Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis

Morrison, Charles; Chen, Pai Lien; Kwok, Cynthia; Baeten, Jared M.; Brown, Joelle; Crook, Angela M.; Damme, Lut Van; Delany‐Moretlwe, Sinead; Francis, Suzanna C.; Friedland, Barbara; Hayes, Richard; Heffron, Renee; Kapiga, Saidi; Karim, Quarraisha Abdool; Karpoff, Stephanie; Kaul, Rupert; McClelland, R. Scott; McCormack, Sheena; McGrath, Nuala; Myer, Landon; Rees, Helen; Straten, Ariane van der; Watson-Jones, Deborah; Wijgert, Janneke van de; Stalter, Randy M; Low, Nicola

doi:10.1371/journal.pmed.1001778

Cited by 179 publications

(218 citation statements)

References 72 publications

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“…Recently, a study on hormonal contraception and HIV acquisition reports individual patient data of several studies. Meta-analysis indicates that DMPA may increase HIV acquisition (controlling confounders and adjusted odds ratio of 1.5) compared with other methods of contraception (Morrison et al 2015). In vitro studies on hormone effects support the clinical studies discussed earlier.…”

Section: Introductionsupporting

confidence: 52%

“…The use of contraceptive pills by HIV-1-seropositive women is considered to be important for preventing unintended pregnancies and reducing mother-to-child transmissions. Although these hormones help to prevent unintended pregnancies, they also enhance HIV-1 acquisition (Ramjee & Wand 2012, Morrison et al 2015. Several epidemiological reports are inconsistent for progesterone-containing contraceptive use and risk of HIV-1 acquisition.…”

Section: Introductionmentioning

confidence: 99%

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Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

Ragupathy

Wang

Tan

et al. 2016

Journal of Molecular Endocrinology

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In human immunodeficiency virus type 1 (HIV-1)-infected women, oral or injectable progesterone containing contraceptive pills may enhance HIV-1 acquisition in vivo, and the mechanism by which this occurs is not fully understood. In developing countries, Herpes simplex virus type-2 (HSV-2) co-infection has been shown to be a risk for increase of HIV-1 acquisition and, if co-infected women use progesterone pills, infections may increase several fold. In this study, we used an in vitro cell culture system to study the effects of progesterone on HIV-1 replication and to explore the molecular mechanism of progesterone effects on infected cells. In our in vitro model, CEMss cells (lymphoblastoid cell line) were infected with either HIV-1 alone or co-infected with HSV-2. HIV-1 viral load was measured with and without sex hormone treatment. Progesterone-treated cells showed an increase in HIV-1 viral load (1411.2 pg/mL) compared with cells without progesterone treatment (993.1 pg/mL). Increased cell death was noted with HSV-2 co-infection and in progesterone-treated cells. Similar observations were noted in peripheral blood mononuclear cells (PBMC) cells derived from three female donors. Progesterone-treated cells also showed reduced antiviral efficacy. Inflammatory cytokines and associations with biomarkers of disease progression were explored. Progesterone upregulated inflammatory cytokines and chemokines conversely and downregulated anti-apoptotic Bcl-2 expression. Nuclear protein analysis by electrophoretic mobility shift assay showed the association of progesterone with progesterone response element (PRE), which may lead to downregulation of Bcl-2. These data indicate that progesterone treatment enhances HIV-1 replication in infected cells and co-infection with HSV-2 may further fuel this process.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

Ragupathy

Wang

Tan

et al. 2016

Journal of Molecular Endocrinology

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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%

“…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). Furthermore, progestins, which are synthetic progesterone derivatives commonly used in injectable hormonal contraceptives, have been shown to increase HIV acquisition risk by as much as 1.5-to 2.0-fold based on the latest meta-analysis (7,11). Clearly, these results indicate a link between ovarian hormones and HIV risk, and understanding the mechanisms underpinning these observations may have important implications for sexual and reproductive health.…”

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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“…Although controversial, a meta-analysis of observational studies in sub-Saharan Africa has suggested that DMPA may be associated with increased HIV risk, particularly in younger women. [14] Although more evidence is needed to empirically confirm this association, women who may be at risk for HIV should be counselled to also use condoms if they insist on using DMPA for contraception.…”

Section: Prevention Of Unintended and Unwanted Pregnanciesmentioning

confidence: 99%

Improving adolescent maternal health

Baxter

Moodley

2015

S Afr Med J

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Each year thousands of adolescent girls and young women in South Africa (SA) become pregnant and many die from complications related to pregnancy and childbirth. Although women of all ages are susceptible, girls <15 years of age are five times as likely, and those aged 15 -19 years twice as likely, to die from complications related to childbirth than women in their 20s. In SA, non-pregnancy-related infections (e.g. HIV), obstetric haemorrhage and hypertension contributed to almost 70% of avoidable maternal deaths. In addition to the implementation of standardised preventive interventions to reduce obstetric haemorrhage and hypertension, better reproductive health services for adolescents, access to HIV care and treatment for women infected with HIV, and improved access to and uptake of long-acting reversible contraception are important ingredients for reducing maternal mortality among adolescents.S Afr Med J 2105;105(11):948-952.

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Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis

Abstract: In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.

Cited by 179 publications

References 72 publications

Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

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

Improving adolescent maternal health

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