title: Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months.
abstract: 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, upward arrow to 8 mg/kg from 15 days to 24 weeks), arm 2, NVP given TW (4 mg/kg from birth to 14 days, upward arrow to 8 mg/kg from 15 days to 24 weeks), and arm 3, NVP given OD (2 mg/kg from birth to 14 days, upward arrow 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.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. avishetty@pol.net
authors.forename: Avinash K
authors.initials: AK
authors.lastname: Shetty
authors.forename: Hoosen M
authors.initials: HM
authors.lastname: Coovadia
authors.forename: Mark M
authors.initials: MM
authors.lastname: Mirochnick
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Maldonado
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Mofenson
authors.forename: Susan H
authors.initials: SH
authors.lastname: Eshleman
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.forename: Lynda
authors.initials: L
authors.lastname: Emel
authors.forename: Kathy
authors.initials: K
authors.lastname: George
authors.forename: David A
authors.initials: DA
authors.lastname: Katzenstein
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wells
authors.forename: Charles C
authors.initials: CC
authors.lastname: Maponga
authors.forename: Anthony
authors.initials: A
authors.lastname: Mwatha
authors.forename: Samuel Adeniyi
authors.initials: SA
authors.lastname: Jones
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.forename: Mary T
authors.initials: MT
authors.lastname: Bassett
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control / Q000635:transmission*; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001942:Breast Feeding; D015340:Epidemiologic Research Design; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008423:Maternal Age; D008657:Metabolic Clearance Rate; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000517:prevention & control / Q000821:virology*; D012449:Safety; D013019:South Africa; D013997:Time Factors; D015030:Zimbabwe
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine