This analysis from HIVNET 012 includes 610 firstborn infants with HIV test results available (). There were 122 HIV-infected infants, of which 99 (81%) had early HIV infection and 23 (19%) were late transmissions. Fifty-six infants (46%) overall had HIV detected at birth (in utero transmissions), 43 (35%) overall were infected within 56 days of life (intrapartum/early breastfeeding transmissions). Of the 610 included in the early transmission study, 114 died or were diagnosed with HIV infection at or before 56 days. Hence, 496 were alive and free from HIV infection after 56 days; 491 of those infants had HIV testing performed after 56 days and were included in the analysis of predictors of late transmission. Among the 5 infants not included in the analysis, 2 died at ages 11 and 12 weeks and 3 were lost to follow-up (2 at 10 weeks and 1 at 4 months). There were 23 HIV infections among the 491 infants included in the late HIV transmission analyses (4.7%). The breastfeeding HIV incidence per infant month of follow-up during the late transmission period was 0.8% (0.3%–1.7%) between 2 and 4 months, 0.6% (0.3%–1.0%) between 4 and 12 months and 0.8% (0.2%–2.3%) between 12 and 18 months. The overall (2–18 months) HIV incidence per infant month was 0.7% (0.4%–1.0%).
HIVNET 012 predictors of early and late transmission.
HIV subtyping was performed for 297 of the 306 women enrolled in the NVP arm. The following subtypes were identified: 156 women (52.5%) had subtype A, 7 (2.4%) had subtype C, 104 (35.0%) had subtype D, and 30 (10.1%) had intersubtype recombinant strains.
The population baseline characteristics of the women and infants by infection period are summarized in . Maternal CD4 cell count and VL at pre-entry and 6–8 weeks and maternal age at pre-entry were significantly different for the uninfected and infected cohorts, whereas other demographic characteristics were similar. However, the test for trends across maternal age categories <20, 20–35, and >35 years was not statistically significant (P = 0.22). Breastfeeding practices were also significantly different among the 3 groups, with more mothers of the infected infants choosing to continue breastfeeding.
Characteristics of the Study Population by Infection Period
Predictors of Early HIV Transmission
Women in the NVP arm had a significantly lower risk of early transmission than women in the ZDV arm [hazard ratio (HR) = 0.57, 95% CI: 0.38 to 0.85]. Pre-entry maternal log10 VL (HR = 2.11, 95% CI: 1.59 to 2.80 per unit increase) and pre-entry maternal CD4 cell count (HR = 1.24, 95% CI: 1.13 to 1.36 per decrease of 100 cells/mm3) were significantly associated with early transmission, whereas maternal age, duration of labor, prolonged rupture of membranes (>4 hours or not), mode of delivery (caesarean section or not), maternal HIV subtype (D versus A), infant sex, and low birth weight were not.
In a multivariate model, maternal log10 VL (HR = 1.76, 95% CI: 1.28 to 2.41, per unit increase), maternal CD4 cell count (HR = 1.16, 95% CI: 1.05 to 1.28, per decrease of 100 cells/mm3), and NVP compared with ZDV treatment (HR = 0.57, 95% CI: 0.38 to 0.86) remained significant predictors of early HIV transmission ().
Multivariate Cox Models of Risk Factors for HIVNET 012
Predictors of Late HIV Transmission During Breastfeeding
In univariate analysis, statistically significant risk factors included 6–8 weeks postpartum maternal log10 VL (HR = 4.95, 95% CI: 2.56 to 9.60 per unit increase), as well as pre-entry maternal log10 VL (HR = 2.76, 95% CI: 1.51 to 5.04, per unit increase), and pre-entry maternal CD4 cell count (HR = 1.48, 95% CI: 1.19 to 1.84, per decrease of 100 cells/mm3). However, there was no significant difference in risk of late HIV transmission for women in the NVP arm compared with the ZDV arm (HR = 0.69, 95% CI: 0.30 to 1.56). Maternal age, duration of labor, prolonged rupture of membranes (>4 hours or not), mode of delivery (caesarean section or not), maternal HIV subtype (D versus A), infant sex, and low birth weight were not associated with an increased risk of late transmission.
In a multivariate model, 6–8 weeks postpartum maternal log10 VL (HR = 3.66, 95% CI: 1.78 to 7.50, per unit increase) was the strongest predictor of late HIV transmission (). Pre-entry maternal CD4 cell count had a similar HR for late and early HIV transmission risk, although it was not statistically significant for late transmission (HR = 1.22, 95% CI: 0.98 to 1.52, per decrease of 100 cells/mm3).
NVP Resistance and Late Transmission Risk
We assessed the potential impact of NVP resistance on late transmission risk among mothers enrolled in the NVP arm. Fifty-eight of 239 women (24%) who had HIV genotyping results at 6–8 weeks had detectable NVP resistance (detection of one or more NVP resistance mutation using the ViroSeq assay). Ninety of 207 women (43%) who had K103N measured with the more sensitive LigAmp assay at 6–8 weeks had K103N detected above the assay cutoff (>0.5% K103N). Although there was a higher rate of late transmission among women with NVP resistance detected with the ViroSeq system, that difference was not statistically significant (HR = 1.68, 95% CI: 0.42 to 6.72). Similar results were obtained using the LigAmp assay for K103N detection (HR = 4.09, 95% CI 0.82 to 20.24). In 2 separate multivariate models, one using ViroSeq and the other LigAmp assay results, adjusting for pre-entry maternal CD4 cell count and maternal log10 VL at 6–8 weeks, NVP resistance did not predict late transmission (HR = 0.37, 95% CI: 0.07 to 2.04 for ViroSeq and HR = 1.37, 95% CI: 0.24 to 7.88 for LigAmp). However, in both models, maternal log10 VL at 6–8 weeks was strongly predictive of late transmission (HR = 8.87, 95% CI: 2.32 to 33.90 for ViroSeq and HR= 7.60, 95% CI: 1.91 to 30.19 for LigAmp).
Transmission Rates by Subgroups
demonstrates the changes in maternal VL from delivery through the first 6–8 weeks postpartum among women randomized to the NVP and ZDV arms. The plasma VL for women in the ZDV arm remained stable throughout, although there was a significant drop in plasma VL by 7 days postpartum for those in the NVP arm, which returned to baseline levels by 6–8 weeks postpartum.
Mothers' log10 HIV RNA change from delivery to week 6 by randomization arm. Box ends represent 25th and 75th percentiles. Center horizontal line is drawn at median. Whisker ends represent 1st and 99th percentiles.
Rates of early and late HIV transmission were directly related to maternal VL and inversely related to maternal CD4 cell count during both early and late transmission periods. However, the transmission probabilities were substantially higher in the early relative to the late period in all VL and CD4 cell count categories (). There were no transmissions among women whose pre-entry VL was <500 copies per milliliter. The lowest maternal pre-entry VL observed among mothers with early HIV transmission occurred in a woman with 4945 HIV-1 RNA copies per milliliter. Similarly, the lowest maternal 6- to 8-week VL associated with late transmission occurred in a woman with 4251 HIV-1 RNA copies per milliliter.
Early and late HIV transmission by pre-entry maternal VL, maternal CD4 cell count, and treatment arm.
The differences in early transmission between women in the NVP and ZDV arms were consistent with an overall 43% relative efficacy across all VLs. However, because of the substantial increase in transmission risk with increase in log10 VL, the absolute differences in early transmission risk by treatment arm were more substantial when the VL was >50,000 RNA copies per milliliter ().
illustrates the increase in probability of late transmission with higher baseline VL, which cumulatively exceeds 6.5% when the VL was greater than 50,000 copies per milliliter. Late transmission probabilities as high as 12%–17% were observed for mothers with pre-entry CD4 counts less than 200 cells per cubic millimiter (). Although the observed probabilities of late transmission were slightly lower among women in the NVP arm compared with those in the ZDV arm, the difference was not statistically significant.