Antiretroviral treatment for children with peripartum nevirapine exposure

Abstract

Background: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.

Methods: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board.

Results: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.

Conclusions: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Figure 1. Times to Primary End Point and to Virologic Failure, According to Treatment and Age Stratum

The time to the primary end point of virologic failure or discontinuation of treatment by study week 24 is shown among children 6 to less than 12 months of age (Panel A) and among children 12 months of age or older (Panel B) (P = 0.52 for interaction of age stratum with treatment at week 24); the time to virologic failure or death is also shown among children in the two age groups (Panels C and D, respectively) (P = 0.65 for interaction of age stratum with treatment at week 24).

Figure 2. Time to Primary End Point, According to Treatment and Resistance or Nonresistance to Nevirapine at Baseline

The primary end point was virologic failure or discontinuation of treatment by study week 24. P = 0.02 for interaction between treatment and baseline resistance to NNRTIs.

Figure 3. Changes from Baseline in the Percentage of CD4+ Lymphocytes and Z Scores for Weight and Height

Median changes in the percentage of CD4+ lymphocytes and z scores for weight and height are shown, with 95% confidence intervals, according to the week of treatment.