HIV genotyping results were obtained for 88 (83.8%) of 105 infants with available 14-week samples (43 infants in the extended NVP arm, 45 infants from the extended NVP+ZDV arm). All 88 infants had subtype C infection. Among these infants, prophylaxis was discontinued at a median of 6 weeks of age in both study arms (range 1–14 weeks). We found no significant difference between the 88 infants with genotyping results and the 73 infants without genotyping results in terms of study regimen (the proportion of infants in the extended NVP arm was 43/88=48.9% vs. 36/73=49.3%, p=1.00), maternal sdNVP administration (the proportion of infants whose mothers received sdNVP was 62/88=70.5% vs. 41/73=56.2%, p=0.07), duration of prophylaxis (the proportion of infants who stopped prophylaxis before or at 6 weeks of age was 68/88=77.3% vs. 57/73=78.1%, p=1.00), or median maternal pre-NVP HIV log viral load (4.63, interquartile range: 4.15–4.90, vs. 4.71, interquartile range: 4.02–5.02, p=0.71).
Among the 88 infants with HIV genotyping results, the proportion of infants with one or more NVP resistance mutation detected in the 14-week sample was lower in the extended NVP+ZDV arm than in the extended NVP arm (28/45=62.2% vs. 37/43=86.0%, p=0.015). This association was still observed in a multivariate model (odds ratio (OR): 4.76, 95% confidence limits (CI): 1.48, 15.3, p=0.01) after adjusting for infant age when prophylaxis was stopped (by 6 weeks of age vs. after 6 weeks), median maternal pre-NVP viral load, and administration of maternal sdNVP. None of the other variables in the model were statistically associated with NVP resistance (prophylaxis stopped by vs. after 6 weeks: OR=0.35, 95% CI=0.08–1.41, p=0.14; median maternal HIV RNA, per log unit increase: OR=0.99, 95% CI=0.38–2.56, p=0.98; maternal sdNVP yes/no: OR=1.38, 95% CI=0.44–4.30, p=0.58). The reduced risk of NVP resistance was observed in the subgroup of infants with extended NVP+ZDV whose prophylaxis was stopped by 6 weeks (18/33=54.5% for extended NVP+ZDV vs. 30/35=85.7% for extended NVP, p=0.007), but not in the subgroup of infants whose prophylaxis was continued after 6 weeks (10/12=83.3% for extended NVP+ZDV vs. 7/8=87.5% for extended NVP, p=1.00, Fisher's test, ).
NVP resistance at 14 weeks in infants with in utero HIV
None of the infants had ZDV resistance detected in the 14-week sample, consistent with the high genetic threshold for ZDV resistance [12
]. However, two infants in the extended NVP arm and one infant in the extended NVP+ZDV arm had one or more mutations associated with resistance to other nucleoside reverse transcriptase inhibitors (NRTIs); all three of the corresponding mothers initiated HAART for their own health prior to the 14-week visit. Among the 88 infants with HIV genotyping results, only one other woman initiated HAART prior to 14 weeks post-partum; her infant did not have any NRTI mutations detected. Because the number of women initiating HAART by 14 weeks was small (total: 4/88=4.5%), it was not possible to include maternal HAART in the multivariate model presented above.
Fifty-one infants who had genotyping results from the 14-week study visit also had a sample available from the visit when prophylaxis was stopped. HIV genotyping was successful for 33 of those samples (16 from the extended NVP arm, 17 from the extended NVP+ZDV arm, ). Phylogenetic analysis of the resulting sequences confirmed that paired samples were from the same infant (data not shown). Among the 33 infants with paired samples, the proportion of infants who had NVP resistance at the time when prophylaxis was stopped was significantly higher in the extended NVP arm than in the extended NVP+ZDV arm (16/16=100% vs. 11/17=64.7%, p=0.018). When prophylaxis was stopped, the mean number of NVP resistance mutations detected per infant was also significantly higher in the extended NVP arm than in the extended NVP+ZDV arm (2.1 vs. 0.71, p<0.0001, Wilcoxon rank test). However, this difference had almost vanished by 14 weeks of age (1.2 vs. 0.94, p=0.34, Wilcoxon rank test). In the extended NVP arm, there was a statistically significant decrease in the number of mutations detected per infant between the time prophylaxis was stopped and at 14 weeks (2.1 vs. 1.2, p=0.01, signed rank test, ). In contrast, in the extended NVP+ZDV arm, the numbers of mutations detected per infant increased between the time prophylaxis was stopped and 14 weeks, but the change was not statistically significant (0.71 vs. 0.94, p=0.44, ).
NVP resistance mutations detected in infants receiving extended NVP or extended NVP+ZDV prophylaxis.