Research Gaps in Defining the Biological Link between HIV Risk and Hormonal Contraception

Abstract

Epidemiologic data suggest an association between depot medroxyprogesterone acetate (DMPA), a progesterone-based hormonal contraceptive, and increased risk of HIV acquisition and transmission. DMPA is highly effective and is among the most commonly used form of hormonal contraception in areas of high HIV prevalence. Thus, defining the biological mechanisms that contribute to the potential negative synergy between DMPA and HIV is key and may facilitate the identification of alternative contraceptive strategies. Proposed mechanisms include thinning or disruption of the cervicovaginal epithelial barrier, induction of mucosal inflammation, interference with innate and adaptive soluble and cellular immune responses, and/or alterations in the vaginal microbiome. DMPA may also indirectly increase the risk of HIV by promoting genital herpes or other sexually transmitted infections. However, there is a paucity of rigorous in vitro, animal model and clinical data to support these potential mechanisms highlighting the need for future research.

Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV?

“…Several biological mechanisms may underlie an association between DMPA and increased risk of HIV acquisition in women, including: structural changes and alterations in the permeability of the female genital tract, alterations of the frequency and activity of cellular targets for infection, modulation of levels of soluble mediators and defense molecules in the genital tract, alteration of innate and adaptive immune responses, and changes in the female genital tract microbiome [27, 28]. Research in this area has been stymied by lack of identified biomarkers that would predict significant risk of future HIV acquisition.…”

Progesterone-Based Intrauterine Device Use Is Associated with a Thinner Apical Layer of the Human Ectocervical Epithelium and a Lower ZO-1 mRNA Expression1

“…It has been suggested that hormonal contraceptives may affect human immunodeficiency virus (HIV) susceptibility within the vaginal vault by modulating the genital immune system, regulating genital epithelial cells, inducing cervical ectopy, and affecting the local microflora [2][3][4][5][6]. Data regarding vaginal epithelial thickness differences between hormonal contraceptive users and nonusers are however indecisive, and the clinical relevance of some of these limited changes is unclear [7][8][9][10][11][12]. Thus, the global impact of the biological effects of hormonal contraceptives needs to be explored in detail to understand how they may affect susceptibility to HIV acquisition and transmission.…”

Effect of hormonal contraception on the function of plasmacytoid dendritic cells and distribution of immune cell populations in the female reproductive tract

“…This adds to the growing amount of evidence of the biological effect of progestins on the immune system and on the immune environment in lower FRT 7,13,14 . However, it remains to be established whether the contraceptive-mediated alterations to systemic and genital immune mechanisms described here and in other studies exert an effect on the susceptibility to HIV-1 and other infections.…”

“…Multiple studies have sought to understand the biological mechanisms underlying the effect of hormonal contraception on HIV-1 acquisition (reviewed in 7,13,14 ). Hormonal contraception use has been linked to changes in the frequencies of immune cells in genital mucosae [15][16][17][18][19][20][21] and altered levels of cytokines, chemokines, and antiviral factors in cervicovaginal fluid 22,23 .…”

“…Hormonal contraception use is associated with increased acquisition of cervical candidiasis, C. trachomatis, N. gonorrhoeae, and M. genitalium infections, which may independently facilitate HIV-1 acquisition and transmission 10,[24][25][26][27] . Studies using non-human primate models demonstrated that DMPA enhances the risk of simian immunodeficiency virus (SIV) acquisition via vaginal exposure (reviewed in 7,13 ). Medroxyprogesterone acetate (MPA), the contraceptive component of DMPA, was shown to suppress systemic regulators of cellular and humoral immunity, reduce cytokine production by plasmacytoid dendritic cells (pDCs), and increase the replication of HIV-1 in activated peripheral blood mononuclear cells (PBMCs) in vitro [28][29][30][31][32] .…”