Hudgens MG, Taha TE, Omer SB, Jamieson DJ, Lee H, Mofenson LM, et al. Pooled individual data analysis of five randomized trials of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Clin Infect Dis. 2013 Jan;56(1):131-9.
To estimate the relative efficacy of four daily regimens of infant nevirapine prophylaxis in preventing HIV infection through transmission in breastmilk.
Ethiopia, India, Malawi and Uganda.
Secondary pooled analysis of data from five randomized controlled trials (RCT).
Mother-infant pairs who participated in five RCTs testing prevention of mother-to-child transmission (PMTCT) interventions, where the infant was HIV-uninfected at birth.
Infant HIV infection, and a composite outcome of infant HIV infection or death for any reason.
Individual participant data from five RCTs were pooled. These trials comprised the following: the Breastfeeding and Nutrition (BAN) trial, conducted in Malawi, in which 632 infants were randomized to receive the control regimen of single-dose nevirapine (sdNVP) and seven days of zidovudine (AZT) / lamivudine (3TC) and 816 were randomized to receive the control regimen plus 28 weeks of infant nevirapine (NVP); the Post-Exposure Prophylaxis of the Infant (PEPI) trial, also conducted in Malawi, in which 792 infants were randomized to receive the control regimen of sdNVP and seven days of AZT, 823 were randomized to receive the control regimen plus 14 weeks of NVP, and 833 were randomized to receive 14 weeks of daily NVP plus AZT; and the three Six-Week Extended Nevirapine (SWEN) trials, conducted in Ethiopia, India and Uganda, in which 769 infants were randomized to receive the control regimen of sdNVP and 731 were randomized to receive the control regimen plus six weeks of infant NVP.
In the BAN trial, the week 28 visit could occur up to seven days after the infant was 28 weeks old. Therefore HIV infection and death up to 203 days after birth were included in the analysis. Similarly, the primary endpoint for the SWEN trials was HIV infection and death up to day 202. The primary endpoint of the PEPI trial was HIV infection and death by age nine months (approximately 275 days).
The Kaplan-Meier method was used to estimate the probability of infant HIV infection or death by 203 days. For the HIV infection endpoint, time until the first positive HIV antigen test was used in the analysis. Infants who did not reach a study endpoint by 203 days (HIV infection or death) were right-censored at the last negative HIV test or at 203 days, whichever occurred first. Cox proportional-hazards models, stratified by trial site, were used to estimate hazard ratios (HRs) for the study outcomes comparing the different intervention and control groups while adjusting for potentially prognostic baseline factors (e.g. infant birth weight, infant sex, mode of delivery, maternal CD4 count etc.). Stratified Cox regression models were also fit with NVP as a time-varying covariate equal to one for the first six weeks for infants in the intervention arm of SWEN, for the first 14 weeks for infants in the intervention arms of PEPI, and for the first 28 weeks for infants in the intervention arm in BAN, and equal to zero otherwise.
Data from 5,396 mother-infant pairs were included in the pooled analysis. Maternal age and CD4 cell count at baseline were similar across all five trials. The proportion of infants delivered vaginally was significantly lower in the SWEN trials (Χ2 test, p<.0001) as Cesarean delivery was more common in SWEN than in the BAN or PEPI studies (15.1% vs 2.1%). Infant sex and birth weight were similar across trials, with slightly more males in the PEPI and SWEN control arms (p=.07).
Compared with the control arms of BAN, SWEN, and PEPI trials, daily NVP for 28 weeks reduced the rate of HIV infection by 71% (95% confidence interval [CI], 58% to 80%, p<.001) and reduced the rate of HIV infection or death by 58% (95% CI, 45% to 69%, p<.001).
As the duration of NVP prophylaxis increased, HIV transmission decreased. The cumulative risk of HIV infection by 28 weeks in the SWEN six-week NVP arms was 5.8% (95% CI, 4.3% to 7.9%). It was 4.8% (95% CI, 3.5% to 6.7%) in the PEPI 14-week NVP+AZT arm; 3.7% (95% CI, 2.5% to 5.4%) in the PEPI 14-week NVP arm; and in the BAN 28-week NVP arm it was 1.8% (95% CI, 1.0% to 3.1%) (log-rank test for trend, p<.001).
Results were similar for the risk of HIV infection or death. Risk of HIV infection or death by 28 weeks in the SWEN six-week NVP arms was 6.7% (95% CI, 5.0% to 8.8%); in the PEPI 14-week NVP+AZT arm it was 7.2% (95% CI, 5.5% to 9.3%); in the PEPI 14-week NVP arm it was 5.8% (95% CI, 4.3% to 7.8%); and in the BAN 28-week NVP arm it was 3.0% (95% CI, 2.0% to 4.5%).
|Cumulative risk of HIV infection|
|6 weeks NVP (SWEN)||5.8% (95% CI, 4.3% to 7.9%)|
|14 weeks NVP+AZT (PEPI)||4.8% (95% CI, 3.5% to 6.7%)|
|14 weeks NVP (PEPI)||3.7% (95% CI, 2.5% to 5.4%)|
|28 weeks NVP (BAN)||1.8% (95% CI, 1.0% to 3.1%)|
|Cumulative risk of HIV infection or death|
|6 weeks NVP (SWEN)||6.7% (95% CI, 5.0% to 8.8%)|
|14 weeks NVP+AZT (PEPI)||7.2% (95% CI, 5.5% to 9.3%)|
|14 weeks NVP (PEPI)||5.8% (95% CI, 4.3% to 7.8%)|
|28 weeks NVP (BAN)||3.0% (95% CI, 2.0% to 4.5%)|
In each trial, there were no significant differences between the study arms in breastfeeding rates through 28 weeks. In SWEN, mothers were encouraged to wean between four and six months, and only 31% reported still breastfeeding at six months. In PEPI, women were told to exclusively breastfeed for six months and then consider weaning. At six months approximately 90% of PEPI infants were breastfeeding, with most women weaning their infants between ages six and nine months. In BAN, mothers were specifically counseled to wean their babies from 24 to 28 weeks. About a third of BAN infants were still breastfeeding at 28 weeks.
The authors conclude that daily infant NVP prophylaxis during breastfeeding in resource-limited settings is efficacious in preventing infant HIV infection and HIV infection or death by 28 weeks. Longer duration of prophylaxis is associated with greater protection.
The overall risk of bias in this analysis is low. There were no serious methodologic problems with any of the included trials. The methods with which the authors conducted this pooled analysis were rigorous and appropriate.
The HPTN 046 trial (not included in this analysis because both arms received infant NVP prophylaxis) found that extending infant nevirapine from six weeks to six months significantly decreased postnatal HIV infection by 54%.(1) None of the included trials maintained NVP prophylaxis throughout the entire breastfeeding period. The very significant reductions in risk for HIV transmission (or transmission or death) in infants receiving prophylaxis are encouraging, but after prophylaxis ended the risk continued for those infants still breastfeeding. In addition, drugs used for infant prophylaxis would ideally be less likely than NVP to select for resistant strains. Researchers from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) are currently conducting an RCT in four sub-Saharan African countries that addresses both of these concerns.(2) Infants receive one of two alternatives to NVP (lopinavir boosted by ritonavir, LPV/r; or lamivudine, 3TC). Infant prophylaxis is provided throughout the duration of breastfeeding.
Treatment of HIV-infected pregnant women and mothers, regardless of CD4 count, is rapidly being adopted worldwide, and is likely the most efficacious approach to reducing infant HIV transmission. In settings where maternal treatment is not affordable, available, or acceptable, infant NVP prophylaxis may be a feasible alternative.
- Coovadia HM, Brown ER, Fowler MG, et al. for the HPTN 046 Protocol Team. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379:221-28
- ANRS 12174. Comparison of efficacy and safety of infant peri-exposure prophylaxis with lopinavir/ritonavir versus lamivudine to prevent HIV transmission by breastfeeding. ClinicalTrials.gov identifier NCT00640263.(accessed 17 January 2012).