Elsevier

The Lancet

Volume 353, Issue 9156, 13 March 1999, Pages 863-868
The Lancet

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Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study

https://doi.org/10.1016/S0140-6736(99)01122-8Get rights and content

Summary

Background

The efficacy of highly active antiretroviral therapy (HAART) in suppression of HIV-1 is well documented. We investigated virological and clinical outcomes of HAART in routine practice.

Methods

We analysed prospective data from the Swiss HIV Cohort Study on suppression of viral load and progression to AIDS or death in 2674 outpatients (median age 36 years, 27·3% women) who started HAART in 1995–98. Viral rebound was defined as two consecutive HIV-1-RNA measurements of more than 400 copies/mL. We analysed separately outcomes in patients with a history of antiretroviral treatment and in treatment-naïve patients.

Findings

An estimated 90·7% of treatment-naïve patients reached undetectable viral load (<400 copies/mL) by 12 months. Among pretreated patients, estimates ranged from 70·3% treated with one new drug to 78·7% on three new drugs. 2 years after reaching undetectable concentrations, an estimated 20·1% of treatment-naïve patients and 35·7–40·1% of pretreated patients had viral rebound. At 30 months, an estimated 6·6% (95% CI 4·6–8·6) of patients who had maintained undetectable concentrations, 9·0% (5·5–12·5) who had viral rebound, and 20·1% (15·3–24·9) who had never reached undetectable concentrations developed AIDS or died. Compared with patients who maintained undetectable viral load, the adjusted relative hazard of AIDS or death was 1·00 (0·66–1·55) for patients with viral rebound, and 2·40 (1·72–3·33) for patients who failed to reach undetectable concentrations.

Interpretation

The rate of virological failure of HAART was high among these patients, but the probability of clinical progression was low even in patients with viral rebound.

Introduction

Highly active antiretroviral therapy (HAART) is currently the most important component of the treatment of HIV-1 infection. At present, HAART generally consists of one protease inhibitor combined with at least two nucleoside analogue reversetranscriptase inhibitors. The efficacy of HAART in suppression of plasma HIV-1 RNA to undetectable concentrations has been documented in clinical trials.1, 2, 3 The virological and immunological success rates reported from such trials may not, however, be generalisable to the whole population of HIV-1-infected patients.4 Furthermore, new opportunistic diseases or death are rarely used as endpoints in trials of HAART. It is widely accepted that plasma viral loads and CD4 cell counts reflect clinical efficacy, and virological and immunological responses are therefore used as surrogate endpoints. Viral load and CD4 counts are, however, imperfect surrogate markers that do not capture effects due to toxic effects or mediated through other causal pathways.5, 6

In the absence of trials assessing clinical endpoints, observational data are the only source of information relating new treatment regimens to the risk of serious clinical disease. Studies in the USA7 and Europe8, 9 have documented a substantial decrease in the risk of new opportunistic infections and of mortality after HAART was introduced. These studies have not, however, related virological responses to clinical progression.

We analysed the database of the national Swiss HIV Cohort Study to assess virological and immunological responses to HAART in routine care and to relate these findings to clinical disease progression.

Section snippets

Patients

The Swiss HIV Cohort Study is a prospective cohort study with continuing enrolment of HIV-1-infected patients aged 16 years or older.8, 10 Patients are followed up in one of seven outpatient clinics. Enrolment is independent of disease stage or degree of immunosuppression and information is collected according to standardised criteria at registration and follow-up visits every 6 months. Comparisons with the national AIDS registry have shown that the cohort includes 70% of patients with AIDS.10

Patients

Between September, 1995, and November, 1998, 3451 (65·1%) of 5298 patients followed up in the Swiss HIV Cohort study had started HAART. We excluded 252 (7·3%) patients who did not have at least one follow-up visit after HAART was started, and 525 (15·2%) with missing viral load or CD4 count at baseline. The analyses were based on 2674 (77·5%) patients (table 1). Included and excluded patients did not differ significantly for age, sex, transmission group, or clinical stage at baseline. History

Discussion

HAART led to suppression of viral replication in a substantial proportion of patients, but our results were less favourable than those from randomised trials.1, 3, 12 Gulick and colleagues3 showed that initial treatment with a triple-combination therapy, including a protease inhibitor, led to sustained suppression of viral load in pretreated patients. At 100 weeks, viral load continued to be undetectable in 78% of patients. Conversely, we found that 20–30% of pretreated patients never reached

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