Evaluating the impact of three progestin-based hormonal contraceptive methods on immunologic changes in the female genital tract and systemically (CHIME Study): a prospective cohort study protocol.

BACKGROUND: Gonadal hormones can modify immune function, which may impact susceptibility to infectious diseases, including Human Immunodeficiency Virus (HIV). There is limited knowledge about how hormonal contraceptives (HC) influence the immune response during the course of use. The CHIME study aims to evaluate the effect of long-acting progestin-based hormonal contraceptives (depot medroxyprogesterone acetate, etonogestrel implant, and levonorgestrel intrauterine device) on immunologic changes in the female genital tract (FGT) and systemic compartment. METHODS: CHIME is an observational cohort study where participants attend 2 visits prior to initiating the HC method of their choice, and then attend 6 visits over 12 months with biological sampling (vaginal swabs, cervicovaginal lavage, cytobrush and blood) for immunological, bacteriological, and virological analyses at each visit. Immune profiling will be evaluated by multi-color flow cytometry to determine how different T-cell subsets, in particular the CD4 T-cell subsets, change during the course of contraceptive use and whether they have different profiles in the FGT compared to the systemic compartment. The study aims are (1) to characterize the alterations in FGT and systemic immune profiles associated with three long-acting progestin-only HC and (2) to evaluate the vaginal microenvironment, determined by 16 s rRNA sequencing, as an individual-level risk factor and moderator of genital and systemic immune profile changes following exposure to three commonly used HC. Data collection started in March 2019 and is scheduled to be completed in October 2024. DISCUSSION: The CHIME study aims to contribute to the body of research designed to evaluate the comparative impact of three long-acting progestin-only HC on innate and adaptive immune functions to understand how immunologic effects alter STI and HIV susceptibility.

Influence of Hormonal Contraceptive Use and HIV on Cervicovaginal Cytokines and Microbiota in Malawi.

Important questions remain on how hormonal contraceptives alter the local immune environment and the microbiota in the female genital tract and how such effects may impact susceptibility to HIV infection. We leveraged samples from a previously conducted clinical trial of Malawian women with (n = 73) and without (n = 24) HIV infection randomized to depot medroxyprogesterone acetate (DMPA) or the levonogestrel implant in equal numbers within each group and determined the effects of these hormonal contraceptives (HCs) on the vaginal immune milieu and the composition of the vaginal microbiota. Longitudinal data for soluble immune mediators, measured by multiplex bead arrays and enzyme-linked immunosorbent assays (ELISAs), and vaginal microbiota, assessed by 16S rRNA gene amplicon, were collected prior to and over a period of 180 days post-HC initiation. DMPA and levonogestrel had only minimal effects on the vaginal immune milieu and microbiota. In women with HIV, with the caveat of a small sample size, there was an association between the median log10 change in the interleukin-12 (IL-12)/IL-10 ratio in vaginal fluid at day 180 post-HC compared to baseline when these women were classified as having a community state type (CST) IV vaginal microbiota and were randomized to DMPA. Long-lasting alterations in soluble immune markers or shifts in microbiota composition were not observed. Furthermore, women with HIV did not exhibit increased viral shedding in the genital tract after HC initiation. Consistent with the results of the ECHO (Evidence for Contraceptive Options and HIV Outcomes) trial, our data imply that the progestin-based HC DMPA and levonorgestrel are associated with minimal risk for women with HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT02103660). IMPORTANCE The results of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, the first large randomized controlled clinical trial comparing the HIV acquisition risk of women receiving DMPA, the levonorgestrel (LNG) implant, or the copper intrauterine device (IUD), did not reveal an increased risk of HIV acquisition for women on any of these three contraceptives. Our study results confirm that the two different progestin-based hormonal contraceptives DMPA and levonogestrel will not increase the risk for HIV infection. Furthermore, DMPA and levonogestrel have only minimal effects on the immune milieu and the microbiota in the vaginal tract, attesting to the safety of these hormonal contraceptives.

Effect of the depot medroxyprogesterone acetate injectable and levonorgestrel implant on HIV genital shedding: a randomized trial.

OBJECTIVES: To assess the effect of the depot medroxyprogesterone acetate injectable (DMPA) and of the levonorgestrel (LNG) implant on genital HIV shedding among women receiving antiretroviral therapy (ART). METHODS: We randomized HIV-infected Malawian women to either DMPA or LNG implant from May 2014 to April 2015. HIV RNA was measured in cervicovaginal lavage (CVL) fluid and TearFlo Strips (TFS), and HIV DNA was measured in cells collected by CVL. We compared the frequency and magnitude of HIV genital shedding before and for 6 months after initiation of contraception and between arms among women receiving ART. We also compared genital HIV RNA levels obtained by sample type (TFS versus CVL). RESULTS: We analyzed data for 68 HIV-infected women receiving ART: 33 randomized to DMPA and 35 randomized to the LNG implant. Overall, HIV RNA was more often detectable and the quantity was higher on TFS compared with CVL. HIV DNA was detected very rarely in CVL cell samples (4 of 360 samples). The frequency of genital shedding and the genital HIV quantity did not increase after contraceptive initiation with either DMPA or LNG implant among women receiving ART. CONCLUSIONS: HIV-infected women receiving ART initiating contraception with either DMPA or LNG implant did not have any increase in genital HIV shedding during the first 6 months of contraceptive use. These findings are consistent with growing evidence that progestin contraception is not associated with increased HIV transmission risk from such women to their male partners. Consistent with other studies, genital HIV RNA detection was higher in TFS than in CVL fluid. IMPLICATIONS: In this randomized trial, neither DMPA nor the LNG implant, two of the most commonly used hormonal contraceptives among African women with HIV, was associated with increased genital HIV shedding in HIV-infected women receiving ART. These findings are reassuring and add to the currently limited information available for the highly effective contraceptive, LNG implant.