The quotes are classified as:
Ineffectiveness or Lack of Proof of Effectiveness, often Combined with Toxicity
HAART is still often described as having miraculous effects. Not surprisingly, proponents of these drugs are less anxious to discuss the times when the drugs simply donÕt seem to do what they are supposed to.
[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]
Halperin DT et al. A surprising prevention success: Why did the HIV epidemic decline in Zimbabwe. PLoS Medicine. 2011 Feb 8
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]
QuickStats: Annual Rates of Hospitalization with a Diagnosis of HIV/AIDS Among Persons Aged >=45 Years, by Sex National Hospital Discharge Survey, United States, 19972007. MMWR. 2010 Oct 1;59(38):1244.
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.
Harries AD et al. Diagnosis and management of antiretroviral-therapy failure in resource-limited settings in sub-Saharan Africa: challenges and perspectives. Lancet Infect Dis. 2010 Jan;10(1):60-5.
Whether previous U.N. initiatives are responsible for the epidemics 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.
Cheng M. United Nations: HIV outbreak peaked in 1996. AP. 2009 Nov 23
Risk factors for death in patients diagnosed with non-Hodgkins 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.
Prognosis of HIV-associated non-Hodgkin lymphoma in patients starting combination antiretroviral therapy. AIDS. 2009 Sep 24;23(15):2029-37.
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.
Haddow LJ et al. Histopathology of Strongyloides stercoralis hyperinfection during immune reconstitution in an HIV-infected patient. AIDS. 2009 Jul 31;23(12):1609-11.
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 04 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 812 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]
Lawn SD et al. Changing mortality risk associated with CD4 cell response to antiretroviral therapy in South Africa. AIDS. 2009;23:355-42.
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 Kaposis sarcoma and severe malnutrition]
Lawn SD et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008 Oct 1;22(15):1897-908.
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?]
Uganda: ARV Clinics May Put People With HIV At Risk of Catching TB. New Vision (Kampala). 2008 Jun 15
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.
Bisson GP et al. Overestimates of survival after HAART: implications for global scale-up efforts. PLoS One. 2008;3(3):e1725.
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.
Johannessen A et al. Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania. BMC Infect Dis. 2008;8:52.
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.
Martinez E et al. Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area. HIV Med. 2007 May;8(4):251-8.
[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.?]
Susman E. Analysis: Troubling trends in AIDS cases. UPI. 2007 Feb 27
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
Gallo RC. Testimony at appeal hearing of Andre Parenzee. Court of Criminal Appeal. 2007 Feb 12
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.
Madec Y et al. Response to highly active antiretroviral therapy among severely immuno-compromised HIV-infected patients in Cambodia. AIDS. 2007 Jan 30;21(3):351-359.
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]
Lawn SD, Wood R. National adult antiretroviral therapy guidelines in South Africa: concordance with 2003 WHO guidelines?. AIDS. 2007 Jan 2;21(1):121-122.
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]
UN concerned about Malawis rising deaths of AIDS patients on ARVs. People's Daily. 2006 Nov 1
Between 1999 and 2004, the percentage of deaths due to nonHIV-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 nonHIV-related causes. Of deaths due to nonHIV-related causes, 76% could be attributed to substance abuse, cardiovascular disease [which can be caused by AIDS drugs], or a nonAIDS-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 nonHIV-related causes.
Sackoff JE et al. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006 Sep 19;145(6):397-406.
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.
May MT et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet. 2006 Aug 5;368(9534):451-8.
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].
Ylitalo N et al. Risk Factors for Opportunistic Illnesses in Children With Human Immunodeficiency Virus in the Era of Highly Active Antiretroviral Therapy. Arch Pediatr Adolesc Med. 2006 Aug 1;160(8):778-787.
There are no study results demonstrating the effect of APTIVUS [tipranavir]/ritonavir on clinical progression of HIV-1.
Aptivus (tipranavir) prescribing information. Boehringer Ingelheim. 2006 Jun 27
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]
An analysis of the cause of death in patients on ART in Dr. George Mukhari hospital, Pretoria. Medunsa. 2006
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]
Revisions to WHO HIV and AIDS case definitions and classification of HIV related disease. WHO EMRO National Programme Manager Meeting. Amman, Jordan. 2006 Jun
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.
Zuger A. AIDS, at 25, offers no easy answers. NY Times. 2006 Jun 6
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  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
Steinberg J. Tragic illusions in a village split over the treatment of HIV/AIDS. Business Day. 2006 Jun 5
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]
Mulama J. Using ARVs to fill empty stomachs. Inter Press Service. 2006 Jun 2
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.
Vigano A et al. Failure to eradicate HIV despite fully successful HAART initiated in the first days of life. J Pediatr. 2006 Mar;148(3):389-91.
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.
Negredo E et al. The effect of atorvastatin treatment on HIV-1-infected patients interrupting antiretroviral therapy. AIDS. 2006 Feb 28;20(4):619-21.
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 69 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]
Lawn SD et al. Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS. 2005 Dec 2;19(18):2141-8.
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]
Chun T-W et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest. 2005 Nov 1;115:3250-5.
[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)]
Kabamba-Mukadi B et al. Human immunodeficiency virus type 1 (HIV-1) proviral DNA load in purified CD4+ cells by LightCycler real-time PCR. BMC Infect Dis. 2005;5(1):15.
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.
Moerman F et al. Highly active antiretroviral therapy. BMJ. 2005 Jun 11;330(7504):1341-1342.
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].
van Kooten Niekerk NK et al. The First 5 Years of the Family Clinic for HIV at Tygerberg Hospital: Family Demographics, Survival of Children and Early Impact of Antiretroviral Therapy. J Trop Pediatr. 2005 Jun 9
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.
Pulvirenti JJ. Inpatient care of the HIV infected patient in the highly active antiretroviral therapy (HAART) era. Curr HIV Res. 2005 Apr;3(2):133-45.
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.
Ham B. Youth with HIV take more risks after new meds introduced. Health Behavior News Service. 2005 Feb 28
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 interventions 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
Olsen CH et al. Risk of AIDS and death at given HIV-RNA and CD4 cell count, in relation to specific antiretroviral drugs in the regimen. AIDS. 2005 Feb 18;19(3):319-330.
Whether treatment of acute HIV infection results in long-term virologic [decreased 'viral load'], immunologic [increased CD4 cell counts], or clinical benefit is unknown
Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. DHHS. 2004 Oct 29
"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 Kaposis 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 Kaposis 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): 154952.
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]
Wang C et al. Mortality in HIV-Seropositive versus -Seronegative Persons in the Era of Highly Active Antiretroviral Therapy: Implications for When to Initiate Therapy. J Infect Dis. 2004 Sep 15;190(6):1046-54.
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.
Viani RM et al. Decrease in Hospitalization and Mortality Rates among Children with Perinatally Acquired HIV Type 1 Infection Receiving Highly Active Antiretroviral Therapy. Clin Infect Dis. 2004 Sep 1;39(5):725-81.
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]
Gallant JE et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.
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.
Casalino E et al. Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS. 2004 Jul 2;18(10):1429-33.
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.
Piroth L et al. Clinical, immunological and virological evolution in patients with CD4 T-cell count above 500/cubic mm: is there a benefit to treat with highly active antiretroviral therapy (HAART)?. Eur J Epidemiol. 2004;19(6):597-604.
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- AIDSassociated 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-AIDSassociated 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.
Narasimhan M et al. Intensive Care in Patients With HIV Infection in the Era of Highly Active Antiretroviral Therapy. Chest. 2004 May 01;125(5):1800-1804.
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.
van Leth F et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004 Apr 17;363(9417):1253-63.
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.
Smith DE et al. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence?. AIDS. 2004 Mar 26;18(5):709-18.
this IAPAC Monthly article considers the thousands who can and usually do get potent antiretrovirals but die anyway A few examples:  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).  An analysis of 66 deaths in Frances Aquitaine cohort in 1998 and 1999 blamed 11 of them (17 percent) on treatment-induced toxicities.  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.
Mascolini M. Why people with HIV still die and why they dont have to. IAPAC Monthly. 2004 Mar;10:3.
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)]
Palacio H et al. Healthcare use by varied highly active antiretroviral therapy (HAART) strata: HAART use, discontinuation, and naivety. AIDS. 2004 Mar 5;18(4):621-30.
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.
Negredo E et al. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS. 2004 Feb 20;18(3):459-63.
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!]
HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet. 2003 Nov 15;362(9396).
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
van Sighem AI et al. Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS. 2003 Oct 17;17(15):2227-36.
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
Sungkanuparph S et al. Opportunistic infections after the initiation of highly active antiretroviral therapy in advanced AIDS patients in an area with a high prevalence of tuberculosis. AIDS. 2003 Sep 26;17(14):2129-31.
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 Hodgkins 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]
Egger M et al. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet. 2003 Aug 30;362(9385):679-86.
Baseline CD4 count was the strongest predictor of subsequent clinical progression [i.e. a womans 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]
Mayer KH et al. Clinical and immunologic progression in HIV-infected US women before and after the introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2003 Aug 15;33(5):614-24.
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 715% 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 515% of the patients treated with HAART.
Florence E et al. Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med. 2003 Jul;4(3):255-62.
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 715% 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 515% 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%).
Florence E et al. Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med. 2003 Jul;4(3):255-62.
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 WHOs 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.
Duesberg P et al. The chemical bases of the various AIDS epidemics: recreational drugs, anti-viral chemotherapy and malnutrition. J Biosci. 2003 Jun;28(4):383-412.
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.
Havens PL. Postexposure prophylaxis in children and adolescents for nonoccupational exposure to human immunodeficiency virus. Pediatrics. 2003 Jun;111(6 Pt 1):1475-89.
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].
Vigano A et al. Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children. J Acquir Immune Defic Syndr. 2003 Apr 15;32(5):482-9.
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.]
Macias J et al. Mortality due to Liver Failure and Impact on Survival of Hepatitis Virus Infections in HIV-Infected Patients Receiving Potent Antiretroviral Therapy. Eur J Clin Microbiol Infect Dis. 2002 Nov;21(11):775-81.
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.
Dronda F et al. Long-term outcomes among antiretroviral-naive human immunodeficiency virus-infected patients with small increases in CD4+ cell counts after successful virologic suppression. Clin Infect Dis. 2002 Oct 15;35(8):1005-9.
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]
Anastos K et al. Risk of Progression to AIDS and Death in Women Infected With HIV-1 Initiating Highly Active Antiretroviral Treatment at Different Stages of Disease. Arch Intern Med. 2002 Sep 23;162(17):1973-80.
[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.]
Wilde JT et al. The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. AIDS. 2002 Sep 6;16(13):1803-7.
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.
Mocroft A et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study. AIDS. 2002 Aug 16;16(12):1663-71.
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.
Boix V, Merino E, Portilla J. Highly active antiretroviral therapy for patients with tuberculosis: the solution or the problem?. AIDS. 2002 Jul 5;16(10):1436-7.
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.
Taffé P et al. Impact of occasional short interruptions of HAART on the progression of HIV infection: results from a cohort study. AIDS. 2002;16:747-55.
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]
Estaquier J et al. Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death. J Virol. 2002 Jun;76(12):5966-73.
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
Saitoh A et al. Persistence of Human Immunodeficiency Virus (HIV) Type 1 DNA in Peripheral Blood Despite Prolonged Suppression of Plasma HIV-1 RNA in Children. J Infect Dis. 2002;185(10):1409-16.
a subset of non-T cells with NK [Natural Killer] markers are persistently infected [even after 1-2 years of HAART]
Valentin A et al. Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2002 May 14;99(10):7015-20.
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.
Colebunders R, Lambert MI. Management of co-infection with HIV and TB. BMJ. 2002 Apr 6;324:802-3.
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
Palefsky JM et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr. 2001 Dec 15;28(5):422-8.
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]
Murphy EL et al. Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease. Ann Intern Med. 2001 Jul 3;135(1):17-26.
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.
Eisner R. AIDS Medications Extend Lives But Side Effects Are a Serious Problem. ABC News. 2001 Jun 4
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
Gunthard HF et al. Residual human immunodeficiency virus (HIV) type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis. 2001 May 1;183(9):1318-27.
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
Goetz MB et al. Effect of highly active antiretroviral therapy on outcomes in Veterans Affairs Medical Centers. AIDS. 2001 Mar 9;15(4):530-2.
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.
In U.S. cities, successful HIV treatment rare. Reuters. 2001 Feb 7
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.
Sonza S et al. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS. 2001 Jan 5;15:17-22.
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.''
Saltus R. AIDS drug researchers say firm pressured them. Boston Globe. 2000 Nov 1
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.
Jolson HM. Letter to Bristol-Myers Squibb Company. FDA. 2000 Sep 27
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.
Rose S. AIDS toll on the rise. Provincetown Banner. 2000 Sep 21
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.
Hocking JS et al. Late presentation of HIV infection associated with prolonged survival following AIDS diagnosis-characteristics of individuals. Int J STD AIDS. 2000 Aug; 11(8):503-50.
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.
Smith M. Current drugs no match for AIDS epidemic: Fauci. Biotechnology Newswatch. 2000 Jul 17;1.
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.
Harrington M, Carpenter CCJ. Hit HIV-1 hard, but only when necessary. Lancet. 2000 Jun 17;355(9221):2147-52.
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
Rinaldo CR et al. Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency. J Virol. 2000 May;74(9):4127-38.
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]
Atzori C et al. In vitro activity of human immunodeficiency virus protease against Pneumocystis carinii. J Infect Dis. 2000 May;181:1629-34.
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
Mellors J, Montaner J. Salvage therapy for HIV-1 infection - the challenge grows. Lancet. 2000 Apr 22;355(9213):1435.
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.
Henry K. The case for more cautious, patient-focused antiretroviral therapy. Ann Intern Med. 2000 Feb 15;132(4):306-311.
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.
Lambotte O et al. Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2000 Feb 1;23(2):114-9.
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.
Clerici M et al. Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naive patients with undetectable viraemia. AIDS. 2000 Jan 28;14(2):109-116.
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.
Shacker T et al. Rapid Accumulation of Human Immunodeficiency Virus (HIV) in Lymphatic Tissue Reservoirs during Acute and Early HIV Infection: Implications for Timing of Antiretroviral Therapy. J Infect Dis. 2000 Jan;181(1):354-7.
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.
Descamps D et al. Mechanisms of Virologic Failure in Previously Untreated HIV-Infected Patients From a Trial of Induction-Maintenance Therapy. JAMA. 2000 Jan 12;283(2):205-11.
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.
Junghans C, Low N, Chan P et al. Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy:Swiss HIV Cohort Study. AIDS. 1999 Dec 24;13(18):2547-54.
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.
Zhang Z-Q et al. Sexual Transmission and Propagation of SIV and HIV in Resting and Activated CD4+ T Cells. Science. 1999 Nov 12;286(5443):1353-7.
"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.
Seattle Times. 1999 Nov 10;B1.
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]
Dornadula G et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA. 1999 Nov 3;282(17):1627-32.
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.
Dornadula G et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA. 1999 Nov 3;282(17):1627-32.
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
Chun T et al. Re-emergence of HIV after stopping therapy. Nature. 1999 Oct 28;401(6756):874-5.
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.
Chun T et al. Re-emergence of HIV after stopping therapy. Nature. 1999 Oct 28;401(6756):874-5.
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]
Cassone A et al. In vitro and in vivo anticandidal activity of Human Immunodeficiency Virus protease inhibitors. J Infect Dis. 1999 Aug;180(2):448-53.
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
Zaunders JJ et al. Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia. J Infect Dis. 1999 Aug;180(2):320-9.
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
Lucas G et al. Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions. Ann Intern Med. 1999 Jul 24;131(1):81-7.
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.
Loviglio J. Study looks at HIV Cocktail. Associated Press. 1999 Jul 19
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
Ibanez A et al. Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. AIDS. 1999 Jun 18;13(9):1045-9.
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.
Saag MS, Kilby JM. HIV-1 and HAART: A time to cure, a time to kill. Nat Med. 1999 Jun;5(6):609-11.
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.
Lillo FB et al. Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection. AIDS. 1999;13:791-6.
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.
Zhang L et al. Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy. N Engl J Med. 1999 May 27;340(21):1605-13.
Potent antiretroviral therapy seems unable to eradicate latent HIV-1 reservoirs in CD4+ T cells.
Furtado M et al. Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy. N Engl J Med. 1999 May 27;340(21):1614-22.
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.
Hockett RD et al. Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA. J Exp Med. 1999 May 17;189(10):1545-54.
The efficacy of HIV chemoprophylaxis [AIDS drugs] following consensual or nonconsensual sexual exposure [rape] is unknown.
Bamberger JD et al. Postexposure prophylaxis for human immunodeficiency virus (HIV) infection following sexual assault. Am J Med. 1999 Mar;106(3):323-6.
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.
Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med. 1999 Feb 4;340(5):367-73.
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]
OBrien WA. The most potent antiretroviral weapon - cellular immunity. 6th Conference on Retroviruses and Opportunistic Infections. 1999 Feb 2
In 3 of the 5 patients, the percentage of productively infected cells increased while on therapy
Patterson BK et al. Monitoring HIV-1 treatment in immune-cell subsets with ultrasensitive fluorescence-in-situ hybridisation. Lancet. 1999 Jan 16;353(9148):211-2.
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
Hellerstein M et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans. Nat Med. 1999 Jan;5(1):83-9.
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.
Zhang H et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med. 1998 Dec 17;339(25):1803-16.
Disease progressed faster in participants who sought medical care for their acute seroconversion syndrome (P=0.01)
Schacker TW et al. Biological and Virologic Characteristics of Primary HIV Infection. Ann Intern Med. 1998 Apr 15;128:613-20.
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]
Fischl MA et al. Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. AIDS Clinical Trials Group Study 197. J Acquir Immune Defic Syndr. 1997 Dec 1;16(4):247-53.
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
Lemp GF et al. Projected incidence of AIDS in San Francisco: the peak and decline of the epidemic. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Nov 1;16(3):182-9.
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]
Hammer SM et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725-33.
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]
Bonhoeffer S et al. Virus dynamics and drug therapy. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6971-6.
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
Royce RA et al. Sexual transmission of HIV. N Engl J Med. 1997 Apr 10;336(15):1072-8.
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
Graham NMH et al. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Intern Med. 1996;124:1031-8.
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?]
Poznansky MC et al. HIV positive patients first presenting with an AIDS defining illness: characteristics and survival. BMJ. 1995 Jul 15;311(6998):156-8.
Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days
Wei X et al. Viral dynamics in HIV-1 infection. Nature. 1995 Jan 12;373(6510 ):117-22.
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.
Simonds RJ et al. Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor. N Engl J Med. 1992 Mar 12;326(11):726-32.
Lexivaa protease inhbitor (PI) fit for combination therapy does not cure HIV or prevent passing HIV to others
The HIV life cycle and the role of combination therapy. GlaxoSmithKline.
Courtesy Alberta Reappraising AIDS Society, August 10, 2011.
© Copyright August 10, 2011 by Rethinking AIDS.