Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence

Polis, Chelsea B.; Phillips, Sharon J.; Curtis, Kathryn M.; Westreich, Daniel; Steyn, Petrus S.; Raymond, Elizabeth G.; Hannaford, Philip Christopher; Turner, Abigail Norris

doi:10.1016/j.contraception.2014.07.009

Cited by 83 publications

(115 citation statements)

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“…The use of injectable hormonal contraceptives in women increased from 4.5% in 1995 to 23% in 2006 to 2010 (28). A number of studies have suggested an increased risk of acquisition of HIV in association with DMPA (29)(30)(31). It is of interest that one of the highest reported rates of HSV-1 genital herpes was detected in participants of the Herpevac trial study, all of which were required to use a highly effective method of birth control that included hormonal contraceptives.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Boukhvalova

McKay

Mbaye

et al. 2015

J Virol

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Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data generated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated cotton rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in cotton rats, and yet the model allowed for comparative evaluation of gD/AS04 immunogenicity and efficacy. Cotton rats were intramuscularly vaccinated using a prime boost strategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in cotton rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized cotton rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine strategies and the identification of new correlates of protection. IMPORTANCEIn spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized cotton rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.T he disease burden associated with herpes simplex virus 2 (HSV-2) infection, an important cause of genital herpes worldwide, is high and presents an additional threat due to its association with an increased risk of HIV acquisition and transmission (1-3). Globally, HSV-2 is a major health threat, with 16% of the U.S. population infected by age 30 and 50 to 90% of the population in sub-Saharan Africa infected (3-5). Recent reports emphasize the importance of HSV-1 as an important etiologic agent of genital herpes particularly in the United States and other developed countries (6-8). Seroprevalence of HSV-1 among 14-to 49-year-olds in the Uni...

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Section: Discussionmentioning

confidence: 99%

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Boukhvalova

McKay

Mbaye

et al. 2015

J Virol

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“…[1][2][3][4] In regions of the world where HIV-1 incidence is highest, more women are newly infected per year than men. 5 While social, behavioral, and economic conditions are certainly factors in the increasing incidence of HIV-1 in women, there has been an emphasis on the role of endogenous 6 and exogenous 7 hormones as cofactors in HIV-1 acquisition or infection and disease progression. Observational and prospective longitudinal studies support that pregnancy and lactation, characterized by high serum progesterone (4-pregnene-3,20-dione or P4) and low serum estradiol [1,3,5(10)-estratriene-3,17beta-diol or E2] levels, are also associated with an increased risk of HIV-1 acquisition compared with nonlactating nonpregnant controls.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Thurman

Chandra

Yousefieh

et al. 2016

AIDS Research and Human Retroviruses

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The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1 BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

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“…Understanding biological contributors to HIV risk in women is therefore important for public health. Although still a topic of great debate there is a growing body of evidence that both endogenous and exogenous ovarian hormones, including estradiol and progesterone, are associated with increased HIV acquisition in women (3)(4)(5)(6)(7). Studies of nonhuman primates have shown that SHIV infection occurs more frequently during the progesteronedominant luteal phase of the menstrual cycle (8,9), and recent in vitro explant cultures of human cervical tissue have also shown that HIV infects explants collected during the luteal phase more productively than those collected during the follicular phase (10).…”

mentioning

confidence: 99%

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

Birse

Arnold

Novak

et al. 2015

J Virol

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The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and ex vivo human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (n ‫؍‬ 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (P < 0.05, >2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway, P ‫؍‬ 1.41E-5) and extravasation proteins (P ‫؍‬ 5.62E-4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4؉ T cell and neutrophil gene set signatures with the luteal phase (P < 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV. IMPORTANCERecent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for this enhanced susceptibility has not yet been determined. Understanding the source of this vulnerability will be important for designing efficacious HIV prevention technologies for women. Furthermore, these findings may also be extrapolated to better understand the impact of exogenous hormone application, such as the use of hormonal contraceptives, on HIV acquisition risk. Hormonal contraceptives are the most widely used contraceptive method in sub-Saharan Africa, the most HIV-burdened area of the world. For this reason, research conducted to better understand how hormones impact host immunity and susceptibility factors important for HIV infection is a global health priority. The global HIV incidence rates for women remain high, so much so that every minute a young woman becomes infected with HIV (1). With infection rates twice as high for women aged 15 to 24 compared to their age-matched male counterparts, it is clear that young women are more susceptible to HIV infection (1, 2). Understanding biological contributors to HIV risk in women is therefore impo...

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Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence

Cited by 83 publications

References 70 publications

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

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