Despite the success of antiretroviral prophylaxis in reducing mother-to-child HIV-1 transmission, postpartum transmission through breast milk remains a problem. Antiretroviral administration to the infant during the period of breast-feeding could protect against postnatal transmission. An open-label phase 1/2 study was designed to assess the safety and trough concentrations of nevirapine (NVP) given once weekly (OW), twice weekly (TW), or once daily (OD) to HIV-exposed breast-feeding infants for 24 weeks. Following maternal dosing with 200 mg NVP orally at onset of labor, breast-feeding infants were randomized within 48 hours of birth to 1 of 3 regimens: arm 1, NVP given OW (4 mg/kg from birth to 14 days, ↑ to 8 mg/kg from 15 days to 24 weeks), arm 2, NVP given TW (4 mg/kg from birth to 14 days, ↑ to 8 mg/kg from 15 days to 24 weeks), and arm 3, NVP given OD (2 mg/kg from birth to 14 days, ↑ to 4 mg/kg from 15 days to 24 weeks). Trough NVP concentrations and clinical and laboratory abnormalities were monitored. Of the 75 infants randomized (26 to OW, 25 to TW, and 24 to OD dosing), 63 completed the 32-week follow-up visit. No severe skin, hepatic, or renal toxicity related to NVP was observed. Neutropenia occurred in 8 infants. Trough NVP levels were lower than the therapeutic target (100 ng/mL) in 48 of 75 (64.0%) samples from infants in the OW arm, 3 of 65 (4.6%) samples in the TW arm, and 0 of 72 samples in the OD arm. Median (range) trough NVP concentrations were 64 ng/mL (range: <25-1519 ng/mL) with OW dosing; 459 (range: <25-1386 ng/mL) with TW dosing; and 1348 (range: 108-4843 ng/ml) with OD dosing. Our data indicate that NVP prophylaxis for 6 months was safe and well tolerated in infants. OD NVP dosing resulted in all infants with trough concentration greater than the therapeutic target and maintenance of high drug concentrations. A phase 3 study is planned to assess the efficacy of OD infant NVP regimen to prevent breast-feeding HIV-1 transmission.
Prevention of HIV-1 transmission through breast milk is a major public health challenge in resource-poor countries. 1 Given the overwhelming benefits of breast-feeding, 2-4 the dangers of formula feeding, 5 and the known risk of HIV-1 transmission through breast-feeding, 5-8 there is an urgent need to make breast-feeding by HIV-1-infected women safe from transmission of the virus to their infants. Breast-feeding roughly doubles the risk of mother-to-child transmission of HIV-1 (MTCT). 8-10 Most breast milk transmission seems to occur during the first few months of life, with a lower but continued risk thereafter. 11,12
Short-course antiretroviral (ARV) regimens can significantly reduce MTCT in breast-feeding populations. 13-18 These regimens reduce transmission up to the first week of life, although the risk of HIV-1 transmission through breast milk continues for the duration of breast-feeding. 11 The need to develop interventions to reduce MTCT through breast milk is increasingly urgent as interventions that have been proven to reduce intrapartum transmission are implemented in resource-limited settings. A single-dose regimen of nevirapine (NVP) given intrapartum and to the newborn was shown to reduce MTCT by 47% at 14 to 16 weeks of age and by 42% at 18 months in breast-feeding infants. 13,19 NVP is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) with several properties favorable for use in preventing postnatal transmission through breast milk as well as intrapartum transmission. NVP is rapidly absorbed, has a relatively long half-life, rapidly crosses the placenta, readily enters breast milk, and is generally well tolerated. 20-23 Therefore, a phase 1/2 trial was designed to determine the safety and minimum dosing schedule of NVP to maintain a trough concentration above 100 ng/mL (10 times the in vitro 50% inhibitory concentration [IC50] against HIV-1) among breast-feeding infants for 24 weeks.