This study compared ART prophylactic regimens in a solely formula-fed population of infants whose mothers had not received antenatal ART. On the basis of the results of the Pediatric AIDS Clinical Trials Group Protocol 076 study,15
the standard ART prophylactic regimen for infants born to HIV-1–infected mothers in high-income and middle-income countries has been a 6-week course of zidovudine.16,17
In our study, the overall transmission rate in the zidovudine-alone group (11%) was similar to rates in observational studies in which zidovudine was initiated within 48 hours after birth in postpartum-identified HIV-1–exposed infants.6,7,18
Intrapartum transmissions were reduced by half in the two- and three-drug groups in our study, as compared with the zidovudine-alone group. When we designed the study, we hypothesized that a protease-inhibitor–based three-drug ART regimen might confer a higher level of protection against intrapartum HIV transmission than would a two-drug regimen, given the high virologic efficacy of protease-inhibitor–based treatment regimens.19,20
However, intrapartum infection rates were similar in the multidrug groups in our study.
Although intrapartum infection rates were about half as high as anticipated, with consequent loss of power, we observed significant differences in infection rates. Although transmission rates were similar in the multidrug groups, ease of administration favors the zidovudine–nevirapine regimen (a liquid formulation of nevirapine is commercially available, whereas nelfinavir powder requires reconstitution before each dose). Moreover, unlike nevirapine,11
the absorption of nelfinavir in neonates is quite variable.12
At present, other protease inhibitors are not recommended in the neonatal period, given the adverse effects of lopinavir–ritonavir21
and FDA restrictions on its use in infants younger than 14 days of age. Neutropenia was significantly more common with the three-drug regimen than with the other two regimens, a difference that is probably related to the combined suppressive effects of zidovudine and lamivudine on bone marrow production of blood cells.22–24
Although NNRTI resistance was observed more frequently in the two-drug group, NNRTI resistance mutations were present in all three groups, most frequently among infants infected in utero. Baseline rates of primary NNRTI resistance of 4 to 11% have been reported among Brazilian patients, and transmission of resistant virus from mother to child could explain the presence of NNRTI resistance in all the groups in our study.25–27
Maternal resistance testing to gain a better understanding of the genesis of infant antiretroviral resistance is under way. Coadministration of zidovudine decreases NNRTI resistance after exposure to single-dose nevirapine.28
The clinical significance of NNRTI resistance in infants may be limited, because protease-inhibitor–based therapy is highly effective in infants and is recommended in World Health Organization and U.S. guidelines for the treatment of pediatric HIV infection in infants exposed to NNRTI-based regimens for the prevention of mother-to-child transmission of HIV.29,30
Factors independently associated with an increased rate of HIV-1 transmission included zi- dovudine monotherapy, a higher maternal HIV RNA level at delivery, and maternal use of illegal substances. The latter two have been associated with high rates of HIV transmission in multiple studies.31–35
Although our study identified improved prophylactic alternatives for infants born to late-presenting HIV-1–infected mothers, the present approach does not substitute for the prevention and early identification of HIV-1 infection in women, with prompt initiation of ART during pregnancy. Prenatal care was received by 63% of the mothers in our study, with 48% having had at least 3 visits; these findings indicate that there were numerous missed opportunities to diagnose maternal HIV-1 infection and provide prophylaxis against mother-to-child transmission. Provision of ART prophylaxis in infants will not prevent in utero infection, which accounted for 70% or more of the residual infection in the two- and three-drug groups.
Like the findings in studies investigating rapid intrapartum and postpartum HIV-1 testing,36,37
our findings show that large-scale rapid HIV-1 testing during labor or the immediate postpartum period, followed by prompt initiation of ART in infants, is feasible, acceptable, and effective. The high level of acceptability of postexposure ART prophylaxis in infants is reflected by 96% adherence. In settings where zidovudine prophylaxis is the standard of care for HIV-exposed infants whose mothers have not received ART during pregnancy, our study shows that the administration of additional antiretroviral drugs significantly reduces the risk of intrapartum acquisition of HIV, as compared with zidovudine alone. Our findings are pertinent to countries in which combination ART in mothers throughout pregnancy is standard and ongoing exposure to HIV-1 through breast-feeding does not occur. Our results support combination ART regimens instead of zidovudine alone for prophylaxis in the infants of mothers who have not received antenatal ART. Ease of use, reduced toxicity, availability, and low cost suggest that zi- dovudine plus nevirapine is an attractive option for prophylaxis in infants at high risk for perinatal HIV-1 infection.