”

“in 28 patients treated for up to 2-1/2 years with indinavir, zidovudine [AZT], and lamivudine...HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF [cerebrospinal fluid] samples after 2 years of treatment”

“Of some concern, however, is the observation that despite increased pharmaceutical usage, the total mortality has not decreased since the first quarter of FY1997. Furthermore, we found an upward tendency of per-patient costs over the last 12 months of this study...The virological failure of up to 60% of treatment-experienced patients and the increased recognition of the toxicities of antiretroviral therapy suggests that substantial additional medical costs may eventually accrue in the care of these patients”

“One of the first studies to look at the success of HIV treatment in inner-city patients from the time of diagnosis reveals a dire situation, a doctor working in Atlanta, Georgia, said here on Tuesday at the 8th Conference on Retroviruses and Opportunistic Infections. His study found that only 1 in 10 patients newly diagnosed with HIV achieved a reduction in virus in blood to ''undetectable'' levels--a major goal of treatment...One year after being diagnosed, 24 patients (18%) had died, del Rio reported. Of the 103 eligible to attend an outpatient clinic, the majority discontinued treatment after a few months. Only 55 patients (53%) ever went to the outpatient clinic and 40% of these dropped out within 1 year. Of the 55 patients seen at the outpatient clinic, 30 were prescribed antiretroviral therapy. One year from diagnosis, only 23 were still on therapy and 12 (of the original 135 patients) had undetectable levels of virus in their blood.”

“Five patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more...Virus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined.”

“When it came time to write up the data [on the AIDS 'therapeutic vaccine' called Remune] for publication, Kahn, Lagakos, and others on the team concurred that the analyses showed no benefit from the drug. But scientists from Immune Response performed their own analysis of blood tests on a sample of 250 patients in whom, the company argued, some benefit could be seen - not in longer survival, but in having lower levels of virus ['viral load'] in their blood…[Lead researcher] Lagakos said: ''The company did not want our original analysis to go forward. We were put in a position where we had to agree to terms that were unacceptable to us. We decided to go forward with what we had.''”

“ZERIT [d4T/Stavudine] will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking ZERIT, you may continue to have HIV-related illnesses, including infections caused by other disease-producing organisms. [from the FDA-approved patient information sheet]…Lactic acidosis and severe liver enlargement, including deaths, have been reported among patients taking ZERIT…If you develop peripheral neuropathy [burning sensations in the skin], your doctor may tell you to stop taking ZERIT…Pancreatitis is a dangerous inflammation of the pancreas. It may cause death…neuropathy, the most frequent side effects observed in studies of adults taking the recommended dose of ZERIT were headache, diarrhea, rash, and nausea and vomiting. Other side effects [apart from the above] may include abdominal pain, muscle pain, insomnia, loss of appetite, chills or fever, allergic reactions, and blood disorders.”

“Clinicians are now realizing that the existing therapies are no longer long-term therapies, they start to give out sometimes within two years. In addition, the drugs are having severe side effects, including osteoporosis and cardiac problems.”

“All AIDS diagnoses from 1992-1998 notified to the Victorian State [Australia] AIDS Registry were included. Subjects were grouped as individuals diagnosed with AIDS within 8 weeks of a first positive HIV test (late presenters), or individuals for whom there was more than 8 weeks between AIDS diagnosis and first positive HIV test (non-late presenters) [this group is more likely to have taken anti-HIV drugs]. Of 1021 AIDS diagnoses notified, 24% were late presenters...Late presenters survived longer following AIDS diagnosis.”

“There's no hope for a cure for AIDS with current drugs, the head of the National Institute of Allergy and Infectious Diseases (NIAID) said at the 13th International AIDS Conference. ''Eradication is not possible,'' Anthony Fauci said.”

“If therapy is started too early, cumulative side-effects of the drugs used and the development of multidrug resistance may outweigh the net benefits of the lengthening of life. If therapy is started too late, increases in disease progression and mortality outweigh the risk of adverse events.”

“This study provides evidence that triple-drug antiretroviral therapy (IDV [protease inhibitor Indinavir] plus 3TC [nucleoside analog] plus ZDV [Zidovudine, another nucleoside analog]) fails to produce a sustained increase in anti-HIV-1 CD8+ T-cell functions in HIV-1-infected patients with advanced immunodeficiency”

“our data demonstrated that...HIV PIs [protease inhibitors], which are major components of HAART regimens, can be partially inhibitory on Pneumocystis carinii [cause of PCP, a type of serious pneumonia and one of the first diseases defined as ‘AIDS’], at clinically achievable drug concentrations [meaning that the short-term benefits derived from these drugs in some cases may be due to this, and not anti-HIV activity at all]”

“Amanda Mocroft (Royal Free Centre for HIV Medicine, London, UK) reported that rates of treatment failure in the EuroSIDA cohort were 50%, 70%, and 80% after first, second, and third courses, respectively. Results from several trials confirmed the poor response (about 30%) to salvage regimens in patients who had already taken a protease inhibitor. Previous use of non-nucleoside reverse-transcriptase inhibitors lowered the response rate further (to about 15%)...Over the past year, the development of several promising drugs has been put on hold or stopped because of toxicity, unfavourable pharmacokinetics, and inadequate potency”

“current potent regimens do not completely inhibit HIV replication in most patients...resistance develops during ongoing HIV replication in the presence of anti-HIV drugs...in most patients...Although it may seem reasonable to believe that use of potent therapy could delay or prevent the evolution of more virulent strains of the virus, few data support that argument...cure with current potent therapy may be possible after 10 years of therapy, 60 to 115 years of therapy, or never [depending on the research cited]...it is safe to conclude that a cure is extremely unlikely with the current approach to treatment...There is growing concern about the long-term toxicity and adverse effects of therapy, including liver damage and mitochondrial toxicity caused by nucleosides, the most studied anti-HIV drugs. After drugs are approved, fewer organized efforts are made to monitor them for long-term toxicities...the quest for HIV treatment is fueled by the expensive, technologically oriented approach used in wealthy countries. Current research is not directed toward simple long-term survival...The fastest-growing treatment category in my clinic [Regions Hospital, Minnesota] is no treatment or delayed treatment.”

“The existence of a reservoir of resting CD4+ T cells harboring latent replication-competent HIV has been demonstrated in patients on prolonged highly active antiretroviral therapy (HAART). Latently infected tissue macrophages may constitute a second HIV reservoir...These results demonstrate the long-term persistence of infectious virus in cells of the monocyte-macrophage lineage in patients receiving HAART.”

“Our results show that immune responses are potent in antiretroviral-naive [i.e. not taking antiretroviral therapy] but significantly reduced in HAART-treated patients with undetectable viraemia (< 500 copies/ml)...T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals...because of the side effects associated with HAART and of the known compliance problems of the therapeutic regimens, initiation of therapy might be delayed in those cases where a powerful immune response is detected.”

“These data suggest that a large pool of infectious virus is established soon after infection [as early as 2-4 days] and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network...The FDC pool of virus is established by the time symptoms associated with primary HIV infection are recognized, based on these data. We observed 7-8 log10 copies of HIV-1 RNA/g of LT sampled within a few days of symptom onset [mostly mild symptoms and, in 6 patients, no symptoms were observed, so HIV antibodies were declared to by a ‘symptom’], similar to levels associated with late-stage disease. The fact that this tissue was both axillary and from patients with rectal exposure illustrates the speed at which systemic dissemination occurs after mucosal transmission...This finding was a surprise to us, because it has been reported that accumulation of virus into this pool is gradual...Collectively, these findings on the early accumulation of virus into the FDC pool make it unlikely that antiretroviral therapy initiated as soon as symptoms are recognized will necessarily prevent deposition of large enough quantities of virus in the FDC pool or the FDC network.”

“This study shows that virologic failure [rises in ‘viral load’] during the Trilege trial maintenance phase was not associated with key zidovudine or indinavir resistance mutations. No such mutations were found at viral rebound or baseline, consistent with the patients’ antiretroviral naive status.”

“HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression.”

“Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy.”

“"This virus is a really smart actor," said Dr. Ann Collier, director of the AIDS Clinical Trial Unit at Harborview's Madison Clinic. Collier said about one-third of patients are resistant to the drugs within six months of starting treatment, and the proportion increases over time. Patients are often switched to new combinations of drugs, but their conditions often gradually deteriorate, she said.”

“in a cohort of patients with undetectable viral RNA for between 5 months and several years while taking HAART and with fewer than 50 copies/mL of viral RNA in peripheral blood plasma at the time of these analyses, all subjects had low but detectable levels of HIV-1 RNA in blood plasma. This was surprising in that these data demonstrated that viral expression could not only be shown by viral replication in selected cell types within patients taking suppressive HAART but by actual virion production within blood plasma...Our study...demonstrates that some cell-free virion production may be quite common in patients taking suppressive HAART [although it is not clear how viruses can possibly replicate outside a cell]”

“The current study demonstrates that, in a cohort of patients with undetectable viral RNA for between 5 months and several years while taking HAART and with fewer than 50 copies/mL of viral RNA in peripheral blood plasma at the time of the analyses, all subjects had low but detectable levels of HIV-1 RNA in blood plasma.”

“A dormant reservoir of HIV is established early on during primary infection which consists of latently infected, resting CD4+ T cells carrying replication competent HIV. This pool can persist even in individuals who are receiving HAART. Here we show that this pool rapidly re-emerges within weeks of discontinuing HAART in two patients”

“A dormant reservoir of HIV is established early on during primary infection…This pool can persist even in individuals who are receiving highly active antiretroviral therapy (HAART). Here we show that this pool rapidly re-emerges within weeks of discontinuing HAART in two patients, and that this re-emergence is associated with the appearance of HIV in the plasma (viraemia) of thse patients.”

“our data demonstrate that indinavir and ritonavir [both protease inhibitors (PI)], two major components of HAART regimens, have direct anticandidal effects in vitro and in vivo...Thus, we are tempted to speculate that this novel effect of PI on Candida virulence might concur with and possibly also favor immunoreconstitution in explaining the unprecedented beneficial activity of HAART on candidiasis in persons with AIDS [i.e. these drugs may have beneficial effects due to their activity on this fungal infection, and not from their activity against HIV]”

“All treated PHI [Primary HIV Infection] subjects had detectable HIV-1 DNA in peripheral blood at week 52. No significant difference in the number of copies per microgram PBMC [peripheral blood mononuclear cell] DNA was observed between treated and untreated PHI patients at baseline or at weeks 8, 24, or 52”

“the proportion of patients who experience virologic suppression during HAART in the clinic setting was substantially lower than that in clinical trials...only 23% experienced viral suppression in all three time periods”

“According to the study, [published in 7/20/99 Annals of Internal Medicine] 37 percent of the Johns Hopkins patients getting the cocktail treatment had undetectable HIV levels one year after starting therapy. Only 23 percent suppressed the virus in all three time periods studied - 1-90 days, 3-7 months and 7-14 months. Clinical trials using similar drugs show suppression rates twice as high as those numbers.”

“our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir”

“As the ADARC group suggested, immediate attention should focus on the reasons why three- and four-drug potent anti-retroviral therapy does not completely suppress virus replication. Based on their data, it is unlikely that anatomical sanctuaries are protecting cells from drugs; instead, the positive cells seem to be readily circulating through the body, as suggested by the presence of many of the HIV-expressing cells in lymphoid sinuses.”

“the ultimate therapeutic goal of virus eradication does not seem to be achievable in a period of time compatible with the management of problems such as complexity, toxicity and costs.”

“The researchers concluded that, while combination antiretroviral therapies effectively suppress HIV-1 replication in some patients, the benefit to others may not be as great. Considering the half-life of latently infected CD4 lymphocytes, researchers conclude that efficacious antiretroviral therapy may take years to eliminate such sources of HIV-1...The continued replication of HIV-1 in two patients seems to be due to the presence of drug-sensitive viruses within lymphoid tissues. We are unable, however, to explain why drug-sensitive HIV-1 is capable of replicating at low levels during treatment with three or four drugs. But it is essential to the therapeutic effort that the answer, be it pharmacokinetic or cellular in nature, be obtained promptly.”

“Potent antiretroviral therapy seems unable to eradicate latent HIV-1 reservoirs in CD4+ T cells.”

“The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status.”

“The efficacy of HIV chemoprophylaxis [AIDS drugs] following consensual or nonconsensual sexual exposure [rape] is unknown.”

“Antiretroviral therapy may be initiated early during antituberculosis therapy in HIV-infected patients with tuberculosis. After initial clinical improvement, paradoxical worsening of disease developed in up to 36% of these patients, characterized by fever, worsening chest infiltrates on radiograph, and peripheral and mediastinal lymphadenopathy...In contrast, only 7% of patients who received antituberculosis therapy but not antiretroviral therapy had paradoxical reactions.”

“As the evanescent blush of success with so-called highly active antiretroviral therapy (HAART) regimens begins to recede into the darkness, we have increasingly come to appreciate the importance of the host immune response. As with pharmacotherapy of other infectious diseases, the drugs are not very effective without substantial help from the immune system. [note that AZT, by damaging or destroying bone marrow, damages the immune system]”

“In 3 of the 5 patients, the percentage of productively infected cells increased while on therapy”

“The main kinetic difference in the HAART [ritonavir/saquinavir plus one or more nucleoside analogs] group was therefore higher production rates of circulating T cells and shorter (not longer) half lives…This analysis confirms that the rate of removal of CD4+ T cells is indeed elevated and the half-life is indeed shortened in the HAART group”

“We collected peripheral-blood and semen samples from 7 men with HIV-1 infections who were receiving highly active antiretroviral therapy [HAART] and who had no detectable viral RNA (fewer than 50 copies per milliliter) in plasma and analyzed the samples for cell-associated proviral DNA…Despite the long-term suppression of HIV-1 RNA in the plasma of the 7 men, proviral DNA was detected in seminal cells in 4. Replication-competent viruses were recovered from peripheral-blood cells in 3 men and from the seminal cells in 2 of these 3 men.”

“Disease progressed faster in participants who sought medical care for their acute seroconversion syndrome (P=0.01)”

“The antiviral effect ot adding interferon-alpha was initially more pronounced with teh 6-mIU interferon combination group. However, this effect was lost by 24 weeks of therapy, such that the 1-mIU interferon combination group and the nucleoside combination group experienced a more durable suppression of plasma HIV-1 RNA. The lack of any durable antiviral response for the higher dose of interferon-alpha may be related to the higher toxicity rate in the 6-mIU interferon combination group…No increased in CD4 cell conts were noted with the addition of either dose of interferon-alpha [there was no control group in this study]”

“our analysis shows that San Francisco would have experienced a significant decline in AIDS cases, due to the decrease in HIV seroconversions, even if combination antiretroviral therapy had not been developed...the treatment [AZT] benefit is temporary and confers no long-term survival advantage”

“The proportion of patients whose disease progressed to AIDS or death was lower with indinavir [the first protease inhibitor], zidovudine [AZT] (or stavudine), and lamivudine [3TC, another nucleoside analog] (6%) than with zidovudine (or stavudine) and lamivudine alone (11%). Mortality in the two groups was 1.4% and 3.1%, respectively…The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results…Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine [but there is no information on whether doing nothing, or choosing alternative or nutritional therapies, might not have been even better for these people]…In all, there were 91 AIDS-defining events (including multiple events per patient). Sixty of these occurred among the patients assigned to receive [only nucleoside analogs], as compared with 31 among the patients assigned to [also receive indinavir]. The most common events were infections with P. carinii, cytomegalovirus, and Mycobacterium avium complex (constituting 25 percent, 20 percent, and 16 percent of events, respectively)…The proportion of patients with signs and symptoms that were severe (grade 3) or worse (grade 4) in the group receiving [only nucleoside analogs] was 18%, as compared with 21% in the group [also] receiving indinavir. The most common symptoms were nonspecific discomfort, malaise, fever, headache, and nausea and vomiting, with no difference in the reporting of symptoms between treatment groups. The proportion of patients with severe laboratory abnormalities or worse in the group receiving [only nucleoside analogs] was 26%, as compared with 21% in the group [also] receiving indinavir. This difference primarily reflected a difference between the groups in the incidence of neutropenia [deficiency in neutrophils, a type of infection-fighting white blood cell] (15% and 5%, respectively). In contrast, the proportion of patients with hyperbilirubinemia [a sign of liver, biliary tract or blood disorders] was 1% in the two-nucleoside group, as compared with 6% in the group treated with indinavir, a finding compatible with the known elevation of indirect bilirubin associated with the use of indinavir. 2% of the patients in each treatment group had hyperglycemia [high blood sugar]. Five patients receiving zidovudine (or stavudine) and lamivudine (1%) had episodes of renal colic or nephrolithiasis (irrespective of grade), as compared with 21 patients receiving indinavir, zidovudine (or stavudine), and lamivudine (4%)…Five new diagnoses of diabetes mellitus were recorded; two in the two-nucleoside group and three in the group treated with indinavir [This early protease inhibitor study shows that the metabolic disorders that characterize treatment with protease inhibitors were known early in the use of these drugs]”

“Why Treatment Should be as Early as Possible and as Hard as Possible. The outcome of therapy should depend on the virus population size before treatment. The lower the virus load, the smaller the probability that resistant virus is present. Consequently, treatment will be more succesful in patients with lower virus load. Therefore treatment should start early in infection as long as virus load is still low [the fact that this philosophy is now out of fashion calls into question the models of rapid viral replication without clinical consequences, for some period of time]”

“Decreases in concentrations of and detection of seminal HIV in men taking zidovudine or newer antiretroviral drugs have been observed in some [2 referenced], but not all studies [4 referenced]. Antiretroviral therapy apparently does not affect the detection of HIV in cervicovaginal specimens”

“The median prolongation of survival associated with changing therapy was, at best, 3 to 6 months...Mortality within [3.5-4.9 years, depending on starting CD4 cell counts] was 100%, regardless of treatment group or landmark...Overall long-term survival [in a study comparing AZT monotherapy with various combination therapies] was grim, even among patients who changed therapy; this finding indicates the continued need for newer, more active antiretroviral regimens. The small effect of changing ther”

“The survival of patients in group B [symptomatic at time of HIV diagnosis] after the onset of AIDS was significantly longer than that of patients in group A [asymptomatic at the time of diagnosis] as determined by Kaplan-Meier log rank analysis (P = 0.0026) [i.e. does exposure to antiviral therapy earlier make AIDS worse?]”

“Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days”

“a 77-year-old woman [received a femoral head bone from an HIV-positive donor] during a knee-replacement procedure in December 1985. She…tested positive for HIV-1 antibody in 1987. Her CD4+ count was 0.316 billion cells per liter in September 1989, after which she was treated intermittently with zidovudine and didanosine. In December 1990, her CD4+ count was 0.024 billion cells per liter [more than 10 times lower after taking drugs supposed to kill the virus that kills the CD4 cells!], and oropharyngeal candidiasis developed. The patient died in August 1991 of aspiration pneumonia.”

“Lexiva–a protease inhbitor (PI) fit for combination therapy…does not cure HIV or prevent passing HIV to others”

“ART [anti-retroviral therapy] initiation, by decreasing immune activation and increasing CD4 cell count, may result in development of oedema. Second, onset of kwashiorkor soon after starting ART may be an example of the immune reconstitution inflammatory syndrome (IRIS). The timing of onset and picture of clinical worsening in children with profound immunosuppression and malnutrition at ART initiation are all very reminiscent of IRIS. Although it most frequently presents as unmasking or worsening of a pre-existing infection, protean manifestations of IRIS have been reported, including autoimmune, inflammatory and malignant disease”

“We have previously described in detail the ART service in Gugulethu township in Cape Town where both HIV prevalence and the TB notification rate are high [1,18,19]. The national ART programme provided treatment for those with World Health Organization (WHO) stage 4 disease or a blood CD4 cell count more than 200 cells/µl. The extraordinarily high burden of TB diagnosed during routine clinical practice in this service has been previously reported [i.e. a lot of TB is being diagnosed AFTER initiation of HAART, which is supposed to restore the immune system and prevent things like this]…One or more symptoms of cough for at least 2 weeks, night sweats, fever, or significant recent weight loss were reported by 46 (79%) of TB patients and 109 (62%) of patients who were TB-free. Reporting of chest radiographs for any abnormality consistent with TB had a sensitivity of 71% and a specificity of 48%. A combination of a positive symptom screen and abnormal chest radiograph had a sensitivity of 64% and specificity of just 39%…We ascertained deaths and TB immune reconstitution disease events from enrolment up to 16 weeks of ART…[the death rate, according to Table 2, among 58 patients with TB under treatment at the time of HAART initiation was 9 (16%)]”

“A recent randomized controlled trial, AIDS Clinical Trial Group (ACTG) 5164, showed that HIV-infected patients newly diagnosed with opportunistic infections benefited from starting antiretroviral therapy (ART) within 2 weeks of presentation when compared with more than 8 weeks after presentation, finding no significant differences in rates of immune reconstitution inflammatory syndrome (IRIS) between groups. In an 8-week span following these study results, three HIV-infected patients were admitted to San Francisco General Hospital, diagnosed with Pneumocystis pneumonia (PCP), and started on early ART. These patients subsequently developed life-threatening IRIS due to PCP, illustrating the significant risk that may arise from early initiation of ART in patients with PCP.”

“An HIV-1 antibody positive, 25-year-old female patient initiated ART in April 2007 under the care of a South African outpatient HIV clinic. After 3 months of ART, she reported cough, haemoptysis [coughing up blood], vomiting, diarrhoea and abdominal pain, and subsequently ceased to pass stools for over a week…The patient responded clinically to oral fluconazole and anti-emetic medication, and was discharged from the hospital. The initial symptoms recurred 2 weeks after discharge; this time the presentation was dominated by vomiting, with diarrhoea being less prominent. Despite aggressive correction of fluid and electrolyte disturbance and attempts to identify a cause, the patient died. Corticosteroids had not been given at any time and ART had been given uninterrupted for 5 months.”

“Immune reconstitution inflammatory syndrome (IRIS) after HAART may become manifest in form of aseptic severe leucoencephalopathy. All HIV-1-positive patients in this case series had widespread laboratory tests and follow-up MRI in order to investigate the course and the underlying pathophysiology of IRIS-associated leucoencephalopathy. All patients were treated with corticosteroids, in spite of additional immunosuppression. Three patients were successfully treated with corticosteroids and survived up to now, one died. A neuropathological examination was performed showing massive aseptic intraparenchymal and perivascular invasion of cytotoxic CD8 cells. It is assumed that IRIS-associated leucoencephalopathy is based on other preconditions in Africans and Caucasians.”

“Overall, 34/162 (21%) children developed IRIS at a median of 16 days post-HAART initiation. Bacille Calmette-Guérin reaction was most common occurring in 24/34 (71%) children, primarily injection site lesions and/or ipsilateral axillary lymphadenitis with abscess. Other IRIS conditions (not mutually exclusive) included Mycobacterium tuberculosis (12), cytomegalovirus pneumonia (1), Streptococcus pneumonia sepsis (1), and severe seborrheic dermatitis (1)”

“The present study describes 10 cases of IRIS[immune reconstitution inflammatory syndrome]-associated reversal reaction in a cohort with 28 coinfected HAART patients diagnosed with leprosy from 1996 to 2007 at the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil…Significantly, HAART induced reaction in seven patients who had not been diagnosed with leprosy. The mean time the patients presented [with a] reversal reaction after starting HAART was 7.8 weeks”

“Graves’ is an autoimmune disease in which antithyrotropin receptor antibodies are produced resulting in hyperthyroidism. Clinical manifestations of hyperthyroidism include fatigue, weight loss, tachycardia [rapid heart beat], tremor, hyperreflexia, heat intolerance, sweating, irritability and lid retraction…An 11-year-old African–American male was diagnosed at the age of 9 years with perinatally transmitted HIV…At 11 years of age, he presented with a 4-day history of fever, cough, congestion and heart palpitations and parent-reported weight loss that had occurred over a few weeks. At presentation, physical examination and chest radiograph findings were consistent with right upper lobe pneumonia, and it was believed his symptoms were due to this. The patient was treated with a 10-day course of oral antibiotics. At follow-up, he had resolution of cough and fever; however, weight loss and rapid heartbeat persisted. In addition, on review of symptoms, he reported sweating, feeling hot all the time, increased appetite and some fatigue. On physical examination, elevated heart rate (152 beats per minute), weight loss (2.5 kg over 2 months) and goitre [enlarged thyroid] were documented. No ophthalmologic abnormalities or family history of thyroid disease was found…Graves’ disease in HIV-infected adults is increasingly recognized as a late manifestation of IRIS [immune reconstitution inflammatory syndrome]. The prevalence of Graves’ in the United Kingdom in HIV-infected adults is 2.4% in women and 0.2% in men. The prevalence of Graves’ in HIV-infected children is unknown. Our patient developed clinical manifestations of Graves’ disease 30 months after starting antiretroviral therapy”

“IRIS is defined as a paradoxical [for doctors who cannot believe the drugs they believe have side effects] clinical worsening due to a subclinical opportunistic pathogen (‘unmasking’ IRIS) or previously known treated (completed or ongoing) opportunistic pathogen (‘paradoxical’ IRIS) in the setting of an adequate response to ART [anti-retroviral therapy]. For the ‘unmasking’ form of IRIS, a new localized infection was required [to be detected]…in a patient who, prior to ART, exhibited no signs or symptoms of disease and in whom adequate OI [opportunistic infection] screening and clinical assessment had been performed…For the ‘paradoxical’ form of IRIS, a patient required the diagnosis and treatment initiation of an OI prior to ART initiation with a positive clinical response. Following ART, the patient experienced a new inflammatory process [return or worsening of disease]…Between 6 January 2006 and 7 July 2007, 546 patients initiated ART at the Johannesburg Hospital adult HIV clinic…423 patients [were deemed] eligible for the [study, and] contributed 180.8 person-years of follow-up during the study period, with a median of 182 days…Among the 423 cohort patients initiated on ART, there were 44 cases of IRIS…22 were confirmed cases, 21 were probable and one was a suspect IRIS case…Of the 44 cases, infectious etiologies included TB (18/44, 41%), cryptococcal meningitis (3/44, 6.8%), herpes simplex infection (4/44, 9.1%), varicella zoster infection (6/44, 13.6%), molluscum contagiosum (3/44, 6.8%), and Kaposi’s sarcoma (2/44, 4.5%). Dermatological manifestations including abscess formation and suppurative folliculitis [pus-filled hair follicles] were common, accounting for eight (18.2%) cases. Of the 44 cases, 35 (79.5%) were new presentations, and nine (20.5%) were due to exacerbations or recurrent episodes of previously documented infections.”

“The combination of a very low CD4 cell count and undiagnosed infection at the start of HAART are ideal conditions for immune reconstitution disease (IRD) to occur. This can partly explain the very high mortality rate during the first year of HAART observed in numerous trials conducted in Africa.”

“Clinical: [1] Paradoxical deterioration in clinical status after ART initiation despite improved immune function due to inflammatory response against infectious antigen, which may or may not have been [diagnosed] at initiation of ART; [2] Typically occurs in [patients] with low initial CD4 (usually <50) and rapid decline in viral load; onset usually within 6 wks of ART initiation, but sometimes several [months] later; [3] Inciting pathogens: M. avium complex, M. tuberculosis (30% of cases), and other Mycobacteria, CMV, Cryptococcus, PCP, Leishmania, HSV, VZV, hepatitis B and C, JC virus, HHV8 (Kaposi’s and Castleman’s), JC virus (PML), and others; [4] Common [symptoms] (varies according to causative pathogen): fever, localized lymphadenophathy/lymphadenitis, abscesses, pneumonia, vitritis, CNS disease, hepatitis, and dermatologic manifestations; [5] Presentations of OIs [opportunistic infections] may be atypical (eg, MAC: localized granulomatous lymphadenopathy without mycobacteremia; CMV: vitritis; PML: enhancing CNS lesions; Cryptococcus: marked CSF leukocytosis); [6] Autoimmune diseases (e.g.sarcoidosis, Grave’s disease) may be exacerbated; [7] Despite high risk (>25%) of paradoxical worsening in [patients] with active TB after initiation of ART, overall mortality improved in coinfected [patients] with CD4<100 treated with ART. DIAGNOSIS: [A] Compatible presentation after initiation of ART (usually within 6 wks, with rising CD4 and decrease in VL); [B] [Definitive diagnosis] includes new OI, malignancy (e.g. lymphoma), treatment failure for OI, and drug toxicity (especially with hepatitis).”

“The immune recovery associated with ART results in dramatic clinical benefits, but this restoration of immunity may result in immunopathological reactions and clinical deterioration when ART is initiated in patients with TB. These reactions are termed “immune reconstitution inflammatory syndrome” (IRIS), also known as “immune restoration disease.”…Typically, paradoxical IRIS occurs within 6 weeks of the initiation of HAART [in TB patients], but it has been reported to occur many months after patients commence HAART. The reported incidence of paradoxical TB-associated IRIS is 8%–43%. In one series, worsening conditions were observed on chest radiographs in 45% of patients with TB who were treated with HAART, versus 20% of patients in the control group, which consisted of HIV-seronegative patients and HIV-infected patients not receiving HAART”

“The cohort included all adult HIV patients who started HAART at Seoul National University Hospital between 1998 and 2005…a quarter of all HIV patients in South Korea are seen at this hospital…We included tuberculosis events that were newly manifested after the start of HAART. In patients who already had tuberculosis…only tuberculosis that developed at sites distinct from those of the initial infections were included…27 tuberculosis events developed during the follow-up period [average 2.6 years]. Of 16 cases diagnosed as definite tuberculosis, 4 were classified as IRIS…and 12 as non-IRIS. Of the other 11 cases, diagnosed as probable tuberculosis, 5 were classified as IRIS tuberculosis and 6 as non-IRIS…Of the 11 tuberculosis events that developed within a year after starting HAART, nine were classified as IRIS tuberculosis…56% of IRIS tuberculosis cases did not have overt tuberculosis at the start of HAART.”

“Some HAART-treated patients (10–25%)…exhibit paradoxical deterioration in their clinical status, despite controlled viral replication and improvements in CD4 cell counts…Few cases of acute renal failure have been observed in a Mycobacterium tuberculosis-infected HIV-positive patient. We report such a case of acute granulomatous interstitial nephritis associated with IRIS [Immune Reconstitution Inflammatory Syndrome]…In our patient, acute renal failure occurred within the first 8 weeks, concurrently with skin signs, lymphadenopathy, cholestasis liver dysfunction, and increasing C-reactive protein…IRIS should be considered as a cause of acute renal failure and acute granulomatous interstitial nephritis after the initiation of HAART or antituberculous drugs in HIVinfected patients.”

“Some people infected with HIV who have started such treatment in countries where leprosy is endemic have developed florid leprosy lesions in the initial months of treatment…The manifestations described, however, are a well recognised complication of antiretroviral treatment known as immune reconstitution disease or immune reconstitution inflammatory syndrome (IRIS). This presents with the manifestation (or “unmasking”) of a previously subclinical coinfection or the deterioration of an opportunistic infection that had been responding to treatment…The first published case of leprosy associated immune reconstitution disease occurred in 2003 in a Ugandan living in London…Antiretroviral treatment has been available since 1996 in countries with high average incomes. Immune reconstitution disease has been well characterised in this setting and is associated with a predictable range of opportunistic infections…Immune reconstitution disease has, for example, recently been described in association with the parasitic infections leishmaniasis, strongyloidiasis, and schistosomiasis…From the patient’s perspective, HIV infection and leprosy are both highly stigmatising diseases, and having both is understandably distressing. This distress may be heightened by the patient’s perception that the leprosy was caused by the antiretroviral drugs. Frequent cases of this disease could make patients less enthusiastic about antiretroviral treatment programmes. Importantly, some lesions seen in leprosy associated with immune reconstitution disease are unusually florid, and severe neuropathy triggered during antiretroviral treatment might lead to permanent disability”

“We report the succession of an unusual acute presentation of tuberculous meningitis unmasked by antiretroviral treatment, corresponding to the first such case of IRIS, immediately followed by the onset of a severe ‘paradoxical reaction’ consisting of cerebral tuberculomas…A 26-year-old HIV-1-seropositive woman from Guinea with a CD4 cell count of 101 cells/ml and a viral load of 138 100 copies/ml began antiretroviral treatment. One month later, she had a 3-day history of acute headache and vomiting revealing a meningeal syndrome…Our patient had an unmasking form of IRIS as suggested by: (i) the close temporal relationship between the introduction of HAART and the onset of meningitis; (ii) the rapid and significant immune recovery; and (iii) the unusual acute onset of tuberculous meningitis.”

“Following HAART initiation, 496 (28.6%) patients experienced either incident pulmonary tuberculosis, or a WHO stage IV condition (OI/IRIS). Extra-pulmonary tuberculosis was reported in 145 patients, pulmonary tuberculosis in 108, wasting syndrome in 63, atypical disseminated mycobacteriosis in 25, extra-pulmonary Cryptococcus in 18, and other WHO stage IV conditions in 50 (some patients presented more than one clinical manifestation). The delay from HAART initiation to the diagnostic of OI/IRIS was in median 4 weeks.”

“A total of 756 ART-naive patients who enrolled during the study period initiated ART. Their median age was 33 years…Among patients with prevalent TB, a total of 19 (12%) were diagnosed as having TB-IRD. Symptoms developed a median of 2 weeks after initiation of ART and systemic as well as organ-specific symptoms were present in all. IRD presented as an exacerbation of existing disease manifestations alone in 10 patients with pulmonary disease among the majority (n=Ú9). Seven further patients with initial diagnoses of pulmonary TB developed new disease manifestations at another anatomic site as well as a concurrent exacerbation of respiratory disease in five. Two other patients with disseminated disease developed IRD that culminated in death; both had pulmonary, intra-abdominal and bone marrow involvement. These two cases occurred early in the history of the ART programme; since diagnoses were not established ante-mortem, neither was managed as IRD.”

“With affordable AIDS drugs arriving in many poor countries, experts say a startling and worrisome side effect has emerged: in some patients, the treatment uncovers a hidden leprosy infection…AIDS specialists in Brazil, India, Africa, the Caribbean and elsewhere are reporting that some patients on life-saving antiretroviral drugs are developing painful facial ulcers or losing feeling in their fingers and toes…Doctors have long known that dormant diseases can surge as a weak immune system recovers. The threat is sometimes called “Haart attacks” — a grim pun on the medical acronym for “highly active antiretroviral therapy.” The recovering immune system regains its ability to create fevers, flood infected tissue with white blood cells, break bacteria down into toxic waste products and build nodules around bacteria it cannot kill. But in a weakened patient, that inflammatory response itself can be dangerous. For example, when doctors know that an AIDS patient has tuberculosis, they often try to give TB drugs for two months to suppress the bacteria before starting antiretrovirals, because the patient’s own immune attack on the tuberculosis bacteria in the lungs can be fatal. [At least, that's their story, and they seem to be sticking to it]”

“Immune reconstitution disease, an adverse consequence of restoration of pathogen-specific immune responses, might also be a problem, particularly in those infected with tuberculosis.”

“A total of 3151 HIV-positive individuals who initiated HAART between December 2001 and December 2003 were included in the analysis…Pulmonary TB [tuberculosis in the lungs] was reported within the first 3 months after HAART initiation for 29/38 (76.3%), 21/40 (52.5%), 27/52 (51.9%), 46/69 (66.7%) and 8/10 (80.0%) patients with notified pulmonary TB in Cambodia, Thailand, Kenya, Malawi and Cameroon programmes, respectively [i.e. 6.6% of patients came down with TB within the 3.7-11.1 month followup]…Extra-pulmonary TB was reported within the first 3 months after HAART initiation in 34/62 (54.8%), 9/17 (52.9%), 14/21 (66.7%), 4/11 (36.4%) and 0 patients with notified extra-pulmonary TB in the same programmes, respectively”

“In 1993, a 32-year-old woman was diagnosed [with] HIV infection in our unit…The moment that primoinfection occurred in the past was unknown because it was asymptomatic. Since she declined to receive antiretroviral therapy, a progressive CD4+ T cell count decrease [took place] during the following 9 years [although no actual illness is noted]. In July 2002, she began HAART with zidovudine, lamivudine, and abacavir…In the next 3 months after the initiation of HAART, the patient developed several infectious events such as P. carinii pneumonia after 10 days, which was successfully treated with cotrimoxazole. Seven days later, the patient showed low level of conscience [consciousness?], convulsions…[A] biopsy of the colon…allowed the diagnosis of CMV colitis, which was treated with ganciclovir and foscarnet, while HAART was interrupted 6 weeks after its initiation due to an apparent IRD…Despite this new treatment, symptoms [of] fever, cough, and dyspnea [difficulty breathing] turned up…empiric CMV pneumonia was diagnosed. Ten days later, the patient [reported] loss of vision…Since the patient progressed with adverse clinical events, IRD was ruled out [because symptoms kept worsening even after HAART was ended, although ganciclovir is a drug closely related to some AIDS drugs] and a new HAART regimen including zidovudine, lamivudine, and lopinavir/ritonavir was prescribed…the patient developed fatal meningoencephalitis after 12 weeks of initiation of HAART [translation: the treatment was successful but the patient died]”

“[Ever more] conditions are reported as IRIS events. These most frequently occur with mycobacterial (tuberculosis or Mycobacterium avium complex infection) or cryptococcal disease (each in approximately 30% of cases)”

“It is now also evident that the development of HAART-associated immunity can lead to a variety of new clinical manifestations. These have been collectively termed as immune reconstitution inflammatory syndrome (IRIS), immune restoration or immune restitution disease and immune reconstitution phenomena…Paradoxical hypercalcaemia and acute renal failure following initiation of anti-tuberculosis therapy and HAART add to the more commonly described fever, worsening of lung infiltrates, new lymphadenopathy and swelling of tuberculomata…In a retrospective series based in London, we demonstrated the occurrence of active tuberculosis as an IRIS-like phenomenon in a group of individuals who had recently commenced HAART. This occurred at a median of 37 days, and affected 3% of such patients starting antiretrovirals…The number of clinical conditions associated with credible IRIS phenomena continues to grow. A full description of these is beyond the scope of this review.”

“Zygomycosis is caused by the rapidly growing molds of the orders Mucorales and Entomophthorales. Zygomycosis is often associated with conditions such as diabetic ketoacidosis, lymphoproliferative disorders, immunosuppression after organ transplantation, severe burns, chronic steroid use, chemotherapy, and deferoxamine administration. HIV infection by itself does not seem to be an important risk factor for this mycosis; however, several cases of zygomycosis in HIV-infected patients have been reported. Moreover, as the widespread use of protease inhibitors (PI) can predispose HIV patients to diabetes, zygomycosis may become more common in this population. We describe here a case of rhino-orbital zygomycosis occurring in an HIV-infected patient with PI[protease inhibitor]-induced decompensated [uncontrolled] diabetes mellitus.”

“Four HIV-1-infected patients presented with unusual clinical manifestations in the course of disseminated histoplasmosis, including liver abscesses, compressive lymphadenitis, intestinal obstruction, uveitis and arthritis within a median of 45 days after initiation of highly active antiretroviral therapy (HAART)”

“Antiretroviral therapy (ART) in immunodeficient HIV patients may be complicated by mycobacterial immune restoration disease (IRD) resulting from an immunopathological response to subclinical infections by nontuberculous mycobacteria [i.e. you don't get sick until you start taking AIDS drugs]…A 48-year-old man with past Pneumocystis jiroveci pneumonia and disseminated cytomegalovirus infection was commenced on lopinavir/ritonavir, zidovudine and lamivudine when the CD4 T-cell count was 48 cells/ml (6%) and the plasma HIV-1-RNA level was greater than 100 000 copies/ml. He was receiving prophylactic azithromycin and maintenance valganciclovir. On day 11 of ART he developed fever, and chest radiography (previously normal) showed patchy consolidation in both lungs…Anaemia and leukopenia had been present since starting ART and were not improved by the cessation of valganciclovir or the substitution of tenofovir for zidovudine”

“We run a community-based ART [antiretroviral therapy] programme in Gugulethu, Cape Town, South Africa. Between September 2002 and November 2004, 434 treatment-naive patients started triple-drug ART according to WHO 2002 treatment guidelines…During a total of 460 person-years of observation (PYO), 9 patients developed either recurrent (6) or new (3) symptomatic cryptococcal disease of the central nervous system. The median duration of ART at the onset of symptoms was 4 weeks. 6 of the 9 patients died and cryptococcal disease accounted for 6 out of 22 total deaths (27%) during the first 3 months of ART.”

“We agree with…that the start of antiretroviral therapy (ART) in Africa and other tuberculosis endemic regions is likely to unmask large numbers of cases of undiagnosed active tuberculosis [except they weren't active until AIDS drugs were started]. It is very important that healthcare providers in these settings are aware of this phenomenon and understand the issues involved in management. In a recent retrospective notes review of 131 consecutive patients treated for tuberculosis at our clinic in Kampala, 29 (22%) were patients not known to have tuberculosis, who presented within weeks of starting ART (median of 8 weeks). A good example of such a case is that of a 32-year-old man who had become increasingly unwell over a long period, with weight loss, low-grade fevers and an intermittent cough. Examination revealed a wasted patient, oral candidiasis but no specific features suggestive of active tuberculosis such as chest signs or significant lymphadenopathy…Thirteen days after starting the generic combination of nevirapine, stavudine and lamivudine the patient presented to our clinic acutely unwell with high-grade fever and a persistent dry cough. Examination revealed a temperature of 40.8C but no localizing signs. A chest radiograph revealed obvious milary infiltrations involving all lung zones. A blood slide for malaria and routine blood cultures were negative. The patient was started on standard quadruple antituberculous therapy (ATT),”

“The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.”

“Results: Ten patients developed IRIS during the study period, giving an incidence of 10/239, or 4.2/100 person-years [95% confidence interval (CI), 2.2–7.8]. IRIS consisted of acute symptoms consistent with inflammation occurring within a median of 8 months (range, 2–37) after the diagnosis of cryptococcosis in the context of negative cultures and immunological and/or virological response to HAART. Radiology and histopathology detected features compatible with inflammation. Symptom severity required transfer into intensive care units for three patients and use of anti-inflammatory drugs for four. Three patients with evolutive IRIS died. Compared with patients without IRIS for whom complete clinical and microbiological informationwere available at baseline, previously unknown HIV infection [odds ratio (OR), 4.8; 95% CI, 1.0–21.7], CD4 cell count < 7 106 cells/l (OR, 4.0; 95% CI, 0.9–17.2), fungaemia (OR, 6.1; 95% CI, 1.1–35.2) and HAART initiation within 2 months of cryptococcosis diagnosis (OR, 5.50; 95%CI, 1.0–29.6) were independently associated with the risk of subsequent IRIS”

“Investigators have reported paradoxical effects when some patients begin HAART soon after initiation of therapy in patients with a concurrent opportunistic infection. These disorders are called reconstitution or reactivation syndromes”

“In the mid-1990s, clinicians noticed that certain patients deteriorated after starting HAART despite having decreasing HIV-1 RNA levels and rising CD4 cell counts. In these patients, receipt of HAART results in a pathological inflammatory response to either previously treated infections or subclinical infections. This inflammation could result in deleterious clinical outcomes, such as culture-negative meningitis or necrotizing lymphadenitis; it has been labeled as immune reconstitution disease (IRD) or immune reconstitution inflammatory syndrome (IRIS)…In the largest study of IRIS to-date, 31.6% of HIV-infected patients who were coinfected with M. tuberculosis, M. avium complex, or C. neoformans developed IRIS while on HAART, with an incidence of 15.1/100 patient-years of HAART in this high-risk cohort. These numbers are consistent with published data from smaller case series in which IRIS was seen in approximately 25-35% of HIV-infected patients responding to HAART. The majority of cases of IRIS occurred within the first 60 days of initiating HAART, which is in accord with prior individual reports and case series. As described previously, the onset of IRIS continues for up to 2 years following the initiation of HAART…As we hypothesized, having a more pronounced decrease in HIV-1 RNA levels within 90 days of starting HAART was associated with development of IRIS. The independent association of being antiretroviral drug naive and development of IRIS is likely related to having a more robust virological and immunological response to therapy in these group of subjects compared with those who were on prior therapy. A significant association between CD4 cell count increase and the diagnosis of IRIS was not seen until later in therapy…These [IRD/IRIS] patients often require significant interventions to minimize short-term morbidity [sickness] but their long-term outcome appears relatively good. Further studies looking at how to decrease the rate of IRIS in high-risk patients appear warranted by its prevalent nature and the association of IRIS with increased hospitalizations and invasive procedures.”

“Primary cerebellar degeneration is still rare in HIV disease. HIV cerebellar syndromes are commonly caused by opportunistic infection, neoplasm, or encephalitis, and may be accompanied by cognitive impairment…We report a case of cerebellopontine atrophy in the setting of immune reconstitution.A 33-year-old HIV-positive man with a previously low absolute CD4 cell count and a high plasma viral burden achieved undetectable plasma virus levels on indinavir, lamivudine and stavudine. After 9 months, when his CD4 cell count had improved…he developed acute progressive ataxia [lack of coordination]. Within 4 months he was wheelchair bound. Concomitant nystagmus [involuntary oscillation of the eyeball], dysarthria [difficulty speaking], and dysdiadochokinesis [inability to execute rapidly alternating movements] suggested a cerebellar syndrome…Magnetic resonance imaging scans…indicated cerebellar atrophy 4 months later. Serology and cultures revealed no signs of opportunistic pathogens…The CD4 cell count continued to rise and the viral load remained undetectable until compassionate discontinuation of HAART. After discontinuing antiretroviral agents he died of an unrelated infection, with no change in the neurological findings.”

“Suppression of HIV viraemia by antiretroviral therapy is accompanied by atypical ‘opportunistic infections’ or other inflammatory diseases in some patients. When these conditions were first reported, there was uncertainty about whether they were a consequence of the restoration of an immune response against opportunistic pathogens, or opportunistic infections resulting from residual defects of cell-mediated immunity. Subsequently, there has been acceptance that they are a consequence of immune reconstitution in patients who experience a virological response to HAART…Here, we argue that atypical ‘opportunistic infections’ after commencing HAART are the consequence of restoring an immune response against the antigens of opportunistic pathogens that is immunopathological rather than protective. These conditions are therefore considered to be immune restoration disease (IRD) rather than immunodeficiency disease. [i.e. it's the immune system that's the problem, not the solution! Although why is it that when your immune system is suppressed you get opportunistic infections yet when drugs 'restore' your immune system you also get opportunistic infections?]…The observation of atypical presentations of Mycobacterium avium complex (MAC) disease in patients treated with zidovudine [AZT] monotherapy was the first indication that restoring pathogen-specific immune responses can cause immunopathology…Soon after the introduction of HAART, it was observed that some patients presented with an initial or recurrent episode of cryptococcal meningitis during the first few weeks of therapy…Pneumocystis carinii pneumonitis [PCP] that has improved on anti-Pneumocystis therapy may relapse following the introduction of HAART…Hepatotoxicity [liver damage] is an adverse effect of HAART in up to 18% of patients. This is a direct effect of antiretroviral drugs, particularly nevirapine and high-dose ritonavir, in some patients but hepatotoxicity occurs most often in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection…Eye disease is the most common presentation of CMV IRD. It presents as retinitis [acute inflammation of the retina] in the first 3 months of HAART or as uveitis [damage to the back of the iris], usually much later than retinitis…Rates of varicella zoster virus (VZV) disease are increased in patients responding to HAART [i.e. with a lower viral load or higher CD4 cell counts]…HAART is the only effective therapy for progressive multifocal leukoencephalopathy (PML) in HIV patients, probably because it augments CD4 T-cell responses to JC virus (JCV) antigens. However, in some patients who commence HAART, PML may become worse or present for the first time…Granulomatous inflammation of the lungs, which has the characteristics of sarcoidosis [formation of small tumors in the lungs], has been described in patients responding to HAART…Autoimmune diseases presenting for the first time, or as an exacerbation of established disease, have also been reported in HIV patients responding to HAART.”

“To our knowledge . . . cases of lymphoma that appear during the first weeks of therapy have not been published, although this possibility has been mentioned mainly in meetings. We report here three patients who developed rapidly growing lymphomas of different cell lineages within the first 2 months of the initiation of HAART”

“Fever was the initial manifestation of the illness [now known as 'immune reconstitution disorder'] in all [108] patients. It occurred within 2 weeks of starting ZDV therapy and was often profound, with temperatures of >40C occurring in some patients. Patient 4 was hospitalized for 5 weeks because of severe and protracted fevers. No cause for the fevers was demonstrated despite extensive investigations [of course, it couldn't have been the AZT!]…It was notable that the MAI [Mycobacterium avium intracellulare] infection associated with the use of ZDV therapy was localized to tissues without evidence of mycobacteraemia in any patient, despite multiple blood cultures for mycobacterial infection. However, three patients developed mycobaceraemia 8-25 months after commencement”

“Tenofovir disoproxil fumarate (TDF) is generally considered a safe drug, well tolerated by patients and is now recommended as a first-line agent in the backbone of triple agent combination therapy (ART). Since its approval in October 2001 however, there has been a link established between its use and the incidence of proximal renal tubular dysfunction (PRTD) and Fanconi syndrome (Type 2 proximal renal tubular acidosis)…We recently performed a retrospective review of 52 patients who attended our HIV clinic between 1 September and 26 September 2009 and who were on treatment with TDF [Tenofovir] for a minimum duration of six months…Of the 30 patients who had urine analysis performed, five (16.6%) had evidence of proteinuria (with no other identifiable cause for proteinuria)…When uPCR test was performed on the same group, detection of proteinuria rose to 11 patients (36.6%)…the incidence of hypophosphataemia has been found to be around 10% in ART naive patients and this rises up to around 31% in those treated with ART…biochemical abnormalities and urinary abnormalities associated with [Tenofovir] use seem to be common”

“The antiretroviral agents most strongly associated with direct nephrotoxicity [kidney damage] include the nucleotide reverse transcriptase inhibitor, tenofovir, and the protease inhibitor indinavir…Tenofovir and related nucleotide analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir is known to cause nephrolithiasis, obstructive nephropathy, and interstitial nephritis. Kidney damage related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent”

“Patients taking both TDF [Tenofovir] and NRTIs [Nucleoside Analogs, mostly AZT, Abacavir and Stavudine] experienced an initial decline in eGFR [estimated glomerular filtration rate] during the first 180 days of therapy, but eGFR stabilized between 180 and 720 days…we found a significantly greater decline in eGFR between patients who took TDF with a PI/r [Ritonavir boosted Protease Inhibitor] compared with those who took TDF with an NNRTI.…Conclusion: Our data are consistent with results of clinical trials, which have shown no evidence of renal toxicity when TDF is used as part of an initial regimen…[however] eGFR should be monitored more closely when TDF is used with a PI/r.”

“Tenofovir (TDF) is the most widely prescribed antiretroviral drug. Kidney abnormalities are the main concern using the drug…[Patients in this] Cross-sectional study of plasma and 24 h urine markers of kidney tubulopathy could be allocated in three groups: patients under a TDF-containing HAART; patients on HAART never exposed to TDF; and antiretroviral-naive individuals. Significant tubular damage was defined when at least two of these parameters were repeatedly present,…A total of 284 consecutive HIV patients were examined, 154 on TDF, 49 on other HAART regimens and 81 drug-naive…The proportion of patients with tubular damage in groups 1, 2 and 3 were 22[%], 6[%] and 12%, respectively. In a multivariate analysis, the only independent predictors of tubular dysfunction were TDF use and older age”

“Mild-to-moderate nephrotoxicity has been associated with ADV [adefovir dipivoxilat doses of at least 30 mg daily. Nephrotoxicity appears after at least 20 weeks of treatment and usually resolves with dose modification or interruption. ADV 10 mg once daily was not nephrotoxic in two large randomized placebo control long-term studies…[however] We report a case of a patient in whom Fanconi syndrome and acute renal failure (ARF) developed, although treated with ADV 10 mg daily.”]

“[HIV_positive people are] exposed to a variety of adverse effects from long-term use of antiretroviral medications, which may cause clinically important renal toxicities…it often is challenging to distinguish antiretroviral-related renal toxicity from either direct effects of HIV-1 on the kidney [although kidney disease is not an AIDS-defining condition] or from a multitude of non-HIV-related kidney diseases”

“Among the 445 patients initiating tenofovir, 51 (11%) developed a decline in kidney function. In multivariate analysis, there was a significant association between decline in kidney function and concurrent use of amprenavir and didanosine, age over 50 years, and lower baseline weight”

“A 38-year-old Caucasian man developed progressive acute renal failure. He was found to be HIV positive in 1988 and received multiple unsuccessful antiretroviral regimens. He subsequently developed a virus resistant to all US Food and Drug Administration-approved antiretroviral agents; his CD4 cell count had been less than 50 cells/µl for more than 5 years, and at the time of renal failure, was 0 cells/µl. Renal dysfunction developed when he was receiving tenofovir, emtricitabine, saquinavir, lopinavir, and ritonavir. Tenofovir was initially suspected as the etiology, but kidney dysfunction progressed (from 1.6 to 8 mg/dl over a 6-month period) despite discontinuation of all antiretroviral agents and other potential nephrotoxic drugs. [The researchers apparently did not consider the possibility that the damage to the kidney was so severe that even stopping the drugs could not reverse it, so they blamed it on a virus instead]”

“The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis [kidney stones] in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified [note that it's believed that only 1 to 10% of adverse events are reported]. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation.”

“In a multivariate model any use of indinavir [a protease inhibitor] or tenofovir [a nucleoside analog] was associated with increased odds of CRF [chronic renal/kidney failure], as was cumulative exposure to indinavir or tenofovir.”

“our patient sustained widespread podocyte [kidney cells that are critical for proper filtration] damage while taking HAART. The damage appeared to resolve with the cessation of efavirenz and the addition of irbesartan…Aside from one case of severe hypersensitivity to efavirenz, renal damage caused by efavirenz (or non-nucleoside reverse transcriptase inhibitors in general) has not previously been reported. However, in this case, it appears as though efavirenz directly injured the podocytes.”

“Tenofovir disoproxil fumarate (TDF, viread) is a nucleotide analogue used in antiretroviral therapy (ART) for HIV infection. In addition, it is active against hepatitis B virus (HBV). It is excreted renally and not metabolized. Nephrotoxicity caused by TDF has been reported in a small number of patients…Patient 1, a 39-year-old HIV-positive white man, presented with wasting, Candida esophagitis, marked cerebral atrophy, polyneuropathy, and cutaneous Kaposi’s sarcoma. His CD4 cell count was 168 cells/ml and he also had elevated liver enzymes as a result of alcoholic liver disease. ART was initiated with zidovudine, lamivudine, and lopinavir/ritonavir. Because of anemia requiring repeated transfusions, zidovudine was replaced by TDF. Within 10 days, the serum creatinine level rose from 0.8 to 1.4 mg/dl, serum urea from 40 to 61 mg/dl, and serum potassium from 5.0 to 6.0 mmol/l. After TDF was stopped renal function parameters normalized completely within 10 days…Patient 2, a 69-year-old white man, was diagnosed with advanced HIV infection in 2001. In addition, he had congestive heart failure as a result of arterial hypertension, coronary artery disease, and mitral valve insufficiency. ART was initiated with stavudine, lamivudine and abacavir. One year later stavudine was substituted with zidovudine because of peripheral polyneuropathy. Later, zidovudine was replaced by TDF because of transfusion dependent anaemia. Because of an increase in the HIV viral load ART was changed to didanosine, TDF, and lopinavir/ritonavir according to the results of a genotypic resistance test in 2003. In 2004, lopinavir/ritonavir was replaced by atazanavir/ritonavir because of hyperlipidemia. At this time elevated liver enzymes were noted and were thought to be caused by ART, but therapy remained unchanged because of limited therapeutic options. In spring 2005, an increase in serum creatinine to 1.4 mg/dl and glucosuria of 300 mg/dl were recognized, but the patient’s renal function remained stable until 4 months later, when he developed peripheral edema and ascites. A serum creatinine level of 4.3 mg/dl, serum urea of 71 mg/dl, proteinuria of 2175 mg/l, worsening glucosuria, metabolic acidosis and sonographic signs of liver cirrhosis were noted. ART was stopped and medical therapy optimized. Two months later serum creatinine was almost normal.”

“We present a series of 40 patients who developed hypokalemia [low potassium levels which can result in kidney failure] associated with tenofovir [a nucleoside analog AIDS drug]. Identified risk factors included concomitant ritonavir or didanosine use, a lower weight and longer duration of tenofovir use. Recovery or improvement was seen in the majority of patients (66%) after the discontinuation of tenofovir; however, four deaths occurred. The associated consequences of tenofovir-related hypokalemia may be profound and life-threatening.”

“A total of 61 patients were screened of whom 24 were found to be ineligible. This left 37 eligible patients of whom 2 were excluded…Prior to indinavir exposure the cohort had a mean serum creatinine of 82 (12.7) µmol/L, corresponding to an estimated creatinine clearance of 84 mL/min. At baseline for the present study the serum creatinine concentration was 149 (27.7) µmol/L, representing an estimated creatinine clearance of 46 mL/min, and a mean (SD) percentage reduction of creatinine clearance from pre-indinavir exposure of 44 (14) %. After indinavir dose optimization the mean serum creatinine returned to 135 (29) µmol/L, representing an estimated creatinine clearance of 53 (15) mL/min. The mean change in creatinine clearance from study baseline to endpoint was 6.6 (10) mL/min (P = 0.001). At baseline the majority of patients had Grade 2 pyuria (48.6%) [discharge of pus in the urine] and at study end the majority (51.4%) had Grade 1 pyuria (P = 0.09)…we have demonstrated an association between the use of pharmacokinetically guided indinavir dose reductions and amelioration of indinavir-associated renal toxicity, at least in the short-term.”

“kidney disease has emerged as a leading cause of death among HIV-infected patients in the HAART era. This study compared the incidence and predictors of acute renal failure and mortality before [1995] and after [2003] the widespread introduction of HAART, and described the impact of acute renal failure on mortality in a contemporary cohort of patients with HIV infection who were hospitalized in New York State. HIV infection was associated with an increased risk of acute renal failure and in-hospital mortality both before and after the widespread introduction of HAART. Among patients with HIV infection, acute renal failure was a strong predictor of in-hospital mortality in the HAART era. In addition, chronic kidney disease and acute or chronic liver disease were strongly associated with both acute renal failure and in-hospital mortality among patients with HIV, suggesting a need for more aggressive management of chronic kidney disease and hepatitis virus coinfection in the setting of HIV…The unexpected increase in incidence of reported acute renal failure in the HAART era may reflect a combination of factors related and unrelated to HIV…it is possible that both comorbid disease [other conditions] and medication nephrotoxicity [kidney damage from antiretroviral and other medications] play a more important role in the HAART era.”

“Twelve weeks after initiating a tenofovir-containing HAART regimen…[several signs of kidney damage were noted, and two cases with clinical symptoms]…Patients with the above findings should be monitored carefully for renal tubular toxicity.”

“61 patients were enrolled in the study…Twelve (20%) patients underwent IDV [indinavir] dose reduction, mainly because of nephrotoxicity (nine of 12 patients)”

“Patients on tenofovir showed a lower mean glomerular [kidney] filtration rate estimated by creatinine clearance or cystatin C clearance compared with control patients. In total, 24 patients on tenofovir versus five control patients had proteinuria greater than 130 mg/day.”

“We report here seven cases of HIV patients with renal colic [kidney stones causing extreme colic-like pain], cholangitis [infection of the bile ducts, often caused by kidney stones] or parotitis [inflammation of the parotid glands] while receiving LR [Kaletra=Lopinavir+Ritonavir] in association with other antiretroviral therapies…Delay between the beginning of LR and the occurrence of lithiasis [kidney stones] was 8-16 months.”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones...Our cohort study of the prevalence of indinavir nephrolitihiasis [kidney stone formation] included 155 patients with HIV for 5,732 patient-weeks...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported.”

“Reports about the glomerular [filtration portion of kidneys] diseases due to these drugs are rare [but one is reported in this paper]”

“The U.S. Food and Drug Administration announced on January 29 that non-cirrhotic portal hypertension, a rare, but serious, liver disorder, has been reported in some HIV patients taking Videx/Videx EC (didanosine). Videx is an antiretroviral medicine first approved by the FDA in 1991…During an 18-year period, 42 cases of non-cirrhotic portal hypertension were reported to the FDA’s Adverse Event Reporting System [it’s estimated that only 1%-10% of adverse reactions are ever reported to authorities] for patients taking Videx/Videx EC. Four patients died from bleeding or liver failure after developing the condition [about a 10% death rate]. Non-cirrhotic portal hypertension occurs when blood flow in the portal vein – a major vein in the liver – slows down and leads to severely enlarged veins in the esophagus. These enlarged veins, called esophageal varices, are thin and can break open, resulting in serious, and potentially fatal, bleeding…The FDA evaluation concluded that the clinical benefits of Videx/Videx EC in certain patients with HIV continue to outweigh potential safety risks. Videx/Videx EC does not cure HIV infection, may not prevent development of HIV-related illnesses, and may not prevent the spread of HIV to other people. [so, what the heck does it do?]”

“Eleven volunteers started as the first group in this study. No major complaints occurred during day 1–5 (rifampicin only). After addition of [the protease inhibitors] lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in [the liver enzymes] aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n=2; grade 3, n=1; grade 4, n=8) on days 9–10. All values returned to normal within 6 weeks. The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers [but it’s okay with HIV-positive people? Okay with sick people?]. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.”

“Antiretroviral drugs have the potential to cause liver toxicity, especially in hepatitis B virus or hepatitis C virus coinfected patients. Tenofovir [a nucleoside analog] is among the few antiretrovirals that are considered nonhepatotoxic, whereas efavirenz [an NNRTI] can cause liver enzyme elevations. We report three cases of liver enzyme elevations in persistently hepatitis B virus and hepatitis C virus-negative, HIV-infected patients after the addition of tenofovir to an efavirenz-containing regimen.”

“Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity, mortality and treatment discontinuation in HIV-infected patients…Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations, although certain drugs may cause liver injury more frequently than others…Several major mechanisms of ARLI have been described, including metabolic host-mediated injury, hypersensitivity reactions, mitochondrial toxicity, and immune reconstitution phenomena…The severity of ARLI may range from the absence of symptoms to liver decompensation, and the outcome can range from spontaneous resolution to liver failure and death…After initiating HAART, the reported incidence of severe liver toxicity ranges from 2 to 18%…Mechanisms of drug injury observed with NRTI [nucleoside analogs, such as AZT] mainly include mitochondrial toxicity and hypersensitivity reactions…In patients taking nevirapine, the overall incidence of symptomatic events involving the liver enzymes is approximately 5% [44,88]. However, severe liver toxicity, occurring with early latency, has been reported in HIV-infected and HIV-seronegative individuals. Warnings against the use of nevirapine for postexposure prophylaxis were issued after some individuals developed hepatic failure requiring liver transplantation…The phenomenon of ARLI became more evident after the introduction of PI drugs. Rates of hepatotoxicity from registration trials of various PI have ranged from 1% to 9.5%, but few patients had serious liver-related outcomes. In comparison with other drugs in its class, full-dose ritonavir has consistently been shown to be more hepatotoxic…The clinical development of aplaviroc, a CCR5 antagonist, was halted in 2005 after the occurrence of severe hepatotoxicity”

“In a recent article, Mallet and colleagues reported a series of eight cases of nodular regenerative hyperplasia (NRH) of the liver as a new cause of chronic liver disease in HIV-infected patients. NRH is characterized ‘by the presence of diffuse rather small regenerative nodules in the absence of significant fibrosis’. All patients were treated with HAART and all received didanosine included in one of several lines of antiretroviral drugs they had before the diagnosis of NRH…Our case is very similar to those reported by Mallet et al and emphasizes the seriousness of this complication: the risk of variceal haemorrhage, indication for some patients of transplantation (three out of eight of the cases reported by Mallet et al). Only HIV infection and HAART have been identified as potential co-factors. Nevirapine toxicity is well known, has not been specifically incriminated in NRH pathogenesis, but was also taken by our patient as well as by eight patients reported by Mallet et al.”

“There were 235 deaths among the 4471 patients on HAART (5%)…AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time, whereas liver diseases and non-AIDS-defining infections significantly increased over time.”

“From January 2003 to June 2006, eight consecutive HIV-infected patients (seven Caucasian and one African) were referred for cryptogenic [unknown cause] liver disease…During the same period, 178 HIV-infected patients were admitted to the same unit for the treatment or the evaluation of chronic liver disease and 97 underwent liver biopsy…With the exception of HIV infection and the associated liver disease, none of these patients had significant co-morbidity, especially considering cardiac or renal pathology. They did not take any other hepatotoxic medication apart from antiretroviral drugs…No patients had had opportunistic infection…A clear nodular architecture was seen in seven patients, whereas in the last one, NRH [nodular regenerative hyperplasia of the liver] was suspected on the presence of sinusoidal dilatation in a clinical context of portal hypertension…To date, all patients are alive, and three are waiting for liver transplantation.”

“We here report a 52-year-old white male (Centers for Disease Control and Prevention stage C3) with a 20-year history of multidrug-resistant HIV. In February 2005 he was started on an antiretroviral regimen with TPV and RTV (500/200 mg twice daily), continuing the existing regimen of zidovudine/lamivudine (300/150 mg twice daily) and T-20 (90 mg twice daily), which was started 12 months before without hepatic disorders…Two weeks after the initiation of the TPV containing regimen, the patient developed elevated liver enzymes…HBV DNA viral load was low with 20 000 copies/ml, autoimmune markers for hepatitis and cirrhosis were negative, excessive alcohol consumption was denied. Percutaneous liver biopsy showed a mild, non-active hepatitis with moderate lymphocyte infiltration in the portal areas and no intrahepatic steatosis. Following the patient’s wish to interrupt the T-20 [enfuvirtide, a fusion inhibitor] treatment because of severe local skin reactions, and under the assumption of a hepatotoxic effect of the antiretroviral regimen T-20 was discontinued for 6 weeks. Shortly after, liver function improved with a 50% decrease in LFT values. Due to a weight loss of 10 kg and an elevation of the viral load treatment with T-20 was recommenced and 2 weeks later after an increase of the G-GT TPV/RTV was discontinued. The liver function tests returned to normal within 4 weeks.”

“Aptivus [tipranavir] co-administered with 200 mg Ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities”

“Considering the 86 patients in the follow-up study, 17 were found to be HBV-DNA positive, 13 on admission and four in the subsequent observation…28 (32.5%) experienced a hepatic flare [at least a tripling of the liver enzyme serum alanine aminotrasferase between two consecutive measurements]…Of the 13 patients who were HBV-DNA positive on admission, two did not receive HAART; one of these two experienced a hepatic flare after a 12-month observation. The other 11 patients were treated with HAART containing lamivudine and were HBV-DNA negative at the subsequent check points. Of these 11, four became HBV-DNA positive under lamivudine treatment and experienced a hepatic flare; two of these four also experienced a hepatic flare after the discontinuation of the drug. Another two of these 11 patients (Fig. 1f, g) became HBV-DNA positive and experienced a hepatic flare, respectively, 4 and 8 months after lamivudine was discontinued because of lack of efficacy of the HAART regimen. The remaining five patients of the 11 treated remained HBV-DNA negative under HAART containing lamivudine and did not experience a hepatic flare…[in summary] in approximately half of the lamivudine treated patients occult HBV replication became detectable again after 12–40 months of lamivudine treatment, always associated with a hepatic flare.”

“Patients with steatosis [fat deposits in the liver] grade 2/3 [severe] were more likely to be receiving antiretroviral therapy than were patients with grade 1 [mild] steatosis (84% versus 77%) and patients without steatosis (69%). NRTI-based [nucleoside reverse-transcriptase inhibitors such as AZT] treatment was more frequent among patients with steatosis grade 2/3 than among patients with grade 1 or grade 0 steatosis (82%, 75% and 68%, respectively)…Lipodystrophy [fat redistribution, also associated with long-term antiretroviral drug use] was present in 15.7% overall, i.e., 21% in patients with grade 2/3 steatosis, 15% in patients with grade 1 steatosis, and 11% in patients with no steatosis.”

“Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals…All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study [using HCC cases from Brescia, North Italy in 1995-1998 as controls]…41 HIV-infected subjects with HCC were identified…31 patients (77%) were on highly active antiretroviral therapy.”

“We report the first observation of acute hepatic cytolysis associated with atazanavir [a new azapeptide protease inhibitor]…transaminase activity gradually increased after the introduction of atazanavir, with a marked increase between weeks 8 and 30 (up to 10 times the normal value). At admission, physical examination showed afebrile subclinical jaundice. The abdominal examination was strictly normal (no hepatomegaly). No signs of chronic liver disease or liver failure were found. Laboratory tests revealed major cytolysis [breakdown of cells in the liver]”

“Abnormalities in hepatic function have become one of the most common complications occurring among human immunodeficiency virus (HIV)-infected individuals receiving highly active antiretroviral therapy (HAART), and liver disease has become an increasingly important cause of morbidity and mortality in HIV-infected patients. We present a case of a patient with HIV infection and hepatotoxicity that exemplifies the complications currently observed during the treatment of such patients…Although coinfection with HCV and HIV has become a common clinical problem, optimal treatment of such patients remains to be defined and must be individualized to maximize benefit and tolerance.”

“during clinical trials of Kaletra [combination of the protease inhibitors Lopinavir and Ritonavir], approximately 1 in 4 treatment experienced patients saw a serious or life-threatening laboratory abnormality.…The most common laboratory abnormalities [found with Kaletra, a combination of the protease inhibitors Lopinavir and Ritonavir] are increases in some tests of liver function…”

“when mortality [in British hemophiliacs] from other [non-HIV] causes was examined separately, a substantial increase over time remained, with the value during 1991–1996 almost double that for 1985–1990 and no appreciable decline in 1997–1999. The increase was entirely caused by an increase in liver disease, which during 1997–1999 was the certified cause of death for over 25% of deaths in HIV-infected individuals…For deaths that were classified neither as HIV related nor from liver disease, mortality remained virtually constant during 1985–1999, albeit at a higher level than that of HIV-uninfected individuals. It seems likely that at least some of these deaths were attributable to HIV, although there was no indication that the individuals concerned had developed an AIDS-defining condition. HAART has been associated with several categories of major toxic effects, but there was no evidence of any deaths occurring as a result of HAART in this population. [but what other explanation is there?]”

“Women with CD4+ counts >250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, are at considerably higher risk (12 fold) of hepatotoxicity [liver damage]. Some of these events have been fatal…The greatest risk of severe and potentially fatal hepatic events (often associated with rash) occurs in the first 6 weeks of VIRAMUNE [nevirapine] treatment. However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment with VIRAMUNE…In some cases hepatic injury progresses despite discontinuation of treatment. [Boehringer Ingelheim is the manufacturer of Nevirapine]”

“30 non-HIV-infected individuals developed hepatotoxicity [liver toxicity] after 8 to 35 days of single-agent nevirapine (8 people) or a nevirapine-containing PEP regimen (22). Findings included ECOG grade 3 [confined to bed at least half the day] or 4 [completely disabled] hepatotoxicity (n = 14), fevers (n = 11), skin rashes (n = 8), eosinophilia (n = 6), and fulminant hepatic necrosis requiring an orthotopic liver transplant (n = 1). Rates of severe hepatotoxicity (grade 3 or 4) in non-HIV-infected individuals ranged from 10% (4/41) to 62% (5/8). Liver biopsy material from 2 individuals was consistent with a hypersensitivity syndrome.”

“Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were enrolled into 1 of 5 CPCRA [Terry Beim Community Programs for Clinical Research on AIDS] clinical trials…for this analysis…All patients in this cohort were prescribed ART following enrollment…The most common grade 4 events were: liver related (148 patients); neutropenia (89); anemia (64); cardiovascular (51); pancreatitis (50); psychiatric (44); kidney-related (34); thrombocytopenia (32); and hemorrhage (25) [these are much more likely to be therapy-related than HIV-related]…the rate of grade 4 events is greater than the rate of AIDS events, and the risk of death associated with these grade 4 events was very high for many events.”

“In multivariate analysis [of 692 Thai HIV patients], predictors of severe hepatotoxicity [liver toxicity] were HBV [Hepatitis B virus] or HCV [Hepatitis C virus] coinfection, and NNRTI[Non-Nucleoside Reverse Transcriptase Inhibitor]-containing therapy. Incidence of severe hepatotoxicity was particularly high among patients receiving nevirapine and nevirapine/efavirenz”

“306 patients started a nevirapine-containing regimen, of whom 8 developed an acute hepatitis (2.6%) in a median of 24 days. Transaminases peaked at 28 days. Injury pattern was in general mixed-hepatocellular. Withdrawal of the antiretroviral agent led to rapid restoration of transaminase levels and resolution of clinical symptoms.”

“In 655 individuals receiving HIV postexposure prophylaxis (PEP), drug-induced aminotransferase alterations were frequent and severe in the nevirapine-including regimen, rare and mild-to-moderate in other combinations, and always reversible. Grade 3–4 incidence in protease inhibitor or nevirapine PEP was 0.5 and 25.0 per 100 person-months, respectively. Apart from nevirapine, continuing PEP appears to be safe [but without long-term follow-up this claim is a bit shaky] even in the case of aminotransferase alterations. The usefulness of routine monitoring of liver function during PEP could be re-considered.”

“Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis [fatty degeneration]…13 patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases…In all cases, ultrastructural study disclosed mitochondrial abnormalities. Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent [without symptoms] nonspecific disease [but probably not forever, as the side effects worsen]”

“755 HIV-seropositive patients consecutively prescribed new [i.e. changed, not necessarily the first] ART [anti-retroviral therapy] were selected…26 cases of SH [severe hepatotoxicity] were observed with an incidence of 4.2% person-years. Liver failure (LF) was rarely seen (1.1 per 100 person-years)…Death occurred during follow-up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4 count less than 200 cells/mm. Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. [Note that Severe Hepatotoxicity was also somewhat associated with IV drug abuse and alcohol abuse, which may have been contributing factors]”

“the liver-related mortality rate was…twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced.”

“In this investigation, 492 patients…prescribed antiretroviral drugs between April 1989 and September 2000 were included…The median duration of follow-up of the cohort was 1,392 days. HCV [Hepatitis C] infection was present in 323 (68%). Mortality attributable to AIDS decreased from 4.5 to 1.8 per 100 persons per year. Mortality due to liver failure increased from 0.3 to 0.5 per 100 persons per year. The survival of patients with and without HCV infection was similar. Although liver failure is an increasing cause of death among HIV-infected patients receiving HAART, HCV infection has still no impact on the survival of HIV-infected patients.”

“Liver fat content was significantly higher in the HAART+LD+ group than the HIV-…group [obviously not taking HAART]…The severity of the insulin resistance syndrome in patients with HAART-associated lipodystrophy [abnormal fat distribution] is related to the extent of fat accumulation in the liver”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Whether by HAART, viral hepatitis, or alcohol, transaminitis (elevated ALT and AST [liver enzyme levels]) is common among those with HIV infection... In unadjusted analyses, CD4 [immune cell counts], VL [viral load], and AST were significant predictors of survival in both cohorts (p<0.001). ALT was significant only in CHORUS [one cohort]…Transaminitis is a major determinant of survival and should be carefully considered in all phases of HIV therapy [note that the cumulative length of treatment with antiretroviral drugs, which are known to be toxic to the liver, was not considered]”

“The occurrence of a severe elevation of [the liver enzymes] transaminases was associated with poorer survival, although HCV [Hepatitis C Virus] was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments ofantiretroviral treatments currently prescribed to optimize their use.”

“Of the 560 patients, 44 (7.9%) developed grade 4 LEEs [Liver Enzyme Elevation]…9 cases were excluded from the analysis [due to other explanations for their liver problems] leaving 35 cases…6 (17.1%) of 35 patients were symptomatic. The most frequently occurring symptoms were jaundice, dark urine, clay-colored stools, malaise, nausea, vomiting, and right upper quadrant discomfort…the risk factors significantly associated with grade 4 LEE…were highe