Adverse Effects, in General

“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”