Early treatment with a four-drug combination a good option for HIV-infected infants

Christopher Gadd
Published: 11 June 2004

Initiation of a HAART combination consisting of stavudine (d4T, Zerit), lamivudine (3TC, Epivir), nevirapine (Viramune) and nelfinavir (Viracept) in HIV-1-infected infants before the age of three months leads to long-term viral suppression, according to a study presented in the June 10th edition of the New England Journal of Medicine.

HIV infection in children is known to cause more rapid depletion of CD4 cell counts and disease progression than in adults. Since there are currently few data available on the effectiveness of anti-HIV therapy in children, this study (known as PACTG 356 and coordinated by the University of Massachusetts Medical School), was designed to assess the safety, tolerability and activity of three antiretroviral drug regimens in HIV-infected children.

“Our data suggest that an age of no more than three months at the initiation of therapy and treatment with d4T, 3TC, nevirapine and nelfinavir are associated with improved long-term viral suppression,” state the authors. “Since the tempo of disease progression is often accelerated in young HIV-1-infected children and since we lack reliable predictors of outcome in the first year of life, it seems reasonable to consider early initiation of antiretroviral therapy when feasible until further data are available.”

Between May 1997 and November 1998, the investigators recruited 52 HIV-1-infected children aged between 0.5 and 24.0 months (median 3.5) from 25 sites in the United States and Puerto Rico for the Pediatric AIDS Clinical Trials Group Protocol 356 (PACTG 356). Thirty-one (60%) of the children had received antiretroviral therapy before the study. Twenty-seven (87%) of these had been given zidovudine (AZT) monotherapy as attempted prophylaxis against HIV infection, but none of the children had received more than ten weeks of antiretroviral therapy, or had ever received protease inhibitors or NNRTIs.

The infants were assigned sequentially to one of three regimens: AZT, 3TC and nevirapine; AZT, 3TC, nevirapine and abacavir; or d4T, 3TC, nevirapine and nelfinavir. The drug doses used are not reported in the study. The children continued to receive therapy for up to 200 weeks, if viral load was less than 1000 copies/ml by 16 weeks.

After 16 weeks of treatment, HIV viral loads had fallen from a median of 200,000 copies/ml to below 1000 copies/ml in 32 (62%) of the children. This decrease was similar across all three treatment groups.

After 48 weeks of treatment, 15 (83%) of the 18 children receiving d4T, 3TC, nevirapine and nelfinavir had viral loads of below 400 copies/ml. In contrast, four (24%) in the AZT/3TC/nevirapine group, and seven (41%) in the AZT/3TC/nevirapine/abacavir group had low viral loads (p = 0.001).

After 200 weeks of treatment, 13 (72%) of the children receiving d4T, 3TC, nevirapine and nelfinavir still had viral loads below 400 copies/ml, in contrast to five (29%) in each of the other two groups (p = 0.01).

Across the three treatment arms, 60% of the infants who started therapy before three months of age had low viral loads at week 200, compared with 30% of those who started later (p = 0.03). Low baseline viral loads were also associated with treatment success at this time point, but the response to antiretroviral therapy was not dependent on baseline CD4 cell counts or levels of proviral DNA in peripheral blood mononuclear cells.

“The regimen of d4T, 3TC, nevirapine and nelfinavir appeared to be superior to the two regimens of reverse transcriptase inhibitors in suppressing viral replication,” conclude the authors. “Early initiation of therapy also appeared to be associated with long-term suppression of viral replication.”

Twenty-six moderate or severe adverse events occurred in eight (15%) of the children during the study, consisting of rash, neutropenia or anaemia. However, only one child, from the AZT/3TC/nevirapine/abacavir group, was withdrawn from the study following severe fevers and a rash. No adverse events were recorded in the d4T/3TC/nevirapine/nelfinavir group.

Genotyping of HIV protease inhibitor and reverse transcriptase genes from 47 (90%) of the children revealed that four (9%) had mutations associated with resistance to one or more reverse transcriptase inhibitors before the start of the study. Despite good adherence, three of these children had poor long-term suppression of viral replication.

On the basis of their promising findings, the authors of the study suggest that “larger, randomised trials are required to determine the optimal time to initiate therapy and the optimal regimen for [HIV-infected] infants.”

Further information on this website

HIV and children - patient information booklet

Options for children - treatments information

High rates of AIDS and death in first year of life argue for universal ART for kids with HIV - news story

Higher than recommended dose of nevirapine needed for HIV suppression in children - news story

HAART effective at preventing illness and death in babies - news story


Luzuriaga K et al. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med 350: 2471-2480, 2004.

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