Elsevier

The Lancet

Volume 366, Issue 9483, 30 July–5 August 2005, Pages 378-384
The Lancet

Articles
Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study

https://doi.org/10.1016/S0140-6736(05)67022-5Get rights and content

Summary

Background

Evidence on the effectiveness of highly active antiretroviral therapy (HAART) for HIV-infected individuals is limited. Most clinical trials examined surrogate endpoints over short periods of follow-up and there has been no placebo-controlled randomised trial of HAART. Estimation of treatment effects in observational studies is problematic, because of confounding by indication. We aimed to use novel methodology to overcome this problem in the Swiss HIV Cohort Study.

Methods

Patients were included if they had been examined after January 1996, when HAART became available in Switzerland, were not on HAART, and were free of AIDS at baseline. Cox regression models were weighted to create a statistical population in which the probability of being treated at each time point was unrelated to prognostic factors.

Results

Low CD4 counts and increasing HIV-1 viral load were associated with increased probability of starting HAART. Overall hazard ratios were 0·14 (95% CI 0·07–0·29) for HAART compared with no treatment, and 0·49 (0·31–0·79) compared with dual therapy. Compared with no treatment, HAART became more beneficial with increasing time since initiation but was less beneficial for patients whose presumed mode of transmission was via intravenous drug use (hazard ratio 0·27, 0·12–0·61) than for other patients (0·08, 0·03–0·19).

Interpretation

Our results, which are appropriately controlled for confounding by indication, are consistent with reported declines in rates of AIDS and death in developed countries, and provide a context in which to consider adverse effects of HAART.

Introduction

Highly active antiretroviral therapy (HAART) is a combination of at least three drugs, typically including either a protease inhibitor or a non-nucleoside analogue reverse transcriptase inhibitor, and two nucleoside analogue reverse transcriptase inhibitors. Randomised trials have shown substantial reductions in disease progression in HIV-1-infected patients treated with HAART compared with those treated with dual therapy with two nucleoside analogue reverse transcriptase inhibitors,1, 2 although such evidence has several limitations. Most trials3 have focused on increase in CD4 count and virological response after starting treatment, but these measures are imperfect surrogates for clinical progression to AIDS or death.4, 5 In many studies, follow-up was restricted to a year or less, but current treatments have to be taken for life. For ethical reasons, there has been no placebo-controlled randomised trial of HAART. The effectiveness of this treatment over several years is therefore unknown.

Such information is of obvious importance to patients and their carers and is necessary for a better understanding of the course of disease in patients treated with HAART, and to plan health services. Without trial evidence, this information must come from observational cohort studies. However, estimation of treatment effects in observational studies is not straightforward, because of time-dependent confounders (risk factors varying with time and predicting initiation of treatment) that are also affected by treatment.6, 7 For example, CD4 count is a time-dependent confounder for the effect of HAART, because patients with lower counts are more likely to be treated. CD4 count is also affected by HAART, and is thus intermediate on the causal pathway from such treatment to AIDS or death. In this situation, a type of confounding by indication,8 standard approaches such as Cox regression will yield biased estimates of the effect of treatment.6, 9 We aimed to use novel methodology—marginal structural models9—to overcome this problem and estimate the effectiveness of HAART over several years.

Section snippets

Study design and participants

Participants in the Swiss HIV Cohort Study,10, 11 who were examined after January 1996, when HAART became available in Switzerland, were potentially eligible for analysis. Clinical AIDS diagnoses (Centers for Disease Control and Prevention [CDC] stage C) were made by the treating physicians on the basis of the 1993 CDC criteria.12 The baseline month was that of the first follow up visit after January, 1996, during which all variables were available. Patients who died or refused further

Results

2161 patients contributed person-time to the comparison of HAART with no treatment, and 1276 to the comparison of HAART with dual therapy (192 patients contributed to both comparisons). 400 (12%) progressed to AIDS or death and 1705 (53%) were ever treated with HAART. Median follow-up was 54 months (IQR 20–84). Total observation time was 13 562 patient-years, of which 7145 (53%) were time on HAART. Overall progression rates per 100 person-years were lower for patients on HAART than for those

Discussion

Our results indicate that HAART reduced the rate of progression to AIDS or death by 86%, and that its effectiveness compared with no treatment increased with time since initiation. Because most HIV-1 infected patients starting HAART will not have been treated previously, estimates of its effectiveness compared with no treatment are required by patients and their clinicians, especially in view of possible adverse effects.17 The widespread use of potent antiretroviral therapy since 1996 has

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