Numerous clinical trials as well as observational data (i.e. studies from clinical practice) have demonstrated beyond reasonable doubt that the benefits of antiretroviral treatment for people with HIV/AIDS far outweigh their risks. Antiretrovirals are an extremely well tested class of medicines. We present some of the evidence demonstrating that their benefits outweigh their risks here. The current standard of care for people with HIV indicated for treatment, is a combination of three or more antiretroviral drugs taken everyday for life, known as Highly Active Antiretroviral Treatment (HAART). People with HIV generally do not need to begin antiretroviral treatment until their disease reaches an advanced stage. The World Health Organisation treatment guidelines for resource-limited settings explain when HAART should be commenced and what precise combination of antiretrovirals should be used. In the United States, the standard of care for adults and adolescents, as well as children, is described by the US Department of Health and Human Services.
In South Africa, the standard of care is described in the Southern African HIV Clinicians Society’s antiretroviral treatment guidelines. Antiretrovirals have also been shown to reduce the risk of women transmitting the virus to their infants. Here are the US guidelines and the World Health Organisation guidelines.
Evidence from clinical trials
Meta-analysis of antiretroviral trials
- Siegfried, Uthman & Rutherford (2010) Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults (Review). Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD008272. DOI:10.1002/14651858.CD008272.pub2.
PLAIN LANGUAGE SUMMARY
When is the best time to start antiretroviral therapy in people with HIV infection, who have not received antiretroviral treatment before and who do not have any symptoms of HIV illness? Antiretroviral therapy (ART) has been shown to be effective in slowing down the progression of AIDS and in reducing HIV-related illnesses and death. Traditionally, therapy is administered based on a patient’s CD4 cell count, where the number of CD4 cells reflects the body’s immune (defense) system. An HIV-infected individual with a CD4 cell count of 500 cells/μL is considered healthy enough not to need ART. When a patient’s cell count reaches 200 cells/ μL, however, the immune system is severely weakened and ART is necessary. A patient with advanced symptoms receives treatment regardless of CD4 count. Recommendations on the timing for ART initiation differ based on availability of resources, leading to confusion amongst clinicians and policy-makers in determining the most favorable point to begin treatment. The objective of this review is to assess the evidence for the optimal time to initiate ART in HIV-infected adults who have not previously received therapy and who do not have symptoms of HIV illness. The authors reviewed two trials which involved 1,065 participants. Both studies compared the effect of ART initiation at high CD4 counts (350 cells/μL) with ART initiation at low CD4 counts (250 cells/μL). Results showed that starting ART at higher levels of CD4 reduces mortality rates in HIV-infected individuals who have not received antiretroviral treatment before and who do not have any symptoms of HIV illness.ABSTRACTBackground
According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy (ART) is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of ART is clearly complex and must, therefore, be balanced between individual and broader public health needs.
Objectives
To assess the evidence for the optimal time to initiate ART in treatment-naive, asymptomatic, HIV-infected adults
Search strategy
We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). In August 2009, we searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. We also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. We contacted researchers and relevant organizations and checked reference lists of all included studies.
Selection criteria
Randomized controlled trials that compared the effect of ART consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial. Early initiation could be at levels of 201-350, 351-500, or >500 cells/µL, with the comparison group initiating ART at CD4 counts below 200 x 106 cells/µL or as defined by the trial.
Data collection and analysis
Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, we meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs).
Main results
One completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. We combined the mortality data for both trials comparing initiating ART at CD4 levels at 350 cells/µL or between 200 and 350 cells/µL with deferring initiation of ART to CD4 levels of 250 cells/µL or 200 cells/µL. There was a statistically significant reduction in death when starting ART at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting ART early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI: 0.26, 1.12; P = 0.01). Starting ART at enrollment (when participants had CD4 counts of 350 cells/µL) rather than deferring to starting at a CD4 count of 250 cells/µL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).
Authors’ conclusions
There is evidence of moderate quality that initiating ART at CD4 levels higher than 200 or 250 cells/µL reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. Practitioners and policy-makers may consider initiating ART at levels ≤ 350 cells/µL for patients who present to health services and are diagnosed with HIV early in the infection.
AIDS denialists say that the risks of antiretrovirals outweigh their benefits. If this is the case, then surely mortality should be higher, rather than lower, in patients who start taking them earlier?
- Jordan et al. (2002) Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy. BMJ 2002;324:757. This meta-analysis of 54 antiretroviral clinical trials has demonstrated that:
-
- Using one antiretroviral reduced progression to AIDS or death by 30% against placebo.
- Using two antiretrovirals reduced progression to AIDS or death by 40% against one antiretroviral
- Using three antiretrovirals reduced progression to AIDS or death by 40% against two antiretrovirals
AIDS denialists say that the risks of antiretrovirals outweigh their benefits. If this is the case, then why do people do better when they take more antiretrovirals? The denialists cannot rationally explain this.
Continuous treatment versus structured treatment breaks
NIH (2006) International HIV/AIDS Trial Finds Continuous Antiretroviral Therapy Superior to Episodic Therapy.
This randomised trial compared patients who took HAART continuously to patients who took structured treatment breaks. The rate of progression to AIDS or death in the continuous treatment arm was half the structured treatment break arm.
AIDS denialists say that the risks of antiretrovirals outweigh their benefits. If this is the case, then why do people who take antiretrovirals all the time do better than people who take them occasionally? The denialists cannot rationally explain this.
Immediate versus deferred treatment in infants
Violari et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov 20;359(21):2233-44.
This randomised controlled trial known as CHER, run in South Africa, compared what happened to infants who were put onto HAART as soon as they were diagnosed versus those whose treatment was delayed until their CD4 count had declined or they showed clinical signs of AIDS, the standard of care at the time of the trial. 16% of the infants in the delayed group died versus 4% of the immediately treated infants, a 75% improvement. Again, this result cannot be explained by the AIDS denialist position that the toxicity of HAART outweighs its benefits.
Evidence from clinical practice
Here is a small selection from the many studies from clinical practice that have shown HAART substantially reduces death and illness. Besides the studies shown here, HAART has been shown to reduce death and illness in Zambia, Hong Kong and Brazil.
Seminal study on antiretrovirals in clinical practice in the United States
Palella et al. (1998) Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. New England Journal of Medicine. Volume 338:853-860. This important study demonstrated how effective HAART was in clinical practice. Quoting from the abstract:
Mortality among the patients declined from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit … [our emphasis]
Swiss Cohort
Sterne et al. (2005) Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2005 Jul 30-Aug 5;366(9483):346-7. Using leading-edge statistical techniques, the authors calculated that the risk of progression to AIDS or death for patients on HAART in the Swiss Cohort was 14% of patients not on HAART.
Khayelitsha, South Africa Cohort
Coetzee et al. (2004) Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS April 9, 2004, 18:6. Based on excellent results for patients who started HAART with very low CD4 and high viral load counts, The authors concluded “[HAART] can be provided in resource-limited settings with good patient retention and clinical outcomes. With responsible implementation, ART is a key component of a comprehensive response to the epidemic in those communities most affected by HIV.”
Cape Town, South Africa Cohort
Badri et al. (2004) Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines. This study compared patients on HAART and not on HAART in Cape Town, South Africa. It found that “HAART was associated with decreased AIDS [adjusted rate ratio [ARR], 0.16; 95% confidence interval (CI), 0.08-0.31) and death (ARR, 0.10; 95% CI, 0.06-0.18).”
EuroSIDA Cohort
Mocroft et al. (2003) Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 2003 Jul 5;362(9377):22-9. This study of over 9,000 patients in Europe, Argentina and Israel showed the decline in deaths and AIDS as a result of the introduction of HAART. The authors conclude “The initial drop in mortality and morbidity after the introduction of HAART has been sustained. Potential long-term adverse effects associated with HAART have not altered its effectiveness in treating AIDS.”
Children Receiving ART in Soweto, South Africa
Moultrie, Yotebieng, Kuhn & Meyers (2009) Mortality and Virological Outcomes of 2105 HIV-infected Children Receiving ART in Soweto, South Africa. 16th Conference on Retroviruses and Opportunistic Infections.
Background: Roll-out of ART in the public sector in low resource settings makes pediatric HIV infection a manageable chronic condition. However, there are few data demonstrating the success of these programs, particularly on virological response-a crucial outcome to predict drug resistance and long-term program sustainability. We report 4-year outcomes from a pediatric HIV outpatient service at Chris Hani Baragwanath Hospital, which included routine virological monitoring.
Methods: Included in the analysis were 2105 HIV-infected children <15 years of age entering the program and initiating ART from April 2004 to March 2008 who had at least 1 follow-up visit. Children <3 years usually started lopinavir/ritonavir (LPV/r) + lamivudine (3TC) + stavudine (d4T) and children >3 years of age efavirenz (EFV) +3TC+d4T. Viral load, CD4 was measured pre-treatment and 6-monthly and anthropometric measurements every 3 months. All outcomes through April 2008 were included using survival longitudinal analysis.
Results: The median age at ART initiation was 4.3 (interquartile range 1.6 to 7.5) years; 1068 (51%) were male; 602 (29%) were on TB treatment, the mean CD4 percentage was 12.8% (95% confidence interval 11.9 to 13.7%). During the first 90 days of ART, 69 children died (14.4 of 100 child-years, 95%CI 11.40 to 18.28). The mortality rate after 90 days was lower (1.99/100 child-years, 95%CI 1.55 to 2.55). Rates of loss to follow-up (6%) and transfer to other services (5%) were low. Among survivors, the proportion of children who achieved viral suppression (<400 copies/mL) increased progressively from 60.6% (95%CI 58.2 to 63.1%) by 6 months, to 85.1% (95%CI 83.1 to 86.9%) by 12 months, to reach 94.6% (95%CI 92.9 to 96.0%) by 24 months. The mean CD4 cell percentage increased to 25.0% (95%CI 24.3 to 25.7%) at 12 months, and then slowly to 31.7% (95%CI 27.6 to 35.7%) by 42 months. The mean weight-for-age z-score rose from -2.42 (95%CI -2.50 to -2.33) at ART initiation, to -0.67 (95%CI -0.87 to -0.46) at 42 months. The mean height-for-age z-score increased from -2.72 (95%CI -2.78 to -2.65) at baseline to -1.72 (95%CI -1.90 to -1.54) at 42 months.
Conclusions: The vast majority of children achieve viral suppression even in the context of a routine service program. Mortality rates are high during the first few weeks of ART and may reflect failure to identify HIV-infected children early. Programs to strengthen early infant diagnosis combined with prompt referral to treatment programs may be able to reduce these needless deaths.
Clinical trials for specific antiretroviral medicines
This list of clinical trials demonstrating the efficacy of specific antiretrovirals is incomplete. Currently, we neither list all the available antiretrovirals nor, in some cases, all the phase III trials for a particular antiretroviral. We hope to make this list more complete with time.
Zidovudine (AZT)
BW 002: First phase III AZT clinical trial:
Fischl et a. (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185-91. This trial is described as follows by NIAID: “A clinical trial known as BW 002 compared AZT with placebo in 282 patients with AIDS or advanced signs or symptoms of HIV disease. In this study, which led to the approval of AZT by the FDA, only one of 145 patients treated with AZT died compared with 19 of 137 placebo recipients in a six month period. Opportunistic infections occurred in 24 AZT recipients and 45 placebo recipients. In addition to reducing mortality, AZT was shown to have reduced the frequency and severity of AIDS-associated opportunistic infections, improved body weight, prevented deterioration in Karnofsky performance score, and increased counts of CD4+ T lymphocytes in the peripheral blood (Fischl et al., 1987; Richman et al., 1987). Continued follow-up in 229 of these patients showed that the survival benefit of AZT extended to at least 21 months after the initiation of therapy; survival in the original treatment group was 57.6 percent at that time, whereas survival among members of the original placebo group was 51.5 percent at nine months (Richman and Andrews, 1988; Fischl et al., 1989).”
ACTG 016: AZT shown to be effective for symptomatic patients with CD4 of 200-500
Fischl et al. (1990) The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group. Ann Intern Med. 1990 May 15;112(10):727-37. This study is described as follows by NIAID: “In another placebo-controlled study known as ACTG 016, which enrolled 711 symptomatic HIV-infected patients with CD4+ T cell counts between 200 and 500 cells/mm3, those taking AZT were less likely to experience disease progression than those on placebo during a median study period of 11 months (Fischl et al., 1990). In this study, no difference in disease progression was noted among participants who began the trial with CD4+ T cell counts greater than 500/mm3.”
Concorde: A trial grossly misrepresented by AIDS denialists
Concorde Coordinating Committee (1994). MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994;343(8902):871-81. AIDS denialists have claimed that the Concorde trial supports the view that the risks of AZT outweigh its benefits. This is false. Concorde was the biggest AZT monotherapy study over the longest period of time. But it showed unequivocally that AZT is not the cause of AIDS. Concorde only examined people with HIV WITHOUT symptoms of AIDS. It compared two strategies: Approximately half the trial participants took AZT immediately and the other half took placebo UNTIL they developed AIDS. Once patients progressed to AIDS, they were unblinded from the trial and given AZT. The participants taking AZT immediately had slower disease progression in the first year, but this dissipated with time resulting in no statistical difference in progression to AIDS. Since a large, approximately equal, number of participants in both arms progressed to AIDS, it clearly shows that AZT was no more harmful than placebo and therefore cannot be the cause of AIDS. The denialists misrepresent the following about the Concorde trial: In a long-term follow up of the Concorde patients those who deferred AZT treatment until they got AIDS were less likely (slightly, but statistically significantly) to die than those who took it immediately. But at this point the researchers were no longer comparing placebo against AZT. As a scientist involved in the Concorde trial explained in an affidavit rebutting AIDS denialist Anthony Brink in a South African court case which Brink pulled out of, Concorde was not testing whether AZT was better than placebo; this was already known. It was only trying to determine whether AZT should be taken before one developed AIDS symptoms. It concluded that one should not. If the patients in the placebo arm stayed on placebo and never took AZT when they got AIDS, then a comparison would have been possible (and we can conclude from the trials described above that such hypothetical patients would have done very badly). But this is not what happened: patients on placebo indeed started AZT treatment when they developed AIDS because AZT had previously been shown unequivocally to be beneficial for people with AIDS. Also, if the patients who took AZT immediately progressed to AIDS faster than the placebo group then one could conclude that AZT in patients without AIDS symptoms is dangerous. But the study show the opposite result, albeit with reduced benefit over time. We now know why taking AZT as a monotherapy before developing symptoms of AIDS was an unsuccessful strategy. Patients taking one antiretroviral develop a strain of HIV resistant to the virus in very short time (a few months on average). Consequently the drug stops destroying HIV and patients then experience the side-effects without the benefits. Then when they do eventually get AIDS, the drug no longer has a useful effect. With today’s standard of triple-drug therapy, resistance takes, on average, a few years to develop, but resistance is probably not inevitable. When resistance happens, patients have to switch to a new antiretroviral regimen. The current medical consensus is that treatment should still be deferred until a CD4 count of between 200 and 350 or an AIDS-defining illness occurs. It should also be noted that when AZT was originally prescribed as a monotherapy, it was prescribed in very high doses (1500mg per day). Nowadays it is prescribed in much lower doses (usually 500mg per day).
Cochrane review of AZT trials for mother-to-child transmission HIV reduction
Brocklehurst P et al. (2006) Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. The Cochrane Database of Systematic Reviews 2006 Issue 2. (Last substantive update in 2002) This review explains that four AZT versus placebo trials have demonstrated that AZT significantly reduces the risk of mother-to-child transmission of HIV.
Lamivudine
Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet. 1997 May 17;349(9063):1413-21. This trial showed that adding lamivudine to AZT containing regimens slowed HIV progression and improved survival.
Didanosine
Kahn JO. et al. (1992) A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAIDAIDS Clinical Trials Group. N Engl J Med. 1992 Aug 27;327(9):581-7 We include this study to debunk a denialist lie that didanosine was registered by the US Food and Drug Administration (FDA) without a clinical trial being conducted. The FDA registered didanosine before this trial was published but the regulator had access to the trial data and results when registration took place. Hammer et al. (1996) A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 StudyTeam. N Engl J Med. 1996 Oct 10;335(15):1081-90. This trial compared AZT experienced patients randomly assigned to taking didanosine versus AZT experienced patients who continued to take AZT. It demonstrated that didanosine reduced disease progression and deaths.
Nevirapine
Clinical trials demonstrating the efficacy of nevirapine in reducing HIV viral load and increasing CD4 counts are described in the drug’s FDA package insert. Brocklehurst P et al. (2006) (referred to above under AZT) This Cochrane review describes the evidence that single-dose nevirapine is effective at reducing mother-to-child transmission prevention. Lallemant M (2004) Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med. 2004 Jul 15;351(3):217-28. This study showed that “A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks’ gestation, is highly effective in reducing mother-to-child transmission of HIV.”
Indinavir
FDA. (1996) FDA grants accelerated approval to third protease inhibitor to treat HIV. We include the above press release to show that, in contrast to the suggestions of AIDS denialists, indinavir was registered by the FDA on the basis of two trials. These studies demonstrated that indinavir improved the CD4 and viral load counts of patients.