ABSTRACT: The standard prophylactic regimen used as antiretroviral therapy (ART) for infants born to mothers in high-income and middle-income countries who are infected with human immunodeficiency virus (HIV) infection has been a 6-week course of zidovudine.
Randomized controlled trials investigating postexposure prophylaxis for infants born to late-presenting women infected with HIV who did not receive ART in pregnancy have been conducted in breast-fed populations but not in non–breast-fed populations. Several trials showed that prophylaxis with combination ART (zidovudine plus ≥1 antiretroviral drugs) was effective in reducing viral transmission in high-risk breast-fed populations in low-income countries. However, it is unclear whether prophylaxis with combination ART would prevent intrapartum HIV-1 transmission in non–breast-fed infants of women who had not received antenatal ART.
This randomized controlled study compared the efficacy and safety of ART prophylactic regimens in a population of solely formula-fed infants whose mothers had not received ART during pregnancy. In designing the study, the authors hypothesized that a 3-drug ART regimen would confer a higher level of protection against intrapartum HIV transmission than a 2-drug regimen. Both regimens were evaluated in this study. Formula-fed infants exposed to HIV-1 were randomly assigned to 1 of 3 ART regimens within 48 hours after birth. Infants in each of the 3 groups received zidovudine for 6 weeks. The first group was given only zidovudine (zidovudine-alone group, n = 566). In addition to zidovudine, the second group received 3 doses of nevirapine during the first 8 days of life (2-drug group, n = 562). The third group received zidovudine plus nelfinavir and lamivudine for 2 weeks (3-drug group, n = 556). The primary study outcome was HIV-1 infection at 3 months of age among infants uninfected at birth. The Kaplan-Meier method was used to estimate transmission rates.
The study population included 1684 infants enrolled between 2004 and 2010 at 17 sites in Brazil, Argentina, the United States, and South Africa. The overall rate of in utero transmission of HIV-1 was 5.7% (93 infants); there were no significant differences among the groups. At 3 months, the overall rate of intrapartum transmission was 3.2%. Compared with the zidovudine-alone group, intrapartum transmission at 3 months was reduced by half in the 2- and 3-drug groups: The rate was 4.8% (24 infants) in the zidovudine-alone group versus 2.2% (11 infants) in the 2-drug group and 2.4% (12 infants) in the 3-drug group (P = 0.046 for both comparisons). The overall rate of HIV-1 infection in utero or intrapartum was 8.3% (140 infants). Transmission of infection was higher in the zidovudine-alone group (11.0%, 61 infants) than in the 2-drug group (7.1%, 39 infants) or the 3-drug group (7.4%, 40 infants); P = 0.03 for both comparisons. Multivariate analysis showed that zidovudine monotherapy, a higher maternal viral load at delivery, and maternal use of illegal substances during pregnancy were independent risk factors for transmission. Neutropenia occurred in 27.5% of infants in the 3-drug group versus 14.9% in the 2-drug group and 16.4% in the zidovudine-alone group (P < 0.001 for both comparisons).
These findings support the prophylactic use of both the 2- and 3-drug combination ART regimens instead of zidovudine alone to prevent intrapartum HIV transmission in neonates whose mothers did not receive ART during pregnancy. However, the 3-drug regimen has more toxicity than the 2-drug regimen.
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (K.N.-S., Y.J.B.); the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda (D.H.W., G.S., J.M., L.M.M.), and Westat, Rockville, MD (J.B., M. Camarca, J.X.); the Laboratorio de Pesquisa Clinica em DST e AIDS, Instituto de Pesquisa Clinica Evandro Chagas (V.G.V., B.G.), the Laboratorio de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz (J.H.P., M.G.M.), and the Laboratorio de Informacoes em Saude, Instituto de Informacao Cientifica e Tecnologica em Saude (R.I.M., F.I.B.), Fundacao Oswaldo Cruz (Fiocruz), the Hospital Federal dos Servidores do Estado (E.C.J.), and the Hospital Geral de Nova Iguacu (J.H.P.), Rio de Janeiro; the Perinatal HIV Research Unit, University of Witwatersrand and Chris Hani Baragwanath Hospital, Johannesburg (G.G.), and Stellenbosch University and Tygerberg Hospital, Cape Town (G.T.), South Africa; Hospital Conceicao (B.S.), Hospital Femina (R.F.), and Irmandade da Santa Casa de Misericordia de Porto Alegre (R.K.), Porto Alegre, RS; Federal University of Minas Gerais, Belo Horizonte, MG (J.P.); Universidade de Sao Paulo, Ribeirao Preto, SP (M.M.M.-P.); and Universidade Federal de Sao Paulo, Sao Paulo, SP (D.M.), Brazil; the Foundation for Maternal and Infant Health, Buenos Aires (M. Ceriotto); University of California, Davis, California (R.D.); and Boston University School of Medicine, Boston, Massachusetts (M.M.).