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.

Keywords: DMPA; HIV; PrEP; lamivudine; microbiome; tenofovir.

Figure 1.

Concentrations of intracellular metabolites and endogenous nucleotides in cervical tissue. A–D, Box plots showing distribution of analytes measured in cervical homogenates by contraceptive group: tenofovir diphosphate (A), lamivudine triphosphate (B), deoxyadenosine triphosphate (C), and deoxycytidine triphosphate (D). Abbreviations: 3TC-TP, lamivudine triphosphate; dATP, deoxyadenosine triphosphate; dCTP, deoxycytidine triphosphate; DMPA, depot medroxyprogesterone acetate; TFV-DP, tenofovir diphosphate. *P < .05, Wilcoxon rank-sum test.

Figure 2.

Vaginal microbiota and cervical drug concentrations. A, Relative abundance of the 12 genera that separated the depot medroxyprogesterone acetate (DMPA) users (hashed bars) from the nonhormonal (clear bars) group in linear discriminant analysis of effect size. The nonhormonal group was defined by greater abundance of potentially pathogenic bacteria associated with bacterial vaginosis. B, Number of women with each of the most prevalent genera identified, shown for nonhormonal contraception users (clear bars) and DMPA users (hashed bars). C and D, Cervical concentrations of tenofovir diphosphate (C) and lamivudine triphosphate (D) by the most prevalent genera. Abbreviations: 3TC-TP, lamivudine triphosphate; BVAB, bacterial vaginosis–associated bacteria; DMPA, depot medroxyprogesterone acetate; TFV-DP, tenofovir diphosphate.