Analysis of Human Immunodeficiency Virus Type 1 Drug Resistance in Children Receiving Nucleoside Analogue Reverse- Transcriptase Inhibitors plus Nevirapine, Nelfinavir, or Ritonavir (Pediatric AIDS Clinical Trials Group 377)

Studies in children have confirmed that drug-resistant HIV-1 can emerge during antiretroviral therapy and can affect clinical outcome. There have been limited studies of prevalence of drug resistant HIV-1 in children. Most studies have been of adults and may not apply to pediatric cohorts. Due to the increased use of antiretroviral drugs to prevent vertical transmission, the number of children who have drug-resistant HIV-1 before initiating antiretroviral therapy has likely increased in recent years. Children in developed nations have increased incidence of drug-resistant HIV-1, typically as sequential courses of 1- or 2-drug regimens. Finally, infection of a child with drug-resistant HIV-1 by horizontal transmission also has been reported.

This is the largest study to date of HIV-1 drug resistance in children and the first to examine drug resistance in a large pediatric cohort in the context of a randomized, controlled trial of HAART. The participants were randomized to four treatment arms, according to the investigators, "that included different combinations of stavudine (d4T), lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), or ritonavir(Rtv)." The authors evaluated the prevalence of drug resistance mutations in the children before study treatment and the impact of these mutations on virologic response to treatment. They also "evaluated whether there was additional selection of drug resistance mutations in children who experienced virologic failure and whether selection was less common in children who received the 4-drug regimen." A total of 181 children ages 4 months to 17 years were enrolled in Pediatric AIDS Clinical Trials Group 377 (PACTG 377) from December 1997 through September 1998. Children were followed up for 96 weeks for analysis of safety, tolerance and virologic response. Previous treatment with Zdv, ddC or ddI was acceptable: 35 percent had previous treatment with ddI, 60 percent with Zdv/ddI, and 5 percent with other drug combinations. Methods and materials used included quantification of HIV-1 RNA, HIV-1 genotyping, phylogenetic analysis, analysis of drug resistance mutations, and statistical analysis.

Results of the study indicated that 57 percent of the children had satisfactory initial virologic suppression. According to the authors, "Consistent with treatment histories of children in this cohort, we found a high rate of primary mutations associated with resistance to the nRTIs, Zdv, ddI, and ddC. Our findings demonstrate that genotypic resistance is frequent in children receiving highly active regimens with less than complete viral suppression. In this cohort, resistance was more frequent among children receiving 3-drug regimens than in those receiving 4-drug regimens." Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Ritonavir-resistant and nelfinavir-resistant mutations were detected at unexpectedly low rates.

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