Plasma concentration of injectable contraceptive correlates with reduced cervicovaginal growth factor expression in South African women

Abstract

Long-acting injectable contraceptives have been associated with mucosal immune changes and increased HIV acquisition, but studies have often been hampered by the inaccuracy of self-reported data, unknown timing of injection, and interactions with mucosal transmission co-factors. We used mass spectrometry to quantify the plasma concentrations of injectable contraceptives in women from the CAPRISA004 study (n = 664), with parallel quantification of 48 cytokines and >500 host proteins in cervicovaginal lavage. Higher DMPA levels were associated with reduced CVL concentrations of GCSF, MCSF, IL-16, CTACK, LIF, IL-1α, and SCGF-β in adjusted linear mixed models. Dose-dependent relationships between DMPA concentration and genital cytokines were frequently observed. Unsupervised clustering of host proteins by DMPA concentration suggest that women with low DMPA had increases in proteins associated with mucosal fluid function, growth factors, and keratinization. Although DMPA was not broadly pro-inflammatory, DMPA was associated with increased IP-10 in HSV-2 seropositive and older women. DMPA–cytokine associations frequently differed by vaginal microbiome; in non-Lactobacillus-dominant women, DMPA was associated with elevated IL-8, MCP-1, and IP-10 concentrations. These data confirm a direct, concentration-dependant effect of DMPA on functionally important immune factors within the vaginal compartment. The biological effects of DMPA may vary depending on age, HSV-2 status, and vaginal microbiome composition.

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Fig. 1: Correlation between plasma DMPA depletion over time in months.
Fig. 2: The effect of MPA levels on cervicovaginal cytokines milieu stratified by pro-inflammatory cytokines (red), chemokines (green), growth factors (purple), adaptive factors (blue), and anti-inflammatory cytokines (gray).
Fig. 3
Fig. 4

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Acknowledgements

We thank all of the CAPRISA002 and 004 study participants, and the clinical and laboratory staff who worked on these studies. This project was funded by the Canadian Institutes of Health Research CIHR) (A.D.B., L.R.M. TMI 138658). R.P.M. was previously funded by the South African National Research Foundation (NRF) PhD Scholarship and University of KwaZulu-Natal College of Health Science (CHS) for PhD running expenses. L.J.L. is funded by a South African National Research Foundation (NRF) Research Career Advancement Fellowship award. L.R.M. and A.D.B are supported by a CIHR New Investigator Awards. The CAPRISA004 tenofovir gel trial was funded principally by the US Agency for International Development, grants through FHI360, and CONRAD for product manufacturing, with support from the South African Department of Science and Technology (DST).

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Designed the study: R.P.M., S.N., A.D.B., J.A.P., and L.R.M. Performed the experiments: R.P.M., L.J.L., L.N.-R., A.M., M.P., K.B., J.H.A., and K.G. Analyzed the data: R.M., L.J.L., L.N.-R., N.M., M.P., K.B., J.H.A., and L.R.M. Wrote the paper: R.M. L.R.M. wrote the first draft and all authors contributed to editing and finalizing. Supervised clinical and/or experimental aspects of the study: A.L., N.J.G., N.S., A.D.B., S.S.A.K., Q.A.K., J.A.P., and L.R.M.

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Correspondence to Lyle R. McKinnon.

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Molatlhegi, R.P., Liebenberg, L.J., Leslie, A. et al. Plasma concentration of injectable contraceptive correlates with reduced cervicovaginal growth factor expression in South African women. Mucosal Immunol 13, 449–459 (2020). https://doi.org/10.1038/s41385-019-0249-y

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