Closing Research Gaps in Antiretroviral Treatment for Pregnant Women and Infants Living with HIV

Harvard University D/B/A Harvard School Of Public Health, Boston MA

Investigators

Linked publications & trials

Abstract

Project 1: Project Summary/Abstract, Tsepamo Plus (Project 1) Antiretroviral treatment (ART) guidelines depend upon safety and efficacy data in pregnancy, especially in resource-limited settings where programs rely on a single ART regimen as first-line treatment for all pregnant and non-pregnant adults. Current considerations for using modern ART regimens in pregnancy – especially those containing dolutegravir (DTG) and tenofovir alafenamide (TAF) – include understanding the risks for neural tube defects (NTDs) and for the effect of weight gain on pregnancy outcomes. The Tsepamo Study (R01HD080471, R01HD095766) is the largest pregnancy surveillance system in Africa, and has evaluated over 180,000 deliveries in Botswana since 2014. The study has provided critical safety data and treatment guidance related to specific ART regimens that have been adopted for early use within the Botswana ART program. In 2018, the Tsepamo Study demonstrated a potential association with DTG and NTDs, and while this concern has decreased over time following expanded surveillance, it has not disappeared. Ongoing NTD surveillance is required both for DTG and for other new antiretroviral agents. New considerations regarding weight gain with modern ART regimens have also been analyzed successfully in Tsepamo, but further data stratified by baseline maternal weight groups are needed. The existing Tsepamo award was funded to continue birth surveillance through December 2022, and the P01 mechanism can extend surveillance for 4 additional years from January 2023 through December 2026. This will allow the completion of aims that include: 1) ongoing surveillance to understand and characterize the neural tube defect risk associated with DTG over a longer period, and with additional evaluation of dietary folic acid intake; 2) a new aim to conduct an emulated clinical trial comparing the most relevant ART regimens when used at different weight strata; and 3) new aims that utilize a unique identifier to capture data across multiple pregnancies for the first time in our surveillance. These novel aims take advantage of the unique ART landscape in Botswana, and build on the scientific findings from our highly productive surveillance system. Data generated from this study will be critical for updating international guidelines for the use of ART in pregnancy. Project 3: Project Summary/Abstract, Point-of-Care HIV Testing and Early Dolutegravir Use for Infants (Project 3) The stakes of delaying HIV diagnosis and treatment in infancy are high. Infants progress to AIDS and die at a higher rate than any other age group, with over 30% of deaths occurring in the first 42 days of life. Even when treatment is started for infants, the available treatment regimens are limited – current recommendations include drugs such as nevirapine, zidovudine, or lopinavir/ritonavir (LPV/r) that are rarely used in adults – and treatment failure is common. Studies on the use of newer agents in children are lacking, leading to a reluctance to use newer agents in guidelines even after their approval for infants. Dolutegravir (DTG) was approved for use in infants from 30 days of life in June 2020, but has not become the first-line treatment regimen for infants in any current ART program in Africa. There is therefore an urgent need for implementation research to embed early infant diagnostics at the time of birth within national treatment programs in Africa, and to begin using modern DTG-based ART regimens for infants from as early in life as possible. With the support of Botswana's Ministry of Health and Wellness and this P01 program, the Botswana–Harvard AIDS Institute Partnership is uniquely positioned to pioneer a research program to support birth diagnosis and DTG treatment for infants in Botswana. Building on prior research within the Early Infant Treatment (EIT) Study, we will implement targeted birth testing (screening only exposed infants with the highest risk of HIV acquisition) by facility-based point-of-care (POC) testing with the Cepheid Xpert platform. Infants with HIV will be treated immediately, and referred for enrollment into a cohort that is transitioned to DTG-based ART at four weeks of life and followed for at least 96 weeks. With comparisons to alternate diagnostic approaches and to children who received LPV/r-based ART within the EIT Study, the study design will allow us to 1) evaluate the feasibility of adding low-cost, targeted early infant diagnosis to the Botswana national treatment program; 2) quantify the number of children identified as HIV infected at birth and determine time from diagnosis to ART initiation when POC testing is deployed; 3) compare the time to suppression and 12-week suppression between DTG-based and LPV/r-based ART; and 4) compare 96-week outcomes and overall viral suppression between DTG-based and LPV/r-based ART. Results from this study will inform programs that wish to implement birth diagnostics and early infant treatment with DTG-based ART, and will answer critical questions regarding the clinical, virologic, and immunologic impact of early DTG-based ART.