Advancing PrEP Use among Pregnant Women in sub-Saharan Africa

Abstract

In sub-Saharan Africa (SSA), cisgender women are disproportionately affected by HIV, accounting for approximately 63% of all new infections in this region. Pregnancy, a period experienced by many young women in SSA, is associated with an elevated risk of HIV acquisition due to the combined effects of behavioral, immunological, and hormonal changes. Daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) is highly effective in decreasing HIV acquisition risk when taken as prescribed and is recommended by the World Health Organization (WHO) as one of the prevention options for individuals at substantial HIV risk, including cisgender women. However, additional questions on intracellular exposure in HIV target cells during pregnancy and the long-term growth and bone health outcomes for infants with utero TDF/FTC PrEP, remain unanswered.The adherence–concentration–efficacy relationship for TDF/FTC PrEP has been well established among gay, bisexual, and other men who have sex with men (MSM), indicating that taking four doses/week can reduce HIV acquisition risk by approximately 96%. However, this relationship has been less studied in cisgender women, leading to uncertainty about optimal dosing strategies in this population. Based on pharmacologic evidence showing lower drug penetration in female genital track compared to rectal tissue, cisgender women have been advised to take one pill daily to achieve levels of protection similar to those observed in MSM taking four doses/week. This messaging may pose substantial barriers to PrEP initiation and continuation in cisgender women. Additionally, pregnancy is associated with profound physiological changes that may lead to suboptimal drug exposure, reduced efficacy, and uncertainty regarding optimal PrEP dosing strategies for HIV prevention in this critical period. Several studies have reported decreased concentrations of tenofovir diphosphate (TFV-DP), the active metabolite of TDF, in red blood cells measured using dried blood spots (DBS) during pregnancy; however, changes in drug concentrations at clinically relevant sites for HIV prevention remain less understood. Furthermore, while TDF is generally considered safe, its use has been associated with renal and bone toxicity. During pregnancy, tenofovir (TFV), the parent drug of TDF, readily crosses the placenta and may potentially affect fetal bone development. However, few studies have evaluated the impact of maternal TDF exposure on children bone health, and the findings have been mixed. Additional data are needed to determine whether and to what extent in-utero TDF exposure affect bone outcomes in children. The studies presented in this dissertation address these key knowledge gaps to inform the effective and safe use of oral TDF/FTC PrEP among pregnant women in SSA and has the potential to guide clinical guidelines and policy decisions to optimize PrEP delivery in this population. In Chapter 2, we conducted a systematic review to summarize current evidence and identify knowledge gaps related to protective adherence levels of TDF-based oral PrEP in cisgender women, including during pregnancy. We found that women-specific intracellular TFV-DP adherence benchmarks in DBS and peripheral blood mononuclear cells (PBMC) fall within the range of historical U.S.-based thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women; however more data are still needed to refine the intrinsic achievable efficacy estimates for cisgender women. In Chapter 3, we leveraged a directly observed dosing study in Kenya, in which 18 pregnant and 18 non-pregnant women received daily dosing of TDF/FTC for 8 weeks. Blood for DBS and PBMC was collected weekly for non-pregnant and bi-weekly for pregnant women. We characterized paired TFV-DP concentrations in DBS and PBMCs and quantified matrix-specific pharmacokinetic differences by pregnancy status. We found that steady-state TFV-DP concentrations from daily dosing of TDF/FTC were approximately two-fifths lower in DBS during pregnancy, whereas TFV-DP and emtricitabine triphosphate (FTC-TP) concentrations in PBMCs were not meaningfully different between pregnant and non-pregnant women. We also compared growth outcomes of infants exposed to daily dosing of TDF/FTC in pregnancy to historical TDF/FTC-unexposed infants from the placebo arm of the Partners PrEP Efficacy Study. We found Z-scores for infant weight, length, and head circumference were comparable at 6, and 12 months of age. In Chapter 4, by leveraging a prospective cohort that evaluated the oral TDF/FTC PrEP safety in pregnant and postpartum women in Western Kenya, we conducted a matched cohort study to assess the association between in-utero PrEP exposure and bone mineral content (BMC) for whole body less head and lumbar spine at 36 and 52 months of age. We found that mean BMC for whole body less head and lumbar spine were not lower among children with in-utero PrEP exposure. While the overall prevalence of low BMC in our study population was high (20%-30%), in-utero PrEP exposure was not associated with higher prevalence of low BMC. Our findings are reassuring and support the continued use of oral TDF/FTC PrEP during pregnancy.