A six-week postpartum regimen of the antiretroviral drug nevirapine reduces HIV transmission from breast-feeding in the short term, but the benefits are no longer apparent after six months, according to findings from three coordinated randomized trials conducted in Ethiopia, India and Uganda.1 Among infants who were HIV-negative a week after birth, those who received nevirapine for six weeks—an initial dose followed seven days later by five weeks of daily doses—were less likely than those who received a single dose of the drug at birth to have HIV at the end of treatment (odds ratio, 0.5). At the six-month follow-up, the difference in HIV rates was no longer statistically significant; however, infants given the extended regimen did have a reduced risk of death (0.5).
Although breast-feeding can transmit HIV, the World Health Organization recommends that mothers in developing countries who are infected with HIV consider breast-feeding their infants if they do not have access to a safe, affordable alternative, because unsafe sources of nutrition and hydration pose risks of their own, including death from diarrhea and other causes. Providing a single dose of nevirapine to mothers during labor and a dose to infants within a few days of birth helps prevent the immediate transmission of HIV, but does not reduce the risk of transmission through breast-feeding. The new trials were designed to examine whether an extended regimen of nevirapine could reduce transmission in breast-fed infants.
The three trials were originally meant to be independent entities, but the researchers merged their efforts during study development and implementation. As a result, most of the main features of the three trials were identical. Pregnant women with HIV who intended to breast-feed their children were recruited and randomly assigned to receive a single dose of nevirapine during labor; their infants received a single dose at birth, followed by daily multivitamins on days 8–42. Infants randomized to the extended regimen also received a dose of nevirapine on days 8–42. Blood samples were obtained from infants at birth, and at least four additional collections were scheduled for (although not always obtained during) the ensuing six months. Infants were classified as having HIV if they had two independent positive tests or if one test was positive and no subsequent sample was obtained for testing. The primary outcome for the study was HIV status at six months among infants who were uninfected at birth (those who had a positive HIV test within the first week were considered to have been infected at birth); secondary outcomes included HIV status at six weeks, and death from any cause at six weeks and at six months. The researchers also used a combined outcome measure that included both HIV transmission and death from any cause.
The main differences among the three trials were that the Ugandan trial included a third treatment arm, which was not included in the current analysis, and that women receiving antiretroviral therapy other than nevirapine were eligible for participation in India but not in the other two countries.
After omission of infants who were infected at birth and those for whom adequate specimens were unavailable for testing, the study sample consisted of 986 infants who received a single dose of nevirapine and 901 who received the extended regimen. The characteristics of the two groups—including the proportions of infants who were breast-fed or exclusively breast-fed—were generally similar, although infants in the single-dose group were more likely to receive 28 or more doses of study products (vitamins, in their case) than those in the extended-regimen group (54% vs. 48%).
After six weeks, the proportion of infants in the extended regimen group who had become infected with HIV was significantly lower than the proportion in the single-dose group (3% vs. 5%). However, by six months, the difference between the groups (7% vs. 9%) was no longer statistically significant. Mortality was equally common in the two groups at six weeks, but at six months it was lower in the extended-dose group than in the single-dose group (1% vs. 4%). For the combined outcome category that included both HIV transmission and death, adverse outcomes were less common in the extended-dose group than in the single-dose group, both at six weeks (4% vs 7%) and at six months (8% vs. 12%). Seventy-two percent of the deaths occurred among infants who were not infected with HIV; the most common causes were respiratory conditions, gastrointestinal conditions and infections.
Nearly 40% of the infants experienced at least one serious adverse event. The rate of these events did not differ between groups, however. The most common adverse events were abnormal laboratory findings (45%), gastrointestinal conditions (16%) and respiratory illnesses (14%).
The investigators note that the lack of a statistical difference in HIV transmission rates between the two groups at six months may be related to the low rate of HIV transmission in the single-dose group, which reduced the study's statistical power to detect such a difference. Nonetheless, the benefits observed at six weeks in this study, and the findings from another recent study of extended antiretro-viral treatment during the postpartum period, suggest that "extended post-partum nevirapine should be considered for HIV-uninfected infants being breastfed by HIV-infected mothers to improve survival and to reduce the risk of HIV transmission," the researchers contend. They add that "the optimum duration of post-partum infant nevirapine is, however, unclear, and is probably dependent on the duration of breastfeeding and other maternal and infant factors that vary among communities."—P. Doskoch
1. Six Week Extended-Dose Nevirapine Study Team, Extended-dose nevirapine to 6 weeks of age in infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomized controlled trials, Lancet, 2008, 372(9635): 300–313.