Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis

Summary

Background

Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only.

Methods

We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models.

Findings

997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10⁵ copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor.

Interpretation

This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

Introduction

Reports from early cohort studies have shown that 20–25% of children infected with HIV-1 progress rapidly to AIDS or die during infancy, with slower disease progression in older children.¹ The introduction of combination antiretroviral therapy has resulted in major reductions in morbidity and mortality,2, 3 but there have been no trials in either children or adults addressing the question of when such treatment should be started. In the absence of data, guidelines for starting and switching antiretroviral therapy have taken account of the CD4 T-cell count and HIV-1 RNA viral load as predictors of progression to symptomatic disease.4, 5, 6 Although data about the prognostic value of these markers are available from studies in adults, special factors in children include a developing immune system, slow attainment of a virological “set point”,⁷ clinical use of CD4 T-cell percentage (CD4%) rather than CD4 cell count,⁴ and the need to account for age.8, 9 Several studies in paediatric populations have been reported,8, 9, 10, 11 with risk estimates relating to a 2–7 year time horizon. However, because CD4 T cells and viral load are regularly monitored (typically every 3 months), short-term risk estimates are arguably clinically more relevant than long-term predictions.¹²

Based on individual patient data from nearly 4000 HIV-1-infected children participating in cohort studies and randomised trials in Europe and the USA, who received no antiretroviral therapy or zidovudine monotherapy, we have estimated the 12-month risks of progression to AIDS and death, in terms of age and the most recent measurement of CD4% or viral load.