HIV This Week

Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants . N Engl J Med; 2008 20;359(21):2233-44

In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. Violari and colleagues investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial. HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir-ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). They report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy. At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI], 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anaemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy. Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%.

Editors’ note: The findings of this randomised controlled trial of early initiation of antiretroviral therapy confirm results of studies in the global north reporting better outcomes in infants receiving early treatment. Because nevirapine-based regimens may not be as effective in infants who have been exposed to single–dose nevirapine for prevention of mother-to-child transmission, infants in the trial’s intervention arm received a protease inhibitor-based regimen. Increasing the availability of the paediatric formulations of these drugs, as well as that of the polymerase-chain- reaction (PCR) tests for HIV-1 DNA that are needed for early infant diagnosis, is essential if the December 2008 WHO guidelines recommending antiretroviral treatment for all infants with confirmed HIV infection, including those that are asymptomatic, are to be implemented.