Initiating Intramuscular Depot Medroxyprogesterone Acetate Increases Frequencies of Th17-like Human Immunodeficiency Virus Target Cells in the Genital Tract of Women in South Africa: A Randomized Trial

Abstract

Background Cervicovaginal CD4+ T cells are preferential targets for human immunodeficiency virus (HIV) infection and have consequently been used as a proxy measure for HIV susceptibility. The ECHO randomized trial offered a unique opportunity to consider the association between contraceptives and Th17-like cells within a trial designed to evaluate HIV risk. In a mucosal substudy of the ECHO trial, we compared the impact of initiating intramuscular depot medroxyprogesterone acetate (DMPA-IM), copper-IUD, and the levonorgestrel (LNG) implant on cervical T cells. Methods Cervical cytobrushes from 58 women enrolled in the ECHO trial were collected at baseline and 1 month after contraceptive initiation. We phenotyped cervical T cells using multiparameter flow cytometry, characterized the vaginal microbiome using 16s sequencing, and determined proteomic signatures associated with Th17-like cells using mass spectrometry. Results Unlike the LNG implant or copper-IUD, DMPA-IM was associated with higher frequencies of cervical Th17-like cells within 1 month of initiation (P = .012), including a highly susceptible, activated population co-expressing CD38, CCR5, and α4β7 (P = .003). After 1 month, women using DMPA-IM also had more Th17-like cells than women using the Cu-IUD (P = .0002) or LNG implant (P = .04). Importantly, in women using DMPA-IM, proteomic signatures signifying enhanced mucosal barrier function were associated with the increased abundance of Th17-like cells. We also found that a non–Lactobacillus-dominant microbiome at baseline was associated with more Th17-like cells post–DMPA-IM (P = .03), although this did not influence barrier function. Conclusions Our data suggest that DMPA-IM–driven accumulation of HIV-susceptible Th17-like cells might be counteracted by their role in maintaining mucosal barrier integrity.

Copper intrauterine device increases vaginal concentrations of inflammatory anaerobes and depletes lactobacilli compared to hormonal options in a randomized trial

“…From those who enrolled in this mucosal sub-study, sample size calculations indicated that 20 participants per randomized arm per site with complete sample sets at all three timepoints were needed, and thus we randomly selected women who met this criterion at the Johannesburg, South Africa and Kisumu, Kenya sites. However, at the Cape Town, South Africa site, cervical cytobrushes from 80 consecutively enrolled women were processed for phenotyping ex vivo at enrollment and 1 month post-contraception initiation for a separate study 56 , and we elected to include all of these participants, rather than a random subset. In addition, participants that were included in the secondary (case-control) analysis but also had samples available at enrollment, 1 month, and 6 months, were added to the pre-post analysis group if not already included.…”