HIV: Early Time-Limited Therapy Lowers Mortality for Infants

Larry Hand

August 22, 2013

HIV-infected infants who received early antiretroviral therapy (ART) for a limited time and then stopped treatment had a lower risk for death or disease progression compared with infants whose treatment was delayed until medically necessary, in a South African randomized trial.

Researchers report the 5-year follow-up results from the Children With HIV Antiretroviral Therapy (CHER) trial in an article published online August 21 in the Lancet.

The new data confirm preliminary findings from CHER published in 2008, which showed that early ART reduced the risk for death and disease progression by 75%. Those findings prompted the World Health Organization to revise its treatment guidelines to recommend ART be started early in children younger than 1 year.

Mark F. Cotton, MD, PhD, from the Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa, and colleagues analyzed the 5-year follow-up results from CHER, conducted between July 2005 and February 2007.

In the trial, 377 HIV-infected infants, median age 7.4 weeks, were randomly assigned to deferred ART, ART for 40 weeks, or ART for 96 weeks. Initiation of deferred ART or re-initiation of ART after interruption was based on CD4 lymphocyte percentage of less than 20% or CD4 count fewer than 1000 cells/mm3. Another 34 infants were randomly assigned to either 40 or 96 weeks of ART between September 2007 and March 2008 after the trial's Data Safety Monitoring Board recommended in June 2007 that deferred ART recruitment be stopped.

In the latest analysis, researchers found that the hazard ratio (HR) for death or failure of first-line therapy to be 0.59 (95% confidence interval [CI], 0.38 - 0.93, P = .023) for 40 weeks of ART and 0.47 (95% CI, 0.29 - 0.76; P = .002) for 96 weeks of ART, compared with deferred ART. Eleven infants died in each of the early treatment groups (9%) compared with 23 infants (18%) in the deferred ART group.

The risk for clinical disease progression was almost halved with early treatment. Infants treated with 40 weeks of ART early had a 47% reduced risk for progression compared with those in the deferred ART group (HR, 0.53; 95% CI, 0.34 - 0.82; P = .005); those treated with 96 weeks of early ART had a 58% reduction in risk (HR, 0.42; 95% CI, 0.26 - 0.67; P = .0003).

Infants in the deferred treatment group needed to begin ART a median of 20 weeks after randomization. Infants in the early-treatment groups required reinitiation of treatment a median of 33 weeks after stopping therapy in the 40 weeks of ART group and after a median of 70 weeks in the 96 weeks of ART group. At the end of CHER, 19% of children in the 40 of weeks of ART and 32% of infants in the 96 weeks of ART groups remained off treatment.

"This important finding indicates we may be able to temporarily stop treatment and spare infants from some of the toxic effects of continuous ART for a while, if we can monitor them carefully," Dr. Cotton said in a news release.

In an accompanying comment, Robert Colebunders, MD, PhD, from the Institute of Tropical Medicine, Antwerp, Belgium, and Victor Musiime, MBchB, MMed, from the Makerere University College of Health Sciences, Kampala, Uganda, caution that treatment interruptions require that children be closely monitored and that this might not be possible in resource-poor African countries, where most HIV-positive children live.

They conclude, "Certainly, children will benefit from an improved, drug-free quality of life but we will need to be sure that this approach will not cause them any harm."

This research was supported by the US National Institute of Allergy and Infectious Disease, the Departments of Health of Western Cape and Gauteng, South Africa, and GlaxoSmithKline. The commentators have disclosed no relevant financial relationships.

Lancet. Published online August 21, 2013. Article abstract, Comment extract

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