Depot Medroxyprogesterone Acetate and the Vaginal Microbiome as Modifiers of Tenofovir Diphosphate and Lamivudine Triphosphate Concentrations in the Female Genital Tract of Ugandan Women: Implications for Tenofovir Disoproxil Fumarate/Lamivudine in Preexposure Prophylaxis

Abstract

Background Effective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown. Methods Fifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography–mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups. Results 3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues. Conclusions We found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis. Clinical Trials Registration NCT03377608.

Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial

“…In this double-masked, randomized controlled noninferiority trial, eligible WLHIV were ages 18-40, not pregnant or desiring pregnancy within 30 months, screened and treated (as indicated) for reproductive tract infections (RTIs) within 1 month of enrollment, and virologically suppressed using ART or above treatment threshold at enrollment (non-ART). Between October 2013, and December 2016, we randomized consenting women within ART groups, using 1:1 permuted block randomization stratified by ART use,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and recent injectable progestin contraceptive (IPC) exposure, and provided the allocated IUC. At all visits, participants provided specimens for gVL (primary outcome), pVL, RTI, and…”

“…Data for whether IUCs are safe for use among WLHIV and, specifically, whether IUCs impact gVL is germane given expanded global ART use and findings of persistent detectable gVL among WLHIV virally suppressed with very low to undetectable plasma viral load (pVL) [21][22][23]. There are emerging concerns that HIV acquisition and transmission risk may increase in the presence of RTIs, non-Lactobacillus dominant microbiota, and hormonal contraceptives because of local interaction with ART agents [24][25][26]. Thus, evidence regarding gVL change with exposure to hormonal and nonhormonal IUC use among WLHIV with typical ART use patterns in a context with high background RTI prevalence is timely and may help inform this debate.…”

Understanding and interpreting community sequencing measurements of the vaginal microbiome

“…Community sequencing has implicated several taxa as risk factors for PTB, including Gardnerella , Prevotella , Sneathia , Atopobium , and Ureaplasma , but so far agreement across studies regarding the specific non‐ Lactobacillus taxa associated with PTB has been limited . Community sequencing is furthering the study of how BV‐associated microbes increase HIV and HPV risk and reduce efficacy of antiretrovirals for HIV prevention . Metatranscriptomic sequencing of the vaginal microbiome during BV and STI is being used to find pathways related to aetiology, treatment targets, and treatment evasion, as well as to determine the dominant pathogen in STI co‐infection …”

The effect of depot medroxyprogesterone acetate on tenofovir alafenamide in rhesus macaques

“…Studies showing limited penetration of TAF in female genital tissue have raised questions about the ability of TAF to prevent vaginal infection ( Massud et al, 2019 ; Garrett et al, 2016 ; Cottrell et al, 2017 , 2019 ; Nicol et al, 2020a ). In a recent pig-tailed macaque study, the combination of TAF and FTC conferred 91% protection against vaginal SHIV infection while TAF alone was associated with a moderate protective efficacy of 58–73%.…”

“…In a recent ex vivo study, DMPA was found to suppress TAF metabolism in female genital tract cells although little or no effect was seen in blood cells ( Shen et al, 2017 ). Recent clinical evaluations of TFV-based regimens also indicated that mucosal tissue TFV-DP may be affected by exogeneous hormonal treatments, but not by endogenous hormonal cycles ( Cottrell et al, 2019 ; Nicol et al, 2020a , 2020b ).…”