We conducted a large randomized clinical trial (the """"""""Mashi Study"""""""") among HIV-infected women and their infants in Botswana, to evaluate peripartum antiretroviral prophylaxis strategies and infant feeding approaches that would minimize mother to children transmission (MTCT) of HIV-1 while optimizing infant survival. Short-course zidovudine (ZDV) was provided to mothers during pregnancy and to all infants for one month;mothers and infants were also randomized to receive single-dose nevirapine (sd NVP) or placebo at delivery/birth, and infants were randomized to either 6 months of breastfeeding + 6 months ZDV prophylaxis, or to formula feed (FF) with one month of ZDV. Exposure to sd NVP leads to NVP-resistant virus in most mothers and infants, and there is ongoing concern about the implications of this resistance for subsequent adult and pediatric NVP-based combination antiretroviral treatment (HAART) response. We collected (with informed consent and IRB approvals) supplementary data in this valuable cohort of mothers and infants in order to address additional important scientific objectives. We now propose using these data and samples to address the following new objectives, and need one year of additional funding to do this work: 1) To assess the proportion of women with virologic response (plasma HIV-1 RNA <400 copies / mL) by up to 36 months (3 years) after initiating NNRTI-containing ART among women who previously received single-dose NVP versus placebo during labor. 2) To assess the proportion of children with virologic response (plasma HIV-1 RNA <400 copies / mL) by up to 36 months (3 years) after initiating NNRTI-containing ART among infants who were previously exposed to peripartum, single-dose NVP. 3) To determine the proportion of infants with pre-HAART drug-resistant virus (among infants with and without exposure to single dose NVP), and to ascertain whether detectable baseline NVP drug resistance predicts subsequent failure. 4) To study pediatric growth and developmental outcomes, by infant HIV-1 status and by randomized feeding strategy, using abbreviated pediatric neurodevelopmental assessments (modified DST-II and PEDSTest) at 24 and 48 months of age as well as longitudinal growth data. 5) To study factors associated with repeat pregnancy, and maternal decision-making around repeat pregnancy.

Public Health Relevance

Two million children are born to HIV-infected women each year, 420,000 children are newly infected with HIV-1 annually, and nearly 90% of all HIV-infected children live in sub-Saharan Africa [1]. Botswana, a southern African nation, has one of the world's highest HIV-1 infection rates;in 2005, HIV seroprevalence among pregnant women was 33.4% [2]. Studies related to the impact of MTCT prevention interventions on maternal and infant health and subsequent treatment options are therefore critical. The purpose of this application is to answer several new, important clinical research questions using data and samples that were collected in a randomized clinical trial (the """"""""Mashi Study"""""""") in Botswana. The proposed new objectives pertain to HIV-1 drug resistance among HIV-infected infants with prior single-dose nevirapine exposure around the time of birth;long-term (up to 6-year) antiretroviral treatment outcomes among HIV-infected women and infants with prior single-dose nevirapine vs. placebo exposure;and pediatric neurodevelopmental and growth outcomes, by infant feeding modality and antiretroviral exposure history.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD044391-06S1
Application #
8134185
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mofenson, Lynne M
Project Start
2003-05-20
Project End
2012-12-31
Budget Start
2010-09-09
Budget End
2012-12-31
Support Year
6
Fiscal Year
2010
Total Cost
$419,233
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Dryden-Peterson, Scott; Lockman, Shahin; Zash, Rebecca et al. (2015) Initial programmatic implementation of WHO option B in Botswana associated with increased projected MTCT. J Acquir Immune Defic Syndr 68:245-9
Dryden-Peterson, Scott; Bennett, Kara; Hughes, Michael D et al. (2015) An augmented SMS intervention to improve access to antenatal CD4 testing and ART initiation in HIV-infected pregnant women: a cluster randomized trial. PLoS One 10:e0117181
Russell, Elizabeth S; Mohammed, Terence; Smeaton, Laura et al. (2014) Immune activation markers in peripartum women in Botswana: association with feeding strategy and maternal morbidity. PLoS One 9:e89928
Paredes, Roger; Marconi, Vincent C; Lockman, Shahin et al. (2013) Impact of antiretroviral drugs in pregnant women and their children in Africa: HIV resistance and treatment outcomes. J Infect Dis 207 Suppl 2:S93-100
Ciaranello, Andrea L; Lockman, Shahin; Freedberg, Kenneth A et al. (2011) First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial. AIDS 25:479-92
Lin, Nina H; Smeaton, Laura M; Giguel, Françoise et al. (2011) Prevalence and clinical associations of CXCR4-using HIV-1 among treatment-naive subtype C-infected women in Botswana. J Acquir Immune Defic Syndr 57:46-50
Lin, Nina H; Negusse, Daniel M; Beroukhim, Rameen et al. (2010) The design and validation of a novel phenotypic assay to determine HIV-1 coreceptor usage of clinical isolates. J Virol Methods 169:39-46
Novitsky, Vladimir; Wang, Rui; Bussmann, Hermann et al. (2010) HIV-1 subtype C-infected individuals maintaining high viral load as potential targets for the ""test-and-treat"" approach to reduce HIV transmission. PLoS One 5:e10148
MacLeod, Iain J; Rowley, Christopher F; Thior, Ibou et al. (2010) Minor resistant variants in nevirapine-exposed infants may predict virologic failure on nevirapine-containing ART. J Clin Virol 48:162-7
Rowley, Christopher F; Boutwell, Christian L; Lee, Esther J et al. (2010) Ultrasensitive detection of minor drug-resistant variants for HIV after nevirapine exposure using allele-specific PCR: clinical significance. AIDS Res Hum Retroviruses 26:293-300

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