Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study

Abstract

Summary Background The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract. Methods In this prospective cohort, we enrolled HIV-negative South African women aged 18–23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods. Findings Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12·06 per 100 person-years, 95% CI 6·41–20·63) than women using no long-term contraception (3·71 per 100 person-years, 1·36–8·07; adjusted hazard ratio [aHR] 2·93, 95% CI 1·09–7·868, p=0·0326). HIV-negative injectable progestin-only contraceptive users had 3·92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0·0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3·25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0·0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives. Interpretation Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure. Funding The Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases.

Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women

“…We observed no differences between bacterial communities and demographic factors, condom use, frequency or type of sexual acts, or number of sexual partners. The use of injectable progestin contraceptives (IPCs), a known HIV risk factor in the FRESH cohort, was also similar among women with different CTs, which is consistent with our previous finding that cervicovaginal bacterial communities did not vary with IPC use (Byrne et al, 2016). Sexually transmitted infections (STIs) were equally distributed among all groups, except for an increase in Chlamydia trachomatis infection from CT1 through CT4 (Table S1).…”

“…We next assessed factors associated with different genital bacterial communities in our cohort, with particular attention to those that might increase HIV susceptibility (Byrne et al, 2016; McKinnon and Karim, 2016; Ward and Ronn, 2010) (Table S1). We observed no differences between bacterial communities and demographic factors, condom use, frequency or type of sexual acts, or number of sexual partners.…”

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

“…Clinically, the two regimens show therapeutic equivalence and similar effects on weight gain, bone mineral density, bleeding patterns, and frequency of serious adverse effects, which suggests limited differences, if any, in biological responses, despite the 31% dose difference [9]. Furthermore, both DMPA-IM and DMPA-SC result in similar degrees of hypoestrogenism, characterized by systemic estrogen concentrations of 10–100 pg/mL [31, 32, 56]. It is possible that within the initial 30 days following administration of DMPA-IM versus DMPA-SC, with notably different resulting serum concentrations of MPA, some biological responses critical to HIV susceptibility may be differentially impacted.…”

“…DMPA-IM has been shown in some clinical studies to increase surface levels of CCR5 on peripheral and female genital tract (FGT) target T cells [55, 56], increase the frequency of CCR5 + T cells in the FGT mucosa [56], decrease the production of several immune modulators by immune cells [57, 58], increase FGT mucosal permeability and expression of barrier function proteins [59] and alter cervicovaginal levels of select secreted immunomodulators [57, 60–66]. Several of these studies are consistent with results from animal studies where MPA serum concentrations are similar to those of human DMPA-IM users [59, 67–71].…”

A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

“…Estradiol and progesterone regulate multiple functions in the genital tract, including homing of immune cells, chemokines and cytokines, [42] mucosal cellular composition, [43–45] and epithelial cell receptor expression [46]. Progesterone and its derivatives can increase infiltration of antigen-presenting cells in the vaginal epithelium, as well as CD4 + CCR5+ lymphocytes and CD8+ T-lymphocytes in genital tract tissues [44,47–54]. Estrogen, on the other hand, has been shown to decrease recruitment of activated T-cells and macrophages [55].…”