Elsevier

The Lancet

Volume 362, Issue 9385, 30 August 2003, Pages 679-686
The Lancet

Articles
Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies

https://doi.org/10.1016/S0140-6736(03)14229-8Get rights and content

Summary

Background

We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART.

Methods

We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months.

Findings

During 13 408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/μL, adjusted hazard ratios for AIDS or death were 0·55 (95%CI 0·32–0·96) for 25–49 cells/μL, 0·62 (0·40–0·96) for 50–99 cells/μL, 0·42 (0·28–0·64) for 100–199 cells/μL, 0·25 (0·16–0·38) for 200–349 cells/μL, and 0·18 (0·11–0·29) for 350 or more cells/μL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100 000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0·59 (0·41–0·86) for 10 000–99 999 copies/mL, 0·42 (0·29–0·61) for 500–9999 copies/mL, and 0·29 (0·21–0·39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2·4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum.

Interpretation

At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.

Introduction

In patients with HIV-1 who are starting highly active antiretroviral therapy (HAART), prognosis is strongly associated with CD4 cell count at baseline. High levels of HIV replication at baseline, older age, a history of AIDS and infection through injection-drug use are also associated with increased rates of clinical progression.1, 2, 3, 4, 5 Patients' characteristics at the time they start HAART can thus be used to predict their probability of disease-free survival, and overall survival. In a previous analysis of data from the ART Cohort Collaboration, a large database of patients who had not received antiretroviral therapy before starting HAART from 13 cohort studies, the estimated probability of progression to AIDS or death within 3 years of starting HAART, based on these prognostic factors, varied from 3·4% to 50%.1

HIV-1 RNA concentrations decline quickly in many, but not all, patients, with substantial increases in CD4 cell counts within months of starting HAART.2, 5, 6, 7, 8, 9, 10 The accuracy of predictions of disease progression might therefore be improved by accounting for early response to therapy, seen in CD4 cell count and HIV-1 RNA measured some time after HAART is started. This response might allow early identification of patients who are at a high risk of progression and who might benefit from modification or intensification of therapy.

Previous reports of prognosis after early response to therapy were based on single cohorts in which few clinical events were assessed, or that contained mostly patients who had previously received antiretroviral treatment.2, 3, 5, 6 Few data are available in patients who have never undergone antiretroviral treatment. The a-priori defined objective of our study was to provide precise estimates of the probability of clinical progression for antiretroviral-naive patients starting HAART, both from the start of HAART and from month 6, taking into account the initial viral and immunological response. Here we report the results from the second analysis and compare the importance of baseline measurements of CD4 and viral load with the measurements obtained 6 months later.

Section snippets

Patients

The ART Cohort Collaboration was established in 2000 and includes 13 cohort studies.2, 3, 6, 7, 11, 12, 13, 14, 15, 16, 17, 18, 19 The design has been detailed previously.1 Briefly, prospective cohort studies were eligible if they had enrolled at least 100 patients with HIV-1 infection aged 16 years or older who had not previously received antiretroviral treatment and had started such treatment with a combination of at least three drugs, including nucleoside analogue reverse transcriptase

Statistical analysis

We considered the probability of progression to a combined endpoint of new AIDS event or death and to death alone. In both definitions we included deaths from all causes. We used the clinical part of the 1993 US Centers for Disease Control and Prevention revision of the AIDS case definition (ie, people without an AIDS-defining disease but with a CD4 cell count of lower than 200 cells/μL were not classified as having AIDS).20 Relapses of previous opportunistic infections were not deemed to be

Development of prognostic models

The methods used to choose prognostic models have been described previously.1 Briefly, candidate prognostic models were parametric survival models based on the Weibull, loglogistic, and lognormal distributions, with generalisations that use cubic splines to model the baseline hazard function. A backward stepwise selection procedure was used to choose prognostic variables and their categorisation and to assess for evidence of interactions or for an improvement in fit in stratified compared with

Role of the funding source

The funding source had no role in study design, data collection, data analysis, data interpretation, or in the writing of the report.

Results

The characteristics of the 13 participating cohorts have been reported elsewhere.1 Ten cohorts were from European countries, two from Canada, and one from the USA. The total number of patients was 12 574 ranging from 92 to 4739 in the different cohorts. 3251 (26%) patients were not eligible for the present analyses, for the following reasons: 89 died before 6 months, 1000 had a follow-up shorter than 6 months, and 2162 had no CD4 or viral load measurements between 3 and 9 months after the start

Discussion

In this large collaborative study of 9323 patients who started HAART as their first antiretroviral regimen and who survived and were followed up for longer than 6 months, we found that the initial immunological and virological response, as reflected by CD4 count and viral load, were the two most important factors in prediction of progression to AIDS or death over subsequent years. Patients whose 6-month CD4 cell count was less than 25 cells/μL had the worst prognosis. Age 50 years or older,

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