Analysis of nevirapine resistance in HIV-infected infants who received extended nevirapine or nevirapine/zidovudine prophylaxis

Abstract

Background: In the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial, infants received up to 14 weeks of extended nevirapine (NVP) or extended NVP with zidovudine (NVP + ZDV) to prevent postnatal HIV transmission. We examined emergence and persistence of NVP resistance in HIV-infected infants who received these regimens prior to HIV diagnosis.

Methods: Infant plasma samples collected at 14 weeks of age were tested using the ViroSeq HIV Genotyping System and a sensitive point mutation assay, LigAmp (for K103N and Y181C). Samples collected at 6 and 12 months of age were analyzed using LigAmp.

Results: At 14 weeks of age, NVP resistance was detected in samples from 82 (75.9%) of 108 HIV-infected infants. Although the frequency of NVP resistance detected by ViroSeq was lower in the extended NVP + ZDV arm than in the extended NVP arm, the difference was not statistically significant (38/55 = 69.1% vs. 44/53 = 83.0%, P = 0.12). Similar results were obtained using LigAmp. Using LigAmp, the proportion of infants who still had detectable NVP resistance at 6 and 12 months was similar among infants in the two study arms (at 6 months: 17/20 = 85.0% for extended NVP vs. 21/26 = 80.8% for extended NVP + ZDV, P = 1.00; at 12 months: 9/16 = 56.3% for extended NVP vs.10/13 = 76.9% for extended NVP + ZDV, P = 0.43).

Conclusion: Infants exposed to extended NVP or extended NVP + ZDV had high rates of NVP resistance at 14 weeks of age, and resistant variants frequently persisted for 6-12 months. Frequency and persistence of NVP resistance did not differ significantly among infants who received extended NVP only vs. extended NVP + ZDV prophylaxis.

Figure 1

Resistance test results are shown for all infants tested (no shading), infants in the extended NVP arm (dark shading), and infants in the extended NVP+ZDV arm (light shading). (A) Panel A shows results obtained for samples collected at 14 weeks of age using the ViroSeq assay (detection of any NVP resistance mutation) and the LigAmp assay (detection of K103N and/or Y181C). The proportion of infants with NVP resistance detected with ViroSeq vs. LigAmp at 14 weeks was compared using McNemar's test. The proportion of infants with NVP resistance at 14 weeks in the two study arms was compared using Fisher's exact test. In 10 infants, NVP resistance was detected with ViroSeq only. Five of the 10 infants had NVP resistance mutations that were not probed by the LigAmp assay (V106A, Y188C/L, G190A). In four of the 10 infants, K103N or Y181C was encoded by a codon that was not probed with the LigAmp assay (K103N was encoded by AAT rather than AAC, Y181C was encoded by TGC rather than TGT). In six infants, NVP resistance was detected by LigAmp only. In those cases, the level of the relevant mutation (K103N or Y181C) was <20% of the viral population. (B) Panel B shows results obtained for samples collected at 6 and 12 months of age using the LigAmp assay (detection of K103N and/or Y181C). Samples collected at 6 months of age were analyzed if the infant had K103N and/or Y181C detected at 14 weeks. Samples collected at 12 months of age were analyzed if the infant either had K103N and/or Y181C detected at 6 months of age, or had K103N and/or Y181C detected at 14 weeks of age and did not have a 6-month sample available for analysis. The proportions of infants with NVP resistance in the two study arms at 6 and 12 months were compared using Fisher's exact test.