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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

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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.

Introduction

Hormonal contraceptives have empowered women to prevent unwanted pregnancies since being introduced in the 1960s. Unlike condoms, hormonal contraceptives do not need the cooperation of the male partner, can be taken discreetly, and are available in longacting formulations that are more than 99% effective. Injectable progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA) and norethindrone enanthate (NET-EN), are the favoured form of contraception in sub-Saharan Africa, where they are used by more than 8 million women.1 Unfortunately, injectable progestin-only contraceptives do not provide protection against sexually transmitted infections and have been associated with a substantially increased risk of acquiring HIV in most but not all studies.2, 3, 4, 5

In areas with both widespread injectable progestin-only contraceptive use and high HIV incidence, including many regions in sub-Saharan Africa, the questions of whether and how injectable progestin-only contraceptives affect HIV acquisition risk are of utmost importance. Decisions regarding the use of injectable progestin-only contraceptives must carefully balance the risk of HIV acquisition with that of unwanted pregnancy. The epidemiological studies driving these decisions are complicated by behavioural and demographic confounders that might mask the biological effect of injectable progestin-only contraceptives on HIV acquisition.6 Studies of the association between HIV acquisition and injectable progestin-only contraceptives use have not reached consistent conclusions, and although progestins have been shown to have a multitude of effects on immune function in vitro,7, 8, 9, 10 whether these effects are manifest in vivo is unclear.11, 12

Research in context

Evidence before this study

We searched PubMed for articles published before July 7, 2015, using the search terms “depo provera” OR “dmpa” OR “nur isterate” OR “net-en” AND “HIV” and read those written in English. We examined relevant citations from the results of our search and identified studies that examined HIV acquisition and contraceptive use from an epidemiological perspective, with some, but not all, reporting a significant association. We also identified studies that assessed the effect of progestins on the function of immune cells in vitro, in animal models, in ex-vivo tissue, or in blood or assessed cohorts not at high risk of HIV acquisition. Some studies examined the biological associations with contraceptive use in high-risk cohorts but limited their observations to soluble immune mediators and did not find a concomitant increase in HIV acquisition risk.

Added value of this study

Previous studies examining the epidemiological risk of injectable progestin-only contraceptive use and HIV acquisition have variably been confounded by differences in behavioural risk factors reported between those using no long-term contraceptive and injectable progestin-only contraceptive users. These confounders might have masked potential biological effects of injectable progestin-only contraceptive use. Our study characterises a unique cohort of young women in which profiles of HIV risk factors had similar proportions across the cohort, so women using injectable progestin-only contraceptives and women using no hormonal contraception were similar in terms of HIV risk factors.

In this study, we identified an increased frequency of HIV target cells at the cervix of HIV-negative women using injectable progestin-only contraceptives and, in the same group of women, noted a significantly higher incidence of HIV acquisition in injectable progestin-only contraceptive users. We noted a similar pattern in HIV target cell frequency in the naturally high progestin state of the luteal phase in women not using long-term contraceptive, suggesting that progestins, both endogenous and exogenous, might be key mediators of target cell availability. Our work links epidemiological observations of HIV infection to the immunological effects of injectable progestin-only contraceptive use in the female genital tract and provides new mechanistic insight into the role of progestins in HIV acquisition risk in women.

Implications of all the available evidence

Our results, taken together with other studies, have cast further doubt about the safety of injectable progestin-only contraceptive in areas of high HIV incidence. Moreover, by concluding that a high progestin concentration, both in naturally cycling women and in injectable progestin-only contraceptive users, correlates with increased target cell availability at the cervix, we suggest that progestins might induce increased cervical HIV target cell frequency. This work provides new insight into the role of progestins in the female genital tract and might inform the development of biological prophylactics to reduce HIV acquisition for women.

We designed a prospective study and secondarily assessed the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract, hypothesising that there is a biological mediator of the increased risk of HIV acquisition often observed in injectable progestin-only contraceptive users.

Section snippets

Study cohort and participants

HIV-negative women aged 18–23 years were recruited for the Females Rising through Education, Support, and Health (FRESH) study,13 an observational, prospective cohort study in Umlazi, South Africa (appendix). Participants were recruited by referral from three to four community organisations in Umlazi, South Africa, and community outreach events. We included women aged 18–23 years residing in Umlazi, South Africa, who were able to understand the information and consent forms, willing to adhere

Results

Between Nov 19, 2012, to May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 (35%) women used an injectable progestin-only contraceptive (DMPA or NET-EN), 43 women used another form of contraception, 15 women switched contraceptive methods during the study and were not included in the analyses comparing injectable progestin-only contraception users to women using no long-term contraception, and 222 (51%) women used no method of

Discussion

Defining the role of injectable progestin-only contraceptives in HIV acquisition is of utmost relevance, particularly in regions of the world where HIV transmission is highest. By prospectively following HIV-negative women in an area of high incidence, we first establish that injectable progestin-only contraceptives users in this cohort had significantly increased rates of HIV acquisition, an observation that has been shown previously in many2, 3, 4 but not all23, 24 large cohorts. More

References (26)

  • GC Hughes et al.

    Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells

    J Immunol

    (2008)
  • RP Huijbregts et al.

    Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms

    Endocrinology

    (2013)
  • CM Mitchell et al.

    Long-term effect of depot medroxyprogesterone acetate on vaginal microbiota, epithelial thickness and HIV target cells

    J Infect Dis

    (2014)
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