World Health Organization guidelines recommend Atripla (Efavirenz (EFV) / Emtricitabine (FTC) / Tenofovir (TDF)) for antiretroviral treatment (ART), including during all trimesters of pregnancy. Because of concerns for neural tube defects (NTDs) with EFV from early primate data and from limited human reports, EFV use in the first trimester of pregnancy has been rare to date, and few data exist to provide reassurance that the current WHO recommendations do not pose a small increased risk for NTDs. In addition, limited data are available regarding the effect of Atripla on other birth outcomes such as preterm delivery, small for gestational age infants, congenital abnormalities, stillbirths, and neonatal deaths. We therefore plan to create a nationwide surveillance system to capture 50% of births that occur in Botswana, and to study the effect of Atripla on adverse birth outcomes and on the rate of NTDs. National guidelines in Botswana have recently changed to allow Atripla use for both treatment and for the prevention of mother- to-child HIV transmission among HIV-infected women. This guideline change allows us to capture the rollout period for Atripla, and to compare outcomes for both EFV exposures and other ART regimen exposures from conception. In the process of performing this surveillance, we will also establish baseline rates of NTDs and other clinically important congenital abnormalities among infants born to HIV-infected and HIV-uninfected women. Botswana is an ideal setting to establish this surveillance because of the large number of ART exposures from conception (we expect to more than triple the current number of documented outcomes with EFV exposure worldwide), the high percentage of women delivering at maternity wards, and a successful previous surveillance study of over 33,000 births throughout the country. The combined aims of this study will provide a comprehensive understanding of the risks of using Atripla compared with other ART regimens during pregnancy.

Public Health Relevance

The World Health Organization has prioritized research on the potential risk of neural tube defects (NTDs) following Efavirenz (EFV) exposure in early pregnancy. We propose a nationwide birth outcomes surveillance system in Botswana that will capture 50% of all births and establish the risk of NTDs and all other adverse birth outcomes by HIV status and by EFV exposure. Botswana is an ideal setting to establish this surveillance, and the combined aims of this study will provide a comprehensive understanding of the risks of using EFV-based antiretroviral treatment regimens during pregnancy.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1)
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Siberry, George K
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Harvard University
Schools of Public Health
United States
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Zash, Rebecca; Jacobson, Denise L; Diseko, Modiegi et al. (2018) Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health 6:e804-e810
Caniglia, Ellen C; Zash, Rebecca; Jacobson, Denise L et al. (2018) Emulating a target trial of antiretroviral therapy regimens started before conception and risk of adverse birth outcomes. AIDS 32:113-120
Zash, Rebecca; Makhema, Joseph; Shapiro, Roger L (2018) Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med 379:979-981
Zash, Rebecca; Rough, Kathryn; Jacobson, Denise L et al. (2018) Effect of Gestational Age at Tenofovir-Emtricitabine-Efavirenz Initiation on Adverse Birth Outcomes in Botswana. J Pediatric Infect Dis Soc 7:e148-e151
Johnson, Katherine M; Zash, Rebecca; Haviland, Miriam J et al. (2016) Hypertensive disease in pregnancy in Botswana: Prevalence and impact on perinatal outcomes. Pregnancy Hypertens 6:418-422