Peer-Reviewed Articles
This page includes peer-reviewed articles related to the topic of hormonal contraception and the potential acquisition of HIV. Articles are organized chronologically by year and then sorted alphabetically by the last name of the primary author. Please click on the article title to view the abstract and link to the full-text.
Changes to the World Health Organization guideline on hormonal contraceptive eligibility for women at high risk of HIV: South African perspective and response - Nene Z, Hofmeyr GJ, Patel M, Panday M, Rees H, Makua M, Pillay Y
The World Health Organization (WHO) published guidelines for hormonal contraceptive eligibility for women at high risk of HIV in March 2017. This guidance followed from a technical consultative meeting convened by the WHO in December 2016, where all the available evidence on hormonal contraceptives and risk of HIV acquisition was reviewed. This was an expert meeting with representation from global experts in family planning and HIV management, including clinicians, epidemiologists, researchers and civil society. The guideline development group, through a consensus, made recommendations to change the medical eligibility criteria for contraceptive use from category 1 to category 2 for progestogen-only injectable contraceptives among women at high risk of HIV. There was no change in the recommendation for all other methods of hormonal contraception. The data that informed this decision are from observational studies, which have limitations; therefore, causality or association of hormonal contraception and risk of HIV acquisition have not been proven. This guidance will have an impact on countries that have a high HIV disease burden and where progestogen-only injectable contraceptives are the highest used, as in South Africa (SA). The information has to be communicated in line with the WHO's sexual and reproductive health rights principles of ensuring that all women should receive evidence-based recommendations. This will empower them to make informed choices about their reproductive needs. This article seeks to clarify the decision-making process of the WHO and how the new recommendations were formulated. It also gives SA's response to the guidance and a perspective of what informed the National Department of Health's position, taking into account the effect this will have on SA's contraceptive guidelines.
Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV? - Polis CB, Achilles SL, Hel Z, Hapgood JP
Injectable contraceptives are the most widely used method of contraception in sub-Saharan Africa among married or in-union women aged 15–44. Injectable contraceptive use grew more quickly than use of any other contraceptive method between 1994 and 2015: from 2% to 7% of the share of all contraceptive use (among married or in-union women) worldwide, and from 17% to 38% of the share of all contraceptive use in sub-Saharan Africa [1]. Injectables are quick to administer, highly effective, do not require daily user action, and can be used clandestinely. Like all contraceptive methods, injectables can empower women and couples to achieve their reproductive goals, reduce unintended pregnancy, and prevent maternal morbidity and mortality.
From Research to Policy: The WHO Experience With Developing Guidelines on the Potential Risk of HIV Acquisition and Progestogen-Only Contraception Use - Han, L., Patil, E., Kidula, N., Gaffield, M. L., & Steyn, P. S.
To develop guidance for women at high risk of HIV, WHO carefully considered the risks of maternal morbidity and mortality from unintended pregnancy against possible increased risk of HIV acquisition with injectable use. Among the many challenges: (1) balancing timeliness of changing the guidance against the potential impact of it; (2) engaging a range of stakeholders; (3) translating complex research and policy messages to clients; (4) needing additional research; and (5) monitoring and evaluating successes and challenges with implementing new guidelines.
Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study) - G. Justus Hofmeyr, Charles S. Morrison, Jared M. Baeten, Tsungai Chipato, Deborah Donnell, Peter Gichangi, Nelly Mugo, Kavita Nanda, Helen Rees, Petrus Steyn, Douglas Taylor, ECHO Trial Team
Background
In vitro, animal, biological and observational clinical studies suggest that some hormonal methods, particularly depot medroxyprogesterone acetate – DMPA, may increase women’s risk of HIV acquisition. DMPA is the most common contraceptive used in many countries worst affected by the HIV epidemic. To provide robust evidence for contraceptive decision-making among women, clinicians and planners, we are conducting the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study in four countries with high HIV incidence and DMPA use: Kenya, South Africa, Swaziland, and Zambia (Clinical Trials.gov identifier NCT02550067).
Study design
We randomized HIV negative, sexually active women 16-35 years old requesting effective contraception and agreeing to participate to either DMPA, the copper T 380A intrauterine device or levonorgestrel implant. Participants attend a contraception support visit after 1 month and quarterly visits thereafter for 12 to 18 months. Participants receive a standard HIV prevention package and contraceptive side-effect management at each visit. The primary outcome is HIV seroconversion. Secondary outcomes include pregnancy, serious adverse events and method discontinuation. The sample size of 7800 women provides 80% power to detect a 50% difference in HIV risk between any of the three method pairs, assuming 250 incident infections per comparison.
Ethical considerations
Several WHO consultations have concluded that current evidence on HIV risk associated with DMPA is inconclusive and that a randomized trial is needed to guide policy, counselling and choice. Previous studies suggest that women without a specific contraceptive preference are willing to accept randomization to different contraceptive methods. Stringent performance standards are monitored by an independent data and safety monitoring board approximately every 6 months. The study has been conducted with extensive stakeholder engagement.
Conclusions
The ECHO study is designed to provide robust evidence on the relative risks (HIV acquisition) and benefits (pregnancy prevention) between three effective contraceptive methods.
Hofmeyr, G. J., Morrison, C. S., Baeten, J. M., Chipato, T., Donnell, D., Gichangi, P., ... & Taylor, D. (2017). Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study). Gates open research, 1.Re-Evaluating the Possible Increased Risk of HIV Acquisition With Progestin-Only Injectables Versus Maternal Mortality and Life Expectancy in Africa: A Decision Analysis - Rodriguez, M. I., Gaffield, M. E., Han, L., & Caughey, A. B
Objective
The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries.
Methods
We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15–49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results.
Results
In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years.
Conclusion
Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios.
Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial - Balkus, J. E., Brown, E. R., Hillier, S. L., Coletti, A., Ramjee, G., Mgodi, N., … Soto-Torres, L.
OBJECTIVE:
To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial.
STUDY DESIGN:
This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition.
RESULTS:
The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55).
CONCLUSION:
In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures.
IMPLICATIONS:
Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.
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 - Byrne, E. H., Anahtar, M. N., Cohen, K. E., Moodley, A., Padavattan, N., Ismail, N., … Leslie, A.
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.
The safety of hormonal contraceptives for women living with HIV and their sexual partners - Phillips, S. J., Polis, C. B., & Curtis, K. M.
BACKGROUND:
Hormonal contraceptives are important for the health and well-being of some women living with HIV, so evaluation of evidence regarding their safety vis-à-vis HIV-related risks is important.
METHODS:
We updated two prior systematic reviews on the impact of hormonal contraception (HC) on HIV disease progression and female-to-male HIV transmission.
RESULTS:
One new study finds no increased risk for HIV disease progression or death associated with oral contraceptive use [adjusted (adj) hazard ratio (HR) 0.83, confidence interval [CI] 0.48-1.44] or injectables (adj HR 0.72, CI 0.53-0.98). Three new studies did not find significantly increased risks for measures of female-to-male HIV transmission with HC use.
CONCLUSIONS:
Hormonal contraceptive methods do not appear to accelerate HIV disease progression. More research is needed to clarify whether HC impacts HIV transmissibility.
An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women - Polis CB, Curtis KM, Hannaford PC, et al.
OBJECTIVE AND DESIGN:
Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.
METHODS:
We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception.
RESULTS:
We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4.
CONCLUSION:
Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.
Broadening the debate over HIV and hormonal contraception - Colvin, C. J., & Harrison, A.
The question of whether hormonal contraception, particularly depot medroxyprogesterone acetate, increases a woman's risk of acquiring HIV has been debated since an association was first noted in 1991. Subsequent data from observational studies, secondary analyses of trials, and systematic reviews largely support the view that depot medroxyprogesterone acetate makes a moderate contribution to HIV risk. Efforts to synthesise existing evidence, however, have shown significant heterogeneity and serious, uncontrolled risk of confounding.
Interpretation, Communication, and Mechanisms of Associations between Injectable Contraception and HIV Risk - GJ Hofmeyr, M Singata, TA Lawrie, M Temmerman
Data from the VOICE study showing greater HIV-1 acquisition among women who use depot medroxyprogersterone acetate (DMPA) than injectable norethisterone (NET-EN) contraception elicited comment suggesting that use of DMPA be limited. The fundamental uncertainty, which has not been addressed by the VOICE data or recent meta-analyses of other observational data cited in the commentary, is whether DMPA increases susceptibility to HIV, or whether women at increased risk of HIV are more likely to use DMPA.
Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis - Morrison CS, Chen PL, Kwok C, et al.
BACKGROUND:
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
METHODS AND FINDINGS:
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship.
CONCLUSIONS:
This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study - Noguchi LM, Richardson BA, Baeten JM, et al.
BACKGROUND:
Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition.
METHODS
We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679.
FINDINGS
3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%) solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7·57 per 100 person-years, 95% CI 6·61–8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35–10·11) than among NET-EN users (5·67 per 100 person-years, 4·35–7·38; hazard ratio 1·53, 95% CI 1·12–2·08; p=0·007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06–1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26–3·24) compared with 1·09 (0·78–1·52) for HSV-2-seronegative women (pinteraction=0·07).
INTERPRETATION
Although moderate associations in observational analyses should be interpreted with caution, these findings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available.
Hormonal contraceptive use and women’s risk of HIV acquisition: a meta-analysis of observational studies - Ralph, L. J., McCoy, S. I., Shiu, K., & Padian, N. S
Background
Methods
Findings
Interpretation
Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions - Sharma, M, & Walmsley, SL
OBJECTIVES:
Women of reproductive age represent a large proportion of the global population living with HIV/AIDS. With improvements in morbidity and mortality since the advent of combination antiretroviral therapy, contraception and pregnancy planning are an increasingly important issue for women living with HIV. This review aims to outline the key considerations when choosing contraceptive methods in HIV-positive women and provides a review of the literature to inform decision-making.
METHODS:
Pubmed was searched using the terms 'HIV', 'contraception', 'HIV progression', 'HIV acquisition', 'HIV transmission' and the combination of 'antiretroviral' and 'contraception'. Abstracts were reviewed and relevant articles were retrieved. Reference lists were also reviewed for pertinent citations.
RESULTS:
HIV and contraceptive methods can interact in several clinically meaningful ways. Concomitant use may result in altered contraceptive efficacy, drug-drug interactions, or increased toxicity. Hormonal contraceptives have not been shown to affect HIV progression. Notably, the impact of hormonal contraceptives on HIV transmission and acquisition remains unclear, particularly for injectable forms. Data are lacking on several newer methods of contraception including contraceptive rings, patches and intrauterine systems.
CONCLUSIONS:
Effective, reliable contraception is important for HIV-positive women. Efficacy, toxicity, drug interactions, and potential impacts on HIV disease progression, transmission, and acquisition must be assessed when making clinical decisions.
Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994-2012 - Wall KM, Kilembe W, Vwalika B, et al.
OBJECTIVE:
To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners.
STUDY DESIGN:
From 1994-2012, HIV discordant couples recruited from a couples' voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation.
RESULTS:
Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8-10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8-1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9-1.8), or implant (aHR=1.1; 95% CI, 0.5-2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (p<.001), and OCP users were more likely to have sperm on vaginal swab (p=.1) than nonhormonal method users.
CONCLUSIONS:
We found no association between hormonal contraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately.
Contraceptive methods and risk of HIV acquisition or female-to-male transmission - Haddad, L. B., Polis, C. B., Sheth, A. N., Brown, J., Kourtis, A. P., King, C., … Ofotokun, I.
Effective family planning with modern contraception is an important intervention to prevent unintended pregnancies which also provides personal, familial, and societal benefits. Contraception is also the most cost-effective strategy to reduce the burden of mother-to-child HIV transmission for women living with HIV who wish to prevent pregnancy. There are concerns, however, that certain contraceptive methods, in particular the injectable contraceptive depot medroxyprogesterone acetate (DMPA), may increase a woman's risk of acquiring HIV or transmitting it to uninfected males. These concerns, if confirmed, could potentially have large public health implications. This paper briefly reviews the literature on use of contraception among women living with HIV or at high risk of HIV infection. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations place no restrictions on the use of hormonal contraceptive methods by women with or at high risk of HIV infection, although a clarification recommends that, given uncertainty in the current literature, women at high risk of HIV who choose progestogen-only injectable contraceptives should be informed that it may or may not increase their risk of HIV acquisition and should also be informed about and have access to HIV preventive measures, including male or female condoms.
Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs - Huijbregts, R. P., Michel, K. G., & Hel, Z.
OBJECTIVE:
Systematically assess from the literature whether women living with HIV who use hormonal contraception are at increased risk of HIV-disease progression compared with those who do not use hormonal contraception.
METHODS:
We searched PUBMED and EMBASE for articles published in peer-reviewed journals through December 15, 2011 for evidence relevant to all hormonal contraceptive methods and HIV-disease progression.
RESULTS:
Twelve reports of 11 studies met inclusion criteria. One randomized controlled trial (RCT) found increased risk for the composite outcome of a reduced CD4 cell count or death among hormonal contraceptive users when compared with copper intrauterine device (IUD) users. Ten cohort studies reported no increased risk for HIV disease progression (as measured by mortality, time to a CD4 cell count below 200, time to initiation of antiretroviral therapy, an increase in HIV-RNA viral load, or a decrease in CD4 count) among women who used hormonal contraception compared with those who did not.
CONCLUSION:
The preponderance of evidence indicates that HIV-positive women can use hormonal contraceptive methods without concerns related to HIV-disease progression. Cohort studies consistently found no association between hormonal contraceptive use and HIV-disease progression compared with nonuse of hormonal contraceptives. One RCT found that hormonal contraceptive use was associated with increased risk of HIV-disease progression when compared with IUD use, but this study had important methodological shortcomings. Prevention of unintended pregnancy among women living with HIV remains a public health priority to safeguard women's and infants' health and to prevent vertical transmission of HIV.
Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion - Morrison, C., Fichorova, R. N., Mauck, C., Chen, P.-L., Kwok, C., Chipato, T., … Doncel, G. F.
OBJECTIVE:
Hormonal contraception (HC), younger age, and pregnancy have been associated with increased HIV risk in some studies. We sought to elucidate the biological mechanisms for these associations.
DESIGN:
Case-control selection of specimens from a large, prospective, clinical study.
METHODS:
We enrolled and followed 4531 HIV-negative women from Uganda and Zimbabwe using either the injectable depo-medroxyprogesterone acetate (DMPA), combined oral contraception, or no HC (NH). Innate immunity mediators were measured in cervical samples collected from women at their visit before HIV seroconversion (n = 199) and matched visits from women remaining HIV uninfected (n = 633). Generalized linear models were applied after Box-Cox power transformation.
RESULTS:
Higher RANTES and lower secretory leukocyte protease inhibitor (SLPI) levels were associated with HIV seroconversion. DMPA users had higher RANTES and lower BD-2 levels. Most inflammation-promoting and/or inflammation-inducible mediators were higher [interleukin (IL)-1β, IL-6, IL-8, MIP-3α, vascular endothelial growth factor, and SLPI], and the protective BD-2 and IL-1RA:IL-1β ratio were lower among combined oral contraception users. Pregnant women showed a similar cervical immunity status (higher IL-1β, IL-6, IL-8, vascular endothelial growth factor, SLPI, and IL-1RA; lower IL-1RA:IL-1β). Age <25 years was associated with lower SLPI, IL-8, MIP-3α but higher IL-1RA:IL-1β. Zimbabwean women (with higher HIV seroconversion rates) had overall higher pro-inflammatory and lower anti-inflammatory protein levels than Ugandan women.
CONCLUSIONS:
HC use, pregnancy, and young age alter cervical immunity in different ways known to increase risk of HIV, for example, through increased levels of pro-inflammatory cytokines or decreased levels of SLPI. Higher levels of RANTES may be one factor underlying a possible association between DMPA use and risk of HIV acquisition.
Preference for Sayana® Press versus intramuscular Depo-Provera among HIV-positive women in Rakai, Uganda: a randomized crossover trial - Polis, C. B., Nakigozi, G. F., Nakawooya, H., Mondo, G., Makumbi, F., Gray, R. H., & team, R. H. S. P. S. P. study.
INTRODUCTION:
Sayana Press (SP), a subcutaneous formulation of depot medroxyprogesterone acetate (DMPA) prefilled in a Uniject injection system, could potentially improve and expand contraceptive injection services, but acceptability of SP is unknown. HIV-positivewomen need contraception to avoid unintended pregnancy and risk of vertical HIV transmission. We assessed acceptability of SP versusintramuscular DMPA (DMPA-IM) among HIV-positive women and their care providers in Rakai, Uganda.
METHODS:
Women were randomized to DMPA-IM or SP at baseline, received the alternate product at 3 months, and chose their preferred method at 6 months. We determined preferences among new and experienced contraceptive injectable users who had tried both types of injection during the trial, and from providers before and after providing both types of injectables to clients.
RESULTS:
Among 357 women randomized, 314 were followed up at 6 months (88%). Although SP caused more skin irritation than DMPA-IM (3.8% vs. 0% at 6 months, p=.03), it was associated with marginally fewer side effects (30.4% vs. 40.4% at 6 months, p=.06). Participants reported high levels of willingness to recommend the DMPA contraception to a friend and satisfaction with the injection received, and these did not differ by injection type. Sixty-four percent of women and 73% of providers preferred SP to DMPA-IM at 6 months; women's preferences did not differ by previous experience with injectable contraception.
CONCLUSIONS:
SP is acceptable to HIV-positive women and health care providers in this rural Ugandan population.
IMPLICATIONS:
SP appears to be acceptable to HIV-positive women and their care providers in Rakai, Uganda, and strategies for appropriate rollout of this innovative technology should be explored.
Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence - Polis, C. B., Phillips, S. J., Curtis, K. M., Westreich, D. J., Steyn, P. S., Raymond, E., … Turner, A. N.
Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we identified 22 studies published by January 15, 2014 which met inclusion criteria; we classified thirteen studies as having severe methodological limitations, and nine studies as "informative but with important limitations". Overall, data do not support an association between use of oral contraceptives and increased risk of HIV acquisition. Uncertainty persists regarding whether an association exists between depot-medroxyprogesterone acetate (DMPA) use and risk of HIV acquisition. Most studies suggested no significantly increased HIV risk with norethisterone enanthate (NET-EN) use, but when assessed in the same study, point estimates for NET-EN tended to be larger than for DMPA, though 95% confidence intervals overlapped substantially. No data have suggested significantly increased risk of HIV acquisition with use of implants, though data were limited. No data are available on the relationship between use of contraceptive patches, rings, or hormonal intrauterine devices and risk of HIV acquisition. Women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition, and like all women at risk of HIV, should be empowered to access and use condoms and other HIV preventative measures. Programs, practitioners, and women urgently need guidance on how to maximize health with respect to avoiding both unintended pregnancy and HIV given inconclusive or limited data for certain HC methods.
The Contraceptive MPA, Unlike NET, Modulates Expression of Immune Function Genes and Increases HIV-1 Infection in Cervical Tissue Explants and PBMCs - Ray, RM, Avenant, C, Moliki, JM, & Hapgood, JP
BACKGROUND:
The synthetic progestins, medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN), are widely used in developing countries as injectable contraceptives, where disease burden is high. Some studies suggest that MPA, unlike NET, increases HIV-1 acquisition in women. Whether MPA and NET differentially affect HIV-1 infection and the expression of key genes relevant to HIV-1 acquisition via differential molecular mechanisms, is key to understanding choice of progestin contraceptive for HIV-1 prevention.
METHODS:
Regulation of selected genes was investigated in cervical tissue explants and peripheral blood mononuclear cells (PBMCs) by qRT-PCR, western blotting and Luminex assays, in response to physiologically relevant doses of progestogens. Infection assays were performed in the absence and presence of HIV-1 using HIV-1BAL-RENILLA or HIVpNL4.3 IMCs. The GR specific antagonist RU486 or GR siRNA knockdown were used to determine the role of the GR in modulating ligand-specific effects.
RESULTS:
In PBMCs, MPA like dexamethasone (DEX, a GR specific agonist), showed anti-inflammatory effects, decreasing pro-inflammatory IL6, IL8 and RANTES levels and increasing anti-inflammatory GILZ gene expression levels, while NET and progesterone (P4) did not. In primary cervical tissue explants, DEX and MPA repressed IL6 and IL8 and increased GILZ gene expression levels. Differential gene expression by MPA versus NET and P4 were mediated via the GR in PBMCs. Similarly, MPA and DEX, unlike NET and P4, increased HIV-1 replication in viable PBMCs. In primary cervical explants, MPA, but not NET increased HIV-1 replication.
CONCLUSIONS:
Collectively, the data suggest that NET, unlike MPA, would be a safer choice of injectable progestin contraceptive in young women in high risk areas for HIV-1 infection. The molecular basis for this choice most likely involves differential effects of MPA as compared to NET and P4, on transcription of immunomodulatory genes, due to their differential actions via the ubiquitous GR.
A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy - Summer, D. A. Y., Graham, S. M., Masese, L. N., Richardson, B. A., Kiarie, J. N., Jaoko, W., … McClelland, R. S.
Depot medroxyprogesterone acetate (DMPA) use among HIV-1-infected women may increase transmission by increasing plasma and genital HIV-1 RNA shedding. We investigated associations between DMPA use and HIV-1 RNA in plasma and cervical secretions. One hundred two women initiated antiretroviral therapy, contributing 925 follow-up visits over a median of 34 months. Compared with visits with no hormonal contraception exposure, DMPA exposure did not increase detection of plasma (adjusted odds ratio: 0.81, 95% confidence interval: 0.47 to 1.39) or cervical HIV-1 RNA (adjusted odds ratio: 1.41, 95% confidence interval: 0.54 to 3.67). Our results suggest that DMPA is unlikely to increase infectivity in HIV-positive women who are adherent to effective antiretroviral therapy.
Modelling the global competing risks of a potential interaction between injectable hormonal contraception and HIV risk - Butler, A. R., Smith, J. A., Polis, C. B., Gregson, S., Stanton, D., & Hallett, T. B.
BACKGROUND:
Some, but not all, observational studies have suggested an increase in the risk of HIV acquisition for women using injectable hormonal contraception (IHC).
METHODS:
We used country-level data to explore the effects of reducing IHC use on the number of HIV infections, the number of live births and the resulting net consequences on AIDS deaths and maternal mortality for each country.
RESULTS:
High IHC use coincides with high HIV incidence primarily in southern and eastern Africa. If IHC increases the risk of HIV acquisition, this could generate 27 000-130 000 infections per year globally, 87-88% of which occur in this region. Reducing IHC use could result in fewer HIV infections but also a substantial increase in live births and maternal mortality in countries with high IHC use, high birth rates and high maternal mortality: mainly southern and eastern Africa, South-East Asia, and Central and South America. For most countries, the net impact of reducing IHC use on maternal and AIDS-related deaths is dependent on the magnitude of the assumed IHC-HIV interaction.
CONCLUSIONS:
If IHC use increases HIV acquisition risk, reducing IHC could reduce new HIV infections; however, this must be balanced against other important consequences, including unintended pregnancy, which impacts maternal and infant mortality. Unless the true effect size approaches a relative risk of 2.19, it is unlikely that reductions in IHC could result in public health benefit, with the possible exception of those countries in southern Africa with the largest HIV epidemics.
Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues - Chandra, N., Thurman, A. R., Anderson, S., Cunningham, T. D., Yousefieh, N., Mauck, C., & Doncel, G. F.
The relationship between exogenous contraceptive hormones and permissiveness of the female genital tract to human immunodeficiency virus type 1 (HIV-1) is the subject of renewed debate. To better characterize the effect of depot medroxyprogesterone acetate (DMPA) on HIV-1 cellular targets and epithelial integrity in the vagina, we compared leukocyte populations, markers of activation and proliferation, and the density of intercellular junctional proteins in the vaginal epithelium of women during the follicular and luteal phases of the menstrual cycle and approximately 12 weeks after receiving a DMPA injection. This prospective cohort study involved 15 healthy women. Vaginal biopsies were obtained in the follicular and luteal phases of the menstrual cycle, and approximately 12 weeks following a 150-mg intramuscularinjection of DMPA. Leukocyte populations, activation phenotype, and epithelial tight junction and adherens proteins were evaluated by immunohistochemistry. After receiving DMPA, the numbers of CD45, CD3, CD8, CD68, HLA-DR, and CCR5 bearing immune cells were significantly (p<0.05) increased in vaginal tissues, compared to the follicular and/or luteal phases of untreated cycles. There were no significant differences in immune cell populations between the follicular and luteal phases of the control cycle. There were also no statistically significant differences in epithelial thickness and density of epithelial tight junction and adherens proteins among the follicular, luteal, and post-DMPA treatment sampling points. In this pilot study, vaginal immune cell populations were significantly altered by exogenous progesterone, resulting in increased numbers of T cells, macrophages, and HLA-DR- and CCR5-positive cells.
Hormonal contraceptive use and risk of HIV-1 disease progression - Heffron, R., Mugo, N., Ngure, K., Celum, C., Donnell, D., Were, E., … Team, P. in P. H. T. S.
BACKGROUND:
For HIV-1-infected women, hormonal contraception prevents unintended pregnancy, excess maternal morbidity, and vertical HIV-1 transmission. Hormonal contraceptives are widely used but their effects on HIV-1 disease progression are unclear.
METHODS:
In a prospective study among 2269 chronically HIV-1-infected women from seven countries in eastern and southern Africa and with enrollment CD4 cell counts at least 250 cells/μl, we compared rates of HIV-1 disease progression among those using and not using hormonal contraception (i.e. oral or injectable methods). The primary outcome was a composite endpoint of CD4 decline to less than 200 cells/μl, initiation of antiretroviral therapy, or death.
RESULTS:
Three hundred and seventy-two women experienced HIV-1 disease progression during 3242 years of follow-up (incidence rate = 11.5 events per 100 person-years). Rates of HIV-1 disease progression among women who were currently using and not using hormonal contraception were 8.54 and 12.31 per 100 person-years, respectively (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.98, P = 0.04). Rates were 8.58 and 8.39 per 100 person-years for the subsets using injectable and oral contraception (adjusted hazard ratio = 0.72, P = 0.04 for injectable users and adjusted hazard ratio = 0.83, P = 0.5 for oral users compared to women not using hormonal contraception). Sensitivity analyses assessing enrollment or cumulative contraceptive use during the study demonstrated risk estimates closer to 1.0 with no evidence for accelerated disease progression.
CONCLUSION:
Among African women with chronic HIV-1 infection, use of hormonal contraception was not associated with deleterious consequences for HIV-1 disease progression.
Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms - Huijbregts, R. P., Helton, E. S., Michel, K. G., Sabbaj, S., Richter, H. E., Goepfert, P. A., & Hel, Z.
Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.
Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples - Lutalo, T., Musoke, R., Kong, X., Makumbi, F., Serwadda, D., Nalugoda, F., … Wawer, M.
BACKGROUND:
The risk of HIV associated with hormonal contraceptives is controversial. We assessed hormonal contraceptive use and HIV incidence in HIV-discordant couples in Rakai, Uganda.
METHODS:
HIV-discordant couples were retrospectively identified from a cohort between 1999 and 2009. Hormonal contraception included oral contraception, depomedroxyprogesterone acetate (DMPA), and implants (Norplant). Poisson regression estimated adjusted incidence rate ratios (adjIRRs) associated with hormonal contraceptive methods. A case-control subanalysis estimated odds ratios (ORs) of HIV associated with hormonal contraceptive, adjusted for viral load and age.
RESULTS:
We identified 190 male HIV-positive/female HIV-negative (M+F-) and 159 male HIV- negative/female HIV-positive (M-F+) couples not using antiretroviral therapy or condoms. Female HIV incidence was 5.8/100 person-years (py) among nonhormonal contraceptive users, 12.0/100 py among oral contraceptive users [adjIRR 2.65, 95% confidence interval (CI) 0.82-8.60], 4.5 among Norplant users (adjIRR: 0.89, 95% CI 0.11-7.10), and 7.5/100 py among DMPA users (adjIRR 1.42, 95% CI 0.60-3.36). Male HIV incidence was 7.4/100 py during nonhormonal contraceptive use, 16.5/100 py during female oral contraceptive use (adjIRR 2.52, 95% CI 0.49-12.95), and 4.9/100 py with DMPA use (adjIRR 0.57, 95% CI 0.19-1.70). The number of female seroconverters was three among oral contraceptive users, one among Norplant users, and seven among DMPA users. Male seroconverters were two during female oral contraceptive use, none with Norplant use, and three with DMPA use. In a nested case-control analysis after adjustment for HIV viral load, the adjOR associated with oral contraceptive use was 1.59 (95% CI 0.32-97.85) for M+F- and 2.11 (95% CI 0.18-25.26) for M-F+ couples. For DMPA use, the adjOR was 1.44 (95% CI 0.46-4.51) for M+F- and 1.40 (95% CI 0.30-6.49) for M-F+ couples.
CONCLUSION:
We did not observe significant risk of HIV acquisition or transmission with oral contraceptives or DMPA use in HIV discordant couples, but several point estimates were above 1.0 and statistical power was limited.
Hormonal contraception and HIV/AIDS transmission: challenges for Zimbabwe’s reproductive health service providers in promoting informed contraception choices - Mafuva, C., & Marima-Matarira, H. T.
None-barrier methods are the most predominant contraceptive methods of choice among Zimbabwean women, with the contraceptive pill being the most popular. The spread of HIV/AIDS is most prevalent in sub-Saharan African countries, Zimbabwe included. The prevalent mode of transmission is unprotected heterosexual sex. Although Zimbabwe boasts of a high literacy rate some women may still be vulnerable like in other parts of the world, as they may not understand the role of the Zimbabwe National Family Planning Council (ZNFPC) and other reproductive health service providers. This is because some women at risk may expose themselves to unprotected sex while they are on hormonal contraceptives. This paper seeks to infer into pros and cons of hormonal contraceptive use among Zimbabwean women. There is also need to discuss the effectiveness of providers (ZNFPC clinics and the Ministry of Health) in educating women about the risk of HIV transmission, which may be associated with some non-barrier methods of contraception. An understanding of women's attitudes towards the different forms of contraception is of paramount importance as is that of the factors that could contribute to women in different social settings resorting to uninformed contraceptive choices.
Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa - McCoy, S. I., Zheng, W., Montgomery, E. T., Blanchard, K., van Der Straten, A., de Bruyn, G., & Padian, N. S.
OBJECTIVE:
To evaluate the effect of oral and injectable hormonal contraception on the risk of HIV acquisition among women in South Africa and Zimbabwe.
DESIGN:
Secondary data analysis of 4913 sexually active women aged 18-49 years followed for up to 24 months in the Methods for Improving Reproductive Health in Africa (MIRA) phase III effectiveness trial of the diaphragm and lubricant gel for HIV prevention.
METHODS:
Participants were interviewed quarterly about contraception and sexual behavior and were tested for pregnancy, HIV, and other sexually transmitted infections. We used a Cox proportional hazards marginal structural model, weighted by the inverse probability of hormonal contraception use, to compare the risk of HIV acquisition among nonpregnant women reporting use of combined oral contraceptive pills (COC), progestin-only pills (POP), and/or injectable hormonal contraception to women not using these methods.
RESULTS:
During the study, 283 participants seroconverted. Use of oral contraceptives (POP or COC) was not associated with HIV risk [adjusted hazard ratio (HRa) = 0.86, 95% confidence interval (CI) 0.32, 1.78]. Injectable hormonal contraception was associated with a small nonsignificant risk of HIV infection (HR(a) = 1.34, 95% CI 0.75, 2.37). The effect of injectable hormonal contraception was similar in the unweighted site-adjusted only (HR(a) = 1.32, 95% CI 1.00, 1.74) and baseline factor adjusted models (HR(a) = 1.27, 95% CI 0.94, 1.72).
CONCLUSIONS:
In this study, oral contraceptives were not associated with HIV acquisition. There is substantial uncertainty in the effect of injectable hormonal contraception on HIV risk. These findings underscore the importance of dual protection with condoms and the need for diverse contraceptive options for women at risk of HIV infection.
Effect of hormonal contraceptive methods on HIV disease progression: a systematic review - Phillips, S. J., Curtis, K. M., & Polis, C. B.
OBJECTIVE:
Systematically assess from the literature whether women living with HIV who use hormonal contraception are at increased risk of HIV-disease progression compared with those who do not use hormonal contraception.
METHODS:
We searched PUBMED and EMBASE for articles published in peer-reviewed journals through December 15, 2011 for evidence relevant to all hormonal contraceptive methods and HIV-disease progression.
RESULTS:
Twelve reports of 11 studies met inclusion criteria. One randomized controlled trial (RCT) found increased risk for the composite outcome of a reduced CD4 cell count or death among hormonal contraceptive users when compared with copper intrauterine device (IUD) users. Ten cohort studies reported no increased risk for HIV disease progression (as measured by mortality, time to a CD4 cell count below 200, time to initiation of antiretroviral therapy, an increase in HIV-RNA viral load, or a decrease in CD4 count) among women who used hormonal contraception compared with those who did not.
CONCLUSION:
The preponderance of evidence indicates that HIV-positive women can use hormonal contraceptive methods without concerns related to HIV-disease progression. Cohort studies consistently found no association between hormonal contraceptive use and HIV-disease progression compared with nonuse of hormonal contraceptives. One RCT found that hormonal contraceptive use was associated with increased risk of HIV-disease progression when compared with IUD use, but this study had important methodological shortcomings. Prevention of unintended pregnancy among women living with HIV remains a public health priority to safeguard women's and infants' health and to prevent vertical transmission of HIV.
Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence - Polis, C. B., & Curtis, K. M.
OBJECTIVE AND DESIGN:
Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.
METHODS:
We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception.
RESULTS:
We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4.
CONCLUSION:
Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.
Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence - Polis, C. B., Phillips, S. J., & Curtis, K. M.
OBJECTIVE:
To systematically review epidemiologic evidence assessing whether hormonal contraception alters the risk of HIV transmission from an HIV-positive woman to an HIV-negative male partner.
DESIGN:
Systematic review.
METHODS:
We included articles published or in press through December 15, 2011. We assessed studies with direct evidence on hormonal contraception use and HIV transmission, and summarized studies with indirect evidence related to genital or plasma viral load.
RESULTS:
: One study provided direct evidence on oral contraceptive pills (OCPs) or injectable contraception and female-to-male HIV transmission; both injectables [Cox-adjusted hazard ratio (adjHR) 1.95, 95% confidence interval (CI) 1.06-3.58; marginal structural model (MSM) adjusted odds ratio (adjOR) 3.01, 95% CI 1.47-6.16] and OCPs (Cox adjHR 2.09, 95% CI 0.75-5.84; MSM adjOR 2.35, 95% CI 0.79-6.95) generated elevated point estimates, but only estimates for injectables were significant. Findings from 11 indirect studies assessing various hormonal contraception methods and viral genital shedding or setpoint were mixed, and seven of eight studies indicated no adverse effect of various hormonal contraception methods on plasma viral load.
CONCLUSION:
The only direct study on OCPs or injectable contraception and female-to-male HIV transmission suggests increased risk with the use of injectables. Given the potential for confounding in observational data, the paucity of direct evidence on this subject, and mixed indirect evidence, additional evidence is needed.
Hormonal contraception and HIV: the methods have confused the message - Schwartz, S. R., Pettifor, A., Stuart, G. S., & Cohen, M. S.
OBJECTIVE:
To examine different scenarios through which confounding by condom use may lead to inaccurate conclusions about the effect of hormonal contraception on HIV acquisition in women.
DESIGN AND METHODS:
Scenario analyses were conducted to evaluate the impact of coarse adjustment for condom use and condom misreporting on adjusted relative risk estimates for HIV acquisition in injectable hormonal contraception (IHC) users vs. nonusers.
RESULTS:
Analyses crudely accounting for condom use through a binary variable result in biased hormonal contraception-related risk estimates if condoms are used during follow-up periods in which any unprotected sex is reported and condom use differs by hormonal contraception use. We found that over-reporting of condom use is plausible in at least one recent study, as demonstrated by high pregnancy rates given, reported IHC and condom use. Over-reporting of condom use also biases estimates, typically leading to underestimation of IHC-related risk if over-reporting is the same among IHC and non-hormonal contraception users, and overestimation of IHC-related risk if condom misreporting is differential by IHC use. The impact of misreported condom use is most pronounced in study populations with high condom uptake.
CONCLUSIONS:
Discrepant findings in hormonal contraception-HIV-related research may result from inadequate measurement or adjustment for confounding by condom use. Future studies should precisely account for condom use in statistical analyses. Studies should aim to quantify the degree of condom use misreporting, by comparing reported condom use to pregnancy, HIV or other sexually transmitted infection rates, and if possible, testing stored genital swabs for prostate-specific antigen or Y chromosome.
Hormonal contraceptive continuation and switching in South Africa: Implications for evaluating the association of injectable hormonal contraceptive use and HIV - Smit, J. A., & Beksinska, M. E.
Investigating the association between hormonal contraception and HIV is challenging due to high discontinuation rates among users. This secondary analysis of 262 South African adolescent new users of hormonal contraception found continuation rates after 1 year for depot medroxyprogesterone acetate, norethisterone enanthate, or combined oral contraceptives of 40.4%, 64.4%, and 64.6%, respectively. Implications for studies evaluating the association between injectable hormonal contraceptive use and HIV are discussed.
Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study - Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al.
BACKGROUND:
Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners.
METHODS:
In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk.
FINDINGS:
Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6-24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06-3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8-24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12-3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression.
INTERPRETATION:
Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1.
Hormonal contraception and the risk of HIV acquisition among women in South Africa - Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M, et al.
OBJECTIVES:
To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa.
DESIGN/METHODS:
We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular.
RESULTS:
Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users.
CONCLUSIONS:
In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.
Living with uncertainty: acting in the best interests of women - Gollub, Erica and Stein, Zena
A recent multi-country study on hormonal contraceptives (HC) and HIV acquisition and transmission among African HIV-serodiscordant couples reported a statistically significant doubling of risk for HIV acquisition among women as well as transmission from women to men for injectable contraceptives. Together with a prior cohort study on African women seeking health services, these data are the strongest yet to appear on the HC-HIV risk. This paper will briefly review the Heffron study strengths and relevant biological and epidemiologic evidence; address the futility of further trials; and propose instead an alternative framework for next steps. The weight of the evidence calls for a discontinuation of progestin-dominant methods. We propose here five types of productive activities: (1) scaling injectable hormones down and out of the contraceptive mix; (2) strengthening and introducing public health strategies with proven potential to reduce HIV spread; (3) providing maximal choice to reduce unplanned pregnancy, starting with quality sexuality education through to safe abortion access; (4) expanding provider training, end-user counseling and access to male and female barriers, with a special renewed focus on female condom; (5) initiating a serious research agenda to determine anti-STI/HIV potential of the contraceptive cervical cap. Trusting women to make informed choices is critical to achieve real progress in dual protection.
Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy - Robinson, J. A., Jamshidi, R., & Burke, A. E.
BACKGROUND:
Preventing unintended pregnancy in HIV-positive women can significantly reduce maternal-to-child HIV transmission as well as improve the woman's overall health. Hormonal contraceptives are safe and effective means to avoid unintended pregnancy, but there is concern that coadministration of antiretroviral drugs may alter contraceptive efficacy.
MATERIALS AND METHODS:
We performed a literature search of PubMed and Ovid databases of articles published between January 1980 and February 2012 to identify English-language reports of drug-drug interactions between hormonal contraceptives (HCs) and antiretroviral drugs (ARVs). We also reviewed the FDA prescribing information of contraceptive hormone preparations and antiretrovirals for additional data and recommendations.
RESULTS:
Twenty peer-reviewed publications and 42 pharmaceutical package labels were reviewed. Several studies of combined oral contraceptive pills (COCs) identified decreased serum estrogen and progestin levels when coadministered with certain ARVs. The contraceptive efficacy of injectable depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) were largely unaffected by ARVs, while data on the contraceptive patch, ring, and implant were lacking.
CONCLUSIONS:
HIV-positive women should be offered a full range of hormonal contraceptive options, with conscientious counseling about possible reduced efficacy of COCs and the contraceptive implant when taken with ARVs. DMPA and the LNG-IUS maintain their contraceptive efficacy when taken with ARVs.
Evaluating the competing risks of HIV acquisition and maternal mortality in Africa: a decision analysis - Rodriguez, M. I., Reeves, M. F., & Caughey, A. B.
OBJECTIVE:
To model the risk of HIV acquisition and maternal mortality for women in four African countries in the light of previous data on risk of HIV acquisition and hormonal contraceptive use.
DESIGN:
Decision analysis.
SETTING:
Chad, Kenya, South Africa and Uganda.
POPULATION:
Women of reproductive age, at risk of HIV, who do not desire pregnancy.
METHODS:
A decision analysis model was built to compare the consequences of removing progestin injectables from use, assuming an increased risk of HIV acquisition. Three scenarios were considered in four African countries: replacement of progestin injectables with no method, with combined oral contraceptives (COC) or with an intrauterine device (IUD). Health outcomes measured include: life-years, maternal mortality, HIV acquisition and unsafe abortion. Sensitivity analysis, including Monte Carlo simulation, was performed around all variables.
MAIN OUTCOME MEASURES:
HIV acquisition, maternal mortality and life-years.
RESULTS:
If progestin injectables are removed from use, without a minimum of 70-100% of women switching to an IUD or COCs, up to nine additional maternal deaths will occur for every case of HIV averted. Sensitivity analysis demonstrated that this finding persisted across a broad range of variables.
CONCLUSIONS:
Contraception is critical to preserving life for women in Africa. In the absence of clear evidence regarding hormonal contraception and HIV acquisition, policy decisions must not overlook the very real risk of maternal mortality.
The effects of injectable hormonal contraceptives on HIV seroconversion and on sexually transmitted infections - Wand H, Ramjee G.
OBJECTIVES:
To investigate the association between hormonal contraceptives and risk of HIV-1 seroconversion and prevalence of other sexually transmitted infections.
DESIGN:
Prospective cohort.
METHODS:
The study population was 2,236 HIV-negative women who were screened in a biomedical intervention trial in Durban, South Africa. The association between the use of hormonal contraceptives and risk of HIV-1 seroconversion was modeled using Cox proportional hazards regression analysis. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections were assessed using logistic regression models.
RESULTS:
Hormonal injectables were the most common method of contraceptives (46.47%) followed by condom use (28.04%). Overall, compared with women who reported using condoms or other methods as their preferred form of contraceptive, those who reported using hormonal contraceptives (injectables and oral pills) were less likely to use condoms in their last sexual act. Using hormonal injectables during the study was significantly associated with increased risk for HIV-1 infection [adjusted hazard ratio 1.72, 95% confidence interval (CI) 1.19-2.49, P = 0.005]; hormonal injectables were also significantly associated with higher prevalent of C. trachomatis infections (adjusted odds ratio 2.46, 95% CI 1.52-3.97, P < 0.001).
CONCLUSION:
Hormonal injectables are highly effective and well tolerated family planning methods and have played an important role in reducing unplanned pregnancies and maternal and infant mortality. However, they do not protect against HIV-1 and other sexually transmitted infections. This study reinforces the importance of comprehensive contraceptive counseling to women about the importance of dual protection, such as male condoms and hormonal contraceptives use.
Hormonal contraception and HIV: an unanswered question - Morrison, C. S., & Nanda, K.
Most of the 16 million women currently living with HIV are in sub-Saharan Africa, where 60% of HIV infections occur in women. A high proportion of women in this region also use hormonal contraception, especially injectable depot-medroxyprogesterone acetate (DMPA). Since the first report of increased HIV acquisition in women taking oral contraceptives, whether hormonal contraception increases the risk of HIV acquisition remains a crucial unanswered question.
Hormonal Contraception and HIV‐1 Transmission - Blish, CA, & Baeten, JM
Safe and effective contraceptive choices are essential for women with HIV-1 infection and at risk for HIV-1 infection. Epidemiological and laboratory-based studies suggest that hormonal contraception may influence HIV-1 transmission. Several large studies in high-risk populations indicate that hormonal contraceptive use may modestly increase the risk of HIV-1 acquisition. In addition, HIV-1-infected users of hormonal contraceptives may be more infectious to their uninfected partners, although no studies have directly measured HIV-1 transmission risk from women to men. However, several studies failed to demonstrate a link between contraceptive use and HIV-1 acquisition or transmission, and interpretation of many studies limited by methodological considerations, such as infrequent measurements of contraceptive exposure and HIV-1 status. As a result, many questions remain, and high-quality studies remain needed. It is clear that hormonal contraceptives are not protective against HIV-1 infection, and that dual protection with condoms should be the goal for women using hormonal contraception.
Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling - Morrison CS, Chen PL, Kwok C, Richardson BA, Chipato T, Mugerwa R, et al.
Hormonal contraceptives are used widely worldwide; their effect on HIV acquisition remains unresolved. We reanalyzed data from the Hormonal Contraception and HIV Study using marginal structural modeling to reduce selection bias due to time-dependent confounding. Replicating our original analysis closely, we found that depo-medroxyprogesterone acetate (DMPA) but not combined oral contraceptive (COC) was associated with increased HIV acquisition. Also, young (18-24 years) but not older women who used DMPA and COCs were at increased HIV risk.
Risk factors for HIV incidence in women participating in an HSV suppressive treatment trial in Tanzania - Watson-Jones D, Baisley K, Weiss HA, Tanton C, Changalucha J, Everett D, et al.
OBJECTIVES:
A randomized, double-blind, placebo-controlled trial (RCT) of herpes simplex virus type 2 suppressive therapy with acyclovir 400 mg twice daily conducted among women in northwestern Tanzania reported a similar rate of HIV acquisition in both trial arms (Current Controlled Trials number ISRCTN35385041). Risk factors for HIV incidence were examined in the context of 3-monthly follow-up visits offering both voluntary counselling and testing and care for sexually transmitted infections.
DESIGN:
Prospective cohort analysis of trial participants enrolled and followed for up to 30 months.
METHODS:
Risk factors for HIV acquisition were analysed using Cox regression.
RESULTS:
Overall, 821 herpes simplex virus type 2 seropositive, HIV seronegative women were randomized; 400 randomized to acyclovir and 421 to placebo; 659 (80.3%) completed follow-up. HIV incidence was 4.27 per 100 person-years. There was no overall impact of acyclovir on HIV incidence [hazard ratio = 1.01; 95% confidence interval (CI) 0.61-1.66]. HIV acquisition was independently associated with younger age at enrolment (age 16-19 vs. 30-35: hazard ratio = 4.02; 95% CI 1.67-9.68), alcohol consumption at enrolment (> or =30 drinks/week vs. none: hazard ratio = 4.39, 95% CI 1.70-11.33), having paid sex within the previous 3 months (hazard ratio = 1.82, 95% CI 1.09-3.05), recent infection with gonorrhoea (hazard ratio = 3.62, 95% CI 1.62-8.08) and injections in the previous 3 months (hazard ratio = 3.45, 95% CI 1.62-7.34). There was some evidence of an association between HIV incidence and living in the recruitment community for less than 2 years (hazard ratio = 1.75, 95% CI 0.98-3.10) and exposure to hormonal contraception (hazard ratio = 1.60, 95% CI 0.93-2.76).
CONCLUSION:
A high incidence of HIV was observed in this trial cohort, especially in young women. Interventions are needed to address the risk associated with alcohol use and to sustain control of other sexually transmitted infections.
Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women - Baeten JM, Benki S, Chohan V, Lavreys L, McClelland RS, Mandaliya K, et al.
BACKGROUND:
Studies of the effect of hormonal contraceptive use on the risk of HIV-1 acquisition have generated conflicting results. A recent study from Uganda and Zimbabwe found that women using hormonal contraception were at increased risk for HIV-1 if they were seronegative for herpes simplex virus type 2 (HSV-2), but not if they were HSV-2 seropositive.
OBJECTIVE:
To explore the effect of HSV-2 infection on the relationship between hormonal contraception and HIV-1 in a high-risk population. Hormonal contraception has previously been associated with increased HIV-1 risk in this population.
METHODS:
Data were from a prospective cohort study of 1206 HIV-1 seronegative sex workers from Mombasa, Kenya who were followed monthly. Multivariate Cox proportional hazards analyses were used to adjust for demographic and behavioral measures and incident sexually transmitted diseases.
RESULTS:
Two hundred and thirty-three women acquired HIV-1 (8.7/100 person-years). HSV-2 prevalence (81%) and incidence (25.4/100 person-years) were high. In multivariate analysis, including adjustment for HSV-2, HIV-1 acquisition was associated with use of oral contraceptive pills [adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 1.00-2.13] and depot medroxyprogesterone acetate (adjusted HR, 1.73; 95% CI, 1.28-2.34). The effect of contraception on HIV-1 susceptibility did not differ significantly between HSV-2 seronegative versus seropositive women. HSV-2 infection was associated with elevated HIV-1 risk (adjusted HR, 3.58; 95% CI, 1.64-7.82).
CONCLUSIONS:
In this group of high-risk African women, hormonal contraception and HSV-2 infection were both associated with increased risk for HIV-1 acquisition. HIV-1 risk associated with hormonal contraceptive use was not related to HSV-2 serostatus.
Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort - Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B, et al.
OBJECTIVE:
To investigate whether the incidence of HIV infection is higher among sexually active women using depot medroxyprogesterone acetate (DMPA) or noresthisterone enanthate (NET-EN) injections for contraception than among women using nonhormonal or no contraception.
METHODS:
Five hundred and fifty-one initially HIV-negative women were followed up for a total of 491 person-years. Participants were interviewed, counselled, examined, tested for HIV and other STIs, and treated, at three monthly intervals for 1 year.
RESULTS:
There was no significant association between progestin contraceptive use and HIV infection (rate ratio 1.1, 95% CI 0.5 to 2.8; log-rank test, p=.73). In proportional hazards regression, the only significant hazard ratios for HIV acquisition were prevalent Neisseria gonorrhoea (5.2; 95% CI 1.1 to 23.7, p=.035) and Trichomonas vaginalis (4.8; 95% CI 1.0 to 22.8, p=.049); bacterial vaginosis was marginally significant (2.8; 95% CI 1.0 to 8.3, p=.057). The adjusted hazard ratios for NET-EN and DMPA were 1.76 (95% CI 0.64 to 4.84) and 0.46 (95% CI 0.06 to 3.79), respectively, relative to nonuse. Five hundred and twelve of 551 women had one or more confirmed STIs during the study.
CONCLUSIONS:
There is no evidence of an association between HIV infection and injectable contraceptives. Due to the limited power of this study and because similar studies have not included young women using NET-EN, we recommend that further research be carried out to focus on the use of NET-EN and HIV acquisition in high risk groups.
Prospective study of hormonal contraception and women's risk of HIV infection in South Africa - Myer L, Denny L, Wright TC, Kuhn L.
BACKGROUND:
Many women using hormonal contraceptives are also at risk of sexually transmitted HIV infection, but data are mixed on whether hormonal contraception increases women’s risk of HIV. We investigated associations between HIV incidence and use of combined oral contraceptives (COC), norethindrone enanthate (NET-EN) or depot medroxyprogesterone acetate (DMPA) in a cohort of South African women.
METHODS:
Participants were 4200 HIV-negative women aged 35-49 years enrolled into a cervical cancer screening trial. At enrollment, women were tested for sexually transmitted infections and reported on their sexual behaviour and contraceptive use. During the 24 months of follow-up, women reported on their sexual behaviours and contraceptive use and underwent repeat HIV testing.
RESULTS:
During the 5010 person-years of follow-up, 111 incident HIV infections were observed (HIV incidence, 2.2 infections/100 person-years). At enrollment, 21% of women reported using hormonalcontraception, primarily DMPA (14% of all women) or NET-EN (5%). After adjusting for sexual risk behaviours and sexually transmitted infections, the incidence of HIV was similar among women using COC, NET-EN or DMPA compared with women not using any hormonal method [incidence rate ratios and 95% confidence intervals, 0.65, 0.16-2.66; 0.79, 0.31-2.02 and 0.96, 0.58-1.59, respectively]. There was also no association between increased duration of DMPA use and HIV incidence (P-value for trend, 0.51).
CONCLUSIONS:
These findings contribute to the evidence from general population cohorts of women that hormonal contraceptive use is not associated with increased risk of HIV acquisition. Nonetheless, family planning services are an important venue for HIV prevention activities.
Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda - Kiddugavu M, Makumbi F, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al.
BACKGROUND:
Hormonal contraceptives have been associated with increased risk of HIV acquisition.
METHODS:
The association between hormonal contraception use and HIV acquisition was assessed in a rural community-based cohort in Rakai District, Uganda. A group of 5117 sexually active HIV-negative women were surveyed at 10 month intervals between 1994 and 1999. Information on demographic and sociobehavioral characteristics, use of hormonal contraception (pill and injectable methods), condoms and the number of sexual partners was obtained by home-based interview. HIV incidence rate ratios (IRR) and 95% confidence intervals (CI) associated with hormonal contraception were estimated by multivariate Poisson regression after adjustment for age, condom use, number of sexual partners, marital status, education and history of genital ulcer disease.
RESULTS:
At one or more interviews, 16.6% of women reported use of hormonal contraceptives and 23.0% reported condom use. HIV incidence was 2.3/100 person-years in hormonal contraceptive users compared with 1.5/100 person-years in non-hormonal contraceptive users (unadjusted IRR, 1.56; 95% CI, 1.00-2.33). After multivariate adjustment, the IRR associated with hormonal contraceptives was reduced to 0.94 (95% CI, 0.53-1.64). The adjusted IRR was 1.12 (95% CI, 0.48-2.56) with oral contraceptive use and 0.84 (95%CI, 0.41-1.72) with injectable methods.
CONCLUSION:
Use of hormonal contraception is not associated with HIV acquisition after adjustment for behavioral confounding.
The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania - Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ.
OBJECTIVES:
To determine the risk factors for HIV seroconversion and assess the association between contraceptive use and HIV infection among women attending three large family planning clinics in Dar es Salaam, Tanzania.
DESIGN:
Prospective cohort study.
METHODS:
Between 1992 and 1995, 2471 HIV-negative women were followed prospectively. Information about sociodemographic characteristics, sexual behavior, contraceptive use and other risk factors was collected at recruitment and updated at follow-up visits. At the end of the study, specimens were collected for HIV testing and laboratory diagnosis of sexually transmitted diseases.
RESULTS:
The overall HIV incidence was 3.4 per 100 person-years [95% confidence interval (Cl), 2.6-4.1]. The risk of HIV seroconversion decreased with increasing age (P=0.04, test for trend). Women reporting three or more sex partners during the follow-up period had the highest risk of HIV [age-adjusted relative risk (RR), 4.89; 95% Cl, 2.61-9.17]. Having an uncircumcised husband was associated with a significantly increased risk of HIV (age-adjusted RR, 3.60; 95% Cl, 1.12-11.59). The risk of HIV was also significantly increased among women with gonorrhoea (age-adjusted RR, 3.51; 95% Cl, 1.60-7.71) and candidiasis at baseline (age-adjusted RR, 1.98; 95% Cl, 1.17-3.33) and among women reporting alcohol consumption during the follow-up period. After controlling for other risk factors, the risk of HIV infection amongst users of oral contraceptive, intrauterine device and injectable contraceptive was not significantly increased. Similarly, there was no significant trend associated with increasing duration of use of any of these contraceptive methods.
CONCLUSION:
These findings confirm that a large number of new HIV infections continue to occur in this population. Reassuringly, no significant association was observed between HIV and use of specific contraceptive methods. Interventions to reduce further spread of HIV are still urgently needed.
2018
Changes to the World Health Organization guideline on hormonal contraceptive eligibility for women at high risk of HIV: South African perspective and response - Nene Z, Hofmeyr GJ, Patel M, Panday M, Rees H, Makua M, Pillay Y
The World Health Organization (WHO) published guidelines for hormonal contraceptive eligibility for women at high risk of HIV in March 2017. This guidance followed from a technical consultative meeting convened by the WHO in December 2016, where all the available evidence on hormonal contraceptives and risk of HIV acquisition was reviewed. This was an expert meeting with representation from global experts in family planning and HIV management, including clinicians, epidemiologists, researchers and civil society. The guideline development group, through a consensus, made recommendations to change the medical eligibility criteria for contraceptive use from category 1 to category 2 for progestogen-only injectable contraceptives among women at high risk of HIV. There was no change in the recommendation for all other methods of hormonal contraception. The data that informed this decision are from observational studies, which have limitations; therefore, causality or association of hormonal contraception and risk of HIV acquisition have not been proven. This guidance will have an impact on countries that have a high HIV disease burden and where progestogen-only injectable contraceptives are the highest used, as in South Africa (SA). The information has to be communicated in line with the WHO's sexual and reproductive health rights principles of ensuring that all women should receive evidence-based recommendations. This will empower them to make informed choices about their reproductive needs. This article seeks to clarify the decision-making process of the WHO and how the new recommendations were formulated. It also gives SA's response to the guidance and a perspective of what informed the National Department of Health's position, taking into account the effect this will have on SA's contraceptive guidelines.
Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV? - Polis CB, Achilles SL, Hel Z, Hapgood JP
Injectable contraceptives are the most widely used method of contraception in sub-Saharan Africa among married or in-union women aged 15–44. Injectable contraceptive use grew more quickly than use of any other contraceptive method between 1994 and 2015: from 2% to 7% of the share of all contraceptive use (among married or in-union women) worldwide, and from 17% to 38% of the share of all contraceptive use in sub-Saharan Africa [1]. Injectables are quick to administer, highly effective, do not require daily user action, and can be used clandestinely. Like all contraceptive methods, injectables can empower women and couples to achieve their reproductive goals, reduce unintended pregnancy, and prevent maternal morbidity and mortality.
2017
From Research to Policy: The WHO Experience With Developing Guidelines on the Potential Risk of HIV Acquisition and Progestogen-Only Contraception Use - Han, L., Patil, E., Kidula, N., Gaffield, M. L., & Steyn, P. S.
To develop guidance for women at high risk of HIV, WHO carefully considered the risks of maternal morbidity and mortality from unintended pregnancy against possible increased risk of HIV acquisition with injectable use. Among the many challenges: (1) balancing timeliness of changing the guidance against the potential impact of it; (2) engaging a range of stakeholders; (3) translating complex research and policy messages to clients; (4) needing additional research; and (5) monitoring and evaluating successes and challenges with implementing new guidelines.
Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study) - G. Justus Hofmeyr, Charles S. Morrison, Jared M. Baeten, Tsungai Chipato, Deborah Donnell, Peter Gichangi, Nelly Mugo, Kavita Nanda, Helen Rees, Petrus Steyn, Douglas Taylor, ECHO Trial Team
Background
In vitro, animal, biological and observational clinical studies suggest that some hormonal methods, particularly depot medroxyprogesterone acetate – DMPA, may increase women’s risk of HIV acquisition. DMPA is the most common contraceptive used in many countries worst affected by the HIV epidemic. To provide robust evidence for contraceptive decision-making among women, clinicians and planners, we are conducting the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study in four countries with high HIV incidence and DMPA use: Kenya, South Africa, Swaziland, and Zambia (Clinical Trials.gov identifier NCT02550067).
Study design
We randomized HIV negative, sexually active women 16-35 years old requesting effective contraception and agreeing to participate to either DMPA, the copper T 380A intrauterine device or levonorgestrel implant. Participants attend a contraception support visit after 1 month and quarterly visits thereafter for 12 to 18 months. Participants receive a standard HIV prevention package and contraceptive side-effect management at each visit. The primary outcome is HIV seroconversion. Secondary outcomes include pregnancy, serious adverse events and method discontinuation. The sample size of 7800 women provides 80% power to detect a 50% difference in HIV risk between any of the three method pairs, assuming 250 incident infections per comparison.
Ethical considerations
Several WHO consultations have concluded that current evidence on HIV risk associated with DMPA is inconclusive and that a randomized trial is needed to guide policy, counselling and choice. Previous studies suggest that women without a specific contraceptive preference are willing to accept randomization to different contraceptive methods. Stringent performance standards are monitored by an independent data and safety monitoring board approximately every 6 months. The study has been conducted with extensive stakeholder engagement.
Conclusions
The ECHO study is designed to provide robust evidence on the relative risks (HIV acquisition) and benefits (pregnancy prevention) between three effective contraceptive methods.
Re-Evaluating the Possible Increased Risk of HIV Acquisition With Progestin-Only Injectables Versus Maternal Mortality and Life Expectancy in Africa: A Decision Analysis - Rodriguez, M. I., Gaffield, M. E., Han, L., & Caughey, A. B
Objective
The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries.
Methods
We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15–49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results.
Results
In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years.
Conclusion
Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios.
2016
Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial - Balkus, J. E., Brown, E. R., Hillier, S. L., Coletti, A., Ramjee, G., Mgodi, N., … Soto-Torres, L.
OBJECTIVE:
To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial.
STUDY DESIGN:
This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition.
RESULTS:
The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55).
CONCLUSION:
In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures.
IMPLICATIONS:
Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.
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 - Byrne, E. H., Anahtar, M. N., Cohen, K. E., Moodley, A., Padavattan, N., Ismail, N., … Leslie, A.
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.
The safety of hormonal contraceptives for women living with HIV and their sexual partners - Phillips, S. J., Polis, C. B., & Curtis, K. M.
BACKGROUND:
Hormonal contraceptives are important for the health and well-being of some women living with HIV, so evaluation of evidence regarding their safety vis-à-vis HIV-related risks is important.
METHODS:
We updated two prior systematic reviews on the impact of hormonal contraception (HC) on HIV disease progression and female-to-male HIV transmission.
RESULTS:
One new study finds no increased risk for HIV disease progression or death associated with oral contraceptive use [adjusted (adj) hazard ratio (HR) 0.83, confidence interval [CI] 0.48-1.44] or injectables (adj HR 0.72, CI 0.53-0.98). Three new studies did not find significantly increased risks for measures of female-to-male HIV transmission with HC use.
CONCLUSIONS:
Hormonal contraceptive methods do not appear to accelerate HIV disease progression. More research is needed to clarify whether HC impacts HIV transmissibility.
An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women - Polis CB, Curtis KM, Hannaford PC, et al.
OBJECTIVE AND DESIGN:
Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.
METHODS:
We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception.
RESULTS:
We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4.
CONCLUSION:
Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.
2015
Broadening the debate over HIV and hormonal contraception - Colvin, C. J., & Harrison, A.
The question of whether hormonal contraception, particularly depot medroxyprogesterone acetate, increases a woman's risk of acquiring HIV has been debated since an association was first noted in 1991. Subsequent data from observational studies, secondary analyses of trials, and systematic reviews largely support the view that depot medroxyprogesterone acetate makes a moderate contribution to HIV risk. Efforts to synthesise existing evidence, however, have shown significant heterogeneity and serious, uncontrolled risk of confounding.
Interpretation, Communication, and Mechanisms of Associations between Injectable Contraception and HIV Risk - GJ Hofmeyr, M Singata, TA Lawrie, M Temmerman
Data from the VOICE study showing greater HIV-1 acquisition among women who use depot medroxyprogersterone acetate (DMPA) than injectable norethisterone (NET-EN) contraception elicited comment suggesting that use of DMPA be limited. The fundamental uncertainty, which has not been addressed by the VOICE data or recent meta-analyses of other observational data cited in the commentary, is whether DMPA increases susceptibility to HIV, or whether women at increased risk of HIV are more likely to use DMPA.
Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis - Morrison CS, Chen PL, Kwok C, et al.
BACKGROUND:
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
METHODS AND FINDINGS:
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship.
CONCLUSIONS:
This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study - Noguchi LM, Richardson BA, Baeten JM, et al.
BACKGROUND:
Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition.
METHODS
We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679.
FINDINGS
3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%) solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7·57 per 100 person-years, 95% CI 6·61–8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35–10·11) than among NET-EN users (5·67 per 100 person-years, 4·35–7·38; hazard ratio 1·53, 95% CI 1·12–2·08; p=0·007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06–1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26–3·24) compared with 1·09 (0·78–1·52) for HSV-2-seronegative women (pinteraction=0·07).
INTERPRETATION
Although moderate associations in observational analyses should be interpreted with caution, these findings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available.
Hormonal contraceptive use and women’s risk of HIV acquisition: a meta-analysis of observational studies - Ralph, L. J., McCoy, S. I., Shiu, K., & Padian, N. S
Background
Methods
Findings
Interpretation
Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions - Sharma, M, & Walmsley, SL
OBJECTIVES:
Women of reproductive age represent a large proportion of the global population living with HIV/AIDS. With improvements in morbidity and mortality since the advent of combination antiretroviral therapy, contraception and pregnancy planning are an increasingly important issue for women living with HIV. This review aims to outline the key considerations when choosing contraceptive methods in HIV-positive women and provides a review of the literature to inform decision-making.
METHODS:
Pubmed was searched using the terms 'HIV', 'contraception', 'HIV progression', 'HIV acquisition', 'HIV transmission' and the combination of 'antiretroviral' and 'contraception'. Abstracts were reviewed and relevant articles were retrieved. Reference lists were also reviewed for pertinent citations.
RESULTS:
HIV and contraceptive methods can interact in several clinically meaningful ways. Concomitant use may result in altered contraceptive efficacy, drug-drug interactions, or increased toxicity. Hormonal contraceptives have not been shown to affect HIV progression. Notably, the impact of hormonal contraceptives on HIV transmission and acquisition remains unclear, particularly for injectable forms. Data are lacking on several newer methods of contraception including contraceptive rings, patches and intrauterine systems.
CONCLUSIONS:
Effective, reliable contraception is important for HIV-positive women. Efficacy, toxicity, drug interactions, and potential impacts on HIV disease progression, transmission, and acquisition must be assessed when making clinical decisions.
Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994-2012 - Wall KM, Kilembe W, Vwalika B, et al.
OBJECTIVE:
To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners.
STUDY DESIGN:
From 1994-2012, HIV discordant couples recruited from a couples' voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation.
RESULTS:
Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8-10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8-1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9-1.8), or implant (aHR=1.1; 95% CI, 0.5-2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (p<.001), and OCP users were more likely to have sperm on vaginal swab (p=.1) than nonhormonal method users.
CONCLUSIONS:
We found no association between hormonal contraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately.
2014
Contraceptive methods and risk of HIV acquisition or female-to-male transmission - Haddad, L. B., Polis, C. B., Sheth, A. N., Brown, J., Kourtis, A. P., King, C., … Ofotokun, I.
Effective family planning with modern contraception is an important intervention to prevent unintended pregnancies which also provides personal, familial, and societal benefits. Contraception is also the most cost-effective strategy to reduce the burden of mother-to-child HIV transmission for women living with HIV who wish to prevent pregnancy. There are concerns, however, that certain contraceptive methods, in particular the injectable contraceptive depot medroxyprogesterone acetate (DMPA), may increase a woman's risk of acquiring HIV or transmitting it to uninfected males. These concerns, if confirmed, could potentially have large public health implications. This paper briefly reviews the literature on use of contraception among women living with HIV or at high risk of HIV infection. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations place no restrictions on the use of hormonal contraceptive methods by women with or at high risk of HIV infection, although a clarification recommends that, given uncertainty in the current literature, women at high risk of HIV who choose progestogen-only injectable contraceptives should be informed that it may or may not increase their risk of HIV acquisition and should also be informed about and have access to HIV preventive measures, including male or female condoms.
Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs - Huijbregts, R. P., Michel, K. G., & Hel, Z.
OBJECTIVE:
Systematically assess from the literature whether women living with HIV who use hormonal contraception are at increased risk of HIV-disease progression compared with those who do not use hormonal contraception.
METHODS:
We searched PUBMED and EMBASE for articles published in peer-reviewed journals through December 15, 2011 for evidence relevant to all hormonal contraceptive methods and HIV-disease progression.
RESULTS:
Twelve reports of 11 studies met inclusion criteria. One randomized controlled trial (RCT) found increased risk for the composite outcome of a reduced CD4 cell count or death among hormonal contraceptive users when compared with copper intrauterine device (IUD) users. Ten cohort studies reported no increased risk for HIV disease progression (as measured by mortality, time to a CD4 cell count below 200, time to initiation of antiretroviral therapy, an increase in HIV-RNA viral load, or a decrease in CD4 count) among women who used hormonal contraception compared with those who did not.
CONCLUSION:
The preponderance of evidence indicates that HIV-positive women can use hormonal contraceptive methods without concerns related to HIV-disease progression. Cohort studies consistently found no association between hormonal contraceptive use and HIV-disease progression compared with nonuse of hormonal contraceptives. One RCT found that hormonal contraceptive use was associated with increased risk of HIV-disease progression when compared with IUD use, but this study had important methodological shortcomings. Prevention of unintended pregnancy among women living with HIV remains a public health priority to safeguard women's and infants' health and to prevent vertical transmission of HIV.
Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion - Morrison, C., Fichorova, R. N., Mauck, C., Chen, P.-L., Kwok, C., Chipato, T., … Doncel, G. F.
OBJECTIVE:
Hormonal contraception (HC), younger age, and pregnancy have been associated with increased HIV risk in some studies. We sought to elucidate the biological mechanisms for these associations.
DESIGN:
Case-control selection of specimens from a large, prospective, clinical study.
METHODS:
We enrolled and followed 4531 HIV-negative women from Uganda and Zimbabwe using either the injectable depo-medroxyprogesterone acetate (DMPA), combined oral contraception, or no HC (NH). Innate immunity mediators were measured in cervical samples collected from women at their visit before HIV seroconversion (n = 199) and matched visits from women remaining HIV uninfected (n = 633). Generalized linear models were applied after Box-Cox power transformation.
RESULTS:
Higher RANTES and lower secretory leukocyte protease inhibitor (SLPI) levels were associated with HIV seroconversion. DMPA users had higher RANTES and lower BD-2 levels. Most inflammation-promoting and/or inflammation-inducible mediators were higher [interleukin (IL)-1β, IL-6, IL-8, MIP-3α, vascular endothelial growth factor, and SLPI], and the protective BD-2 and IL-1RA:IL-1β ratio were lower among combined oral contraception users. Pregnant women showed a similar cervical immunity status (higher IL-1β, IL-6, IL-8, vascular endothelial growth factor, SLPI, and IL-1RA; lower IL-1RA:IL-1β). Age <25 years was associated with lower SLPI, IL-8, MIP-3α but higher IL-1RA:IL-1β. Zimbabwean women (with higher HIV seroconversion rates) had overall higher pro-inflammatory and lower anti-inflammatory protein levels than Ugandan women.
CONCLUSIONS:
HC use, pregnancy, and young age alter cervical immunity in different ways known to increase risk of HIV, for example, through increased levels of pro-inflammatory cytokines or decreased levels of SLPI. Higher levels of RANTES may be one factor underlying a possible association between DMPA use and risk of HIV acquisition.
Preference for Sayana® Press versus intramuscular Depo-Provera among HIV-positive women in Rakai, Uganda: a randomized crossover trial - Polis, C. B., Nakigozi, G. F., Nakawooya, H., Mondo, G., Makumbi, F., Gray, R. H., & team, R. H. S. P. S. P. study.
INTRODUCTION:
Sayana Press (SP), a subcutaneous formulation of depot medroxyprogesterone acetate (DMPA) prefilled in a Uniject injection system, could potentially improve and expand contraceptive injection services, but acceptability of SP is unknown. HIV-positivewomen need contraception to avoid unintended pregnancy and risk of vertical HIV transmission. We assessed acceptability of SP versusintramuscular DMPA (DMPA-IM) among HIV-positive women and their care providers in Rakai, Uganda.
METHODS:
Women were randomized to DMPA-IM or SP at baseline, received the alternate product at 3 months, and chose their preferred method at 6 months. We determined preferences among new and experienced contraceptive injectable users who had tried both types of injection during the trial, and from providers before and after providing both types of injectables to clients.
RESULTS:
Among 357 women randomized, 314 were followed up at 6 months (88%). Although SP caused more skin irritation than DMPA-IM (3.8% vs. 0% at 6 months, p=.03), it was associated with marginally fewer side effects (30.4% vs. 40.4% at 6 months, p=.06). Participants reported high levels of willingness to recommend the DMPA contraception to a friend and satisfaction with the injection received, and these did not differ by injection type. Sixty-four percent of women and 73% of providers preferred SP to DMPA-IM at 6 months; women's preferences did not differ by previous experience with injectable contraception.
CONCLUSIONS:
SP is acceptable to HIV-positive women and health care providers in this rural Ugandan population.
IMPLICATIONS:
SP appears to be acceptable to HIV-positive women and their care providers in Rakai, Uganda, and strategies for appropriate rollout of this innovative technology should be explored.
Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence - Polis, C. B., Phillips, S. J., Curtis, K. M., Westreich, D. J., Steyn, P. S., Raymond, E., … Turner, A. N.
Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we identified 22 studies published by January 15, 2014 which met inclusion criteria; we classified thirteen studies as having severe methodological limitations, and nine studies as "informative but with important limitations". Overall, data do not support an association between use of oral contraceptives and increased risk of HIV acquisition. Uncertainty persists regarding whether an association exists between depot-medroxyprogesterone acetate (DMPA) use and risk of HIV acquisition. Most studies suggested no significantly increased HIV risk with norethisterone enanthate (NET-EN) use, but when assessed in the same study, point estimates for NET-EN tended to be larger than for DMPA, though 95% confidence intervals overlapped substantially. No data have suggested significantly increased risk of HIV acquisition with use of implants, though data were limited. No data are available on the relationship between use of contraceptive patches, rings, or hormonal intrauterine devices and risk of HIV acquisition. Women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition, and like all women at risk of HIV, should be empowered to access and use condoms and other HIV preventative measures. Programs, practitioners, and women urgently need guidance on how to maximize health with respect to avoiding both unintended pregnancy and HIV given inconclusive or limited data for certain HC methods.
The Contraceptive MPA, Unlike NET, Modulates Expression of Immune Function Genes and Increases HIV-1 Infection in Cervical Tissue Explants and PBMCs - Ray, RM, Avenant, C, Moliki, JM, & Hapgood, JP
BACKGROUND:
The synthetic progestins, medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN), are widely used in developing countries as injectable contraceptives, where disease burden is high. Some studies suggest that MPA, unlike NET, increases HIV-1 acquisition in women. Whether MPA and NET differentially affect HIV-1 infection and the expression of key genes relevant to HIV-1 acquisition via differential molecular mechanisms, is key to understanding choice of progestin contraceptive for HIV-1 prevention.
METHODS:
Regulation of selected genes was investigated in cervical tissue explants and peripheral blood mononuclear cells (PBMCs) by qRT-PCR, western blotting and Luminex assays, in response to physiologically relevant doses of progestogens. Infection assays were performed in the absence and presence of HIV-1 using HIV-1BAL-RENILLA or HIVpNL4.3 IMCs. The GR specific antagonist RU486 or GR siRNA knockdown were used to determine the role of the GR in modulating ligand-specific effects.
RESULTS:
In PBMCs, MPA like dexamethasone (DEX, a GR specific agonist), showed anti-inflammatory effects, decreasing pro-inflammatory IL6, IL8 and RANTES levels and increasing anti-inflammatory GILZ gene expression levels, while NET and progesterone (P4) did not. In primary cervical tissue explants, DEX and MPA repressed IL6 and IL8 and increased GILZ gene expression levels. Differential gene expression by MPA versus NET and P4 were mediated via the GR in PBMCs. Similarly, MPA and DEX, unlike NET and P4, increased HIV-1 replication in viable PBMCs. In primary cervical explants, MPA, but not NET increased HIV-1 replication.
CONCLUSIONS:
Collectively, the data suggest that NET, unlike MPA, would be a safer choice of injectable progestin contraceptive in young women in high risk areas for HIV-1 infection. The molecular basis for this choice most likely involves differential effects of MPA as compared to NET and P4, on transcription of immunomodulatory genes, due to their differential actions via the ubiquitous GR.
A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy - Summer, D. A. Y., Graham, S. M., Masese, L. N., Richardson, B. A., Kiarie, J. N., Jaoko, W., … McClelland, R. S.
Depot medroxyprogesterone acetate (DMPA) use among HIV-1-infected women may increase transmission by increasing plasma and genital HIV-1 RNA shedding. We investigated associations between DMPA use and HIV-1 RNA in plasma and cervical secretions. One hundred two women initiated antiretroviral therapy, contributing 925 follow-up visits over a median of 34 months. Compared with visits with no hormonal contraception exposure, DMPA exposure did not increase detection of plasma (adjusted odds ratio: 0.81, 95% confidence interval: 0.47 to 1.39) or cervical HIV-1 RNA (adjusted odds ratio: 1.41, 95% confidence interval: 0.54 to 3.67). Our results suggest that DMPA is unlikely to increase infectivity in HIV-positive women who are adherent to effective antiretroviral therapy.
2013
Modelling the global competing risks of a potential interaction between injectable hormonal contraception and HIV risk - Butler, A. R., Smith, J. A., Polis, C. B., Gregson, S., Stanton, D., & Hallett, T. B.
BACKGROUND:
Some, but not all, observational studies have suggested an increase in the risk of HIV acquisition for women using injectable hormonal contraception (IHC).
METHODS:
We used country-level data to explore the effects of reducing IHC use on the number of HIV infections, the number of live births and the resulting net consequences on AIDS deaths and maternal mortality for each country.
RESULTS:
High IHC use coincides with high HIV incidence primarily in southern and eastern Africa. If IHC increases the risk of HIV acquisition, this could generate 27 000-130 000 infections per year globally, 87-88% of which occur in this region. Reducing IHC use could result in fewer HIV infections but also a substantial increase in live births and maternal mortality in countries with high IHC use, high birth rates and high maternal mortality: mainly southern and eastern Africa, South-East Asia, and Central and South America. For most countries, the net impact of reducing IHC use on maternal and AIDS-related deaths is dependent on the magnitude of the assumed IHC-HIV interaction.
CONCLUSIONS:
If IHC use increases HIV acquisition risk, reducing IHC could reduce new HIV infections; however, this must be balanced against other important consequences, including unintended pregnancy, which impacts maternal and infant mortality. Unless the true effect size approaches a relative risk of 2.19, it is unlikely that reductions in IHC could result in public health benefit, with the possible exception of those countries in southern Africa with the largest HIV epidemics.
Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues - Chandra, N., Thurman, A. R., Anderson, S., Cunningham, T. D., Yousefieh, N., Mauck, C., & Doncel, G. F.
The relationship between exogenous contraceptive hormones and permissiveness of the female genital tract to human immunodeficiency virus type 1 (HIV-1) is the subject of renewed debate. To better characterize the effect of depot medroxyprogesterone acetate (DMPA) on HIV-1 cellular targets and epithelial integrity in the vagina, we compared leukocyte populations, markers of activation and proliferation, and the density of intercellular junctional proteins in the vaginal epithelium of women during the follicular and luteal phases of the menstrual cycle and approximately 12 weeks after receiving a DMPA injection. This prospective cohort study involved 15 healthy women. Vaginal biopsies were obtained in the follicular and luteal phases of the menstrual cycle, and approximately 12 weeks following a 150-mg intramuscularinjection of DMPA. Leukocyte populations, activation phenotype, and epithelial tight junction and adherens proteins were evaluated by immunohistochemistry. After receiving DMPA, the numbers of CD45, CD3, CD8, CD68, HLA-DR, and CCR5 bearing immune cells were significantly (p<0.05) increased in vaginal tissues, compared to the follicular and/or luteal phases of untreated cycles. There were no significant differences in immune cell populations between the follicular and luteal phases of the control cycle. There were also no statistically significant differences in epithelial thickness and density of epithelial tight junction and adherens proteins among the follicular, luteal, and post-DMPA treatment sampling points. In this pilot study, vaginal immune cell populations were significantly altered by exogenous progesterone, resulting in increased numbers of T cells, macrophages, and HLA-DR- and CCR5-positive cells.
Hormonal contraceptive use and risk of HIV-1 disease progression - Heffron, R., Mugo, N., Ngure, K., Celum, C., Donnell, D., Were, E., … Team, P. in P. H. T. S.
BACKGROUND:
For HIV-1-infected women, hormonal contraception prevents unintended pregnancy, excess maternal morbidity, and vertical HIV-1 transmission. Hormonal contraceptives are widely used but their effects on HIV-1 disease progression are unclear.
METHODS:
In a prospective study among 2269 chronically HIV-1-infected women from seven countries in eastern and southern Africa and with enrollment CD4 cell counts at least 250 cells/μl, we compared rates of HIV-1 disease progression among those using and not using hormonal contraception (i.e. oral or injectable methods). The primary outcome was a composite endpoint of CD4 decline to less than 200 cells/μl, initiation of antiretroviral therapy, or death.
RESULTS:
Three hundred and seventy-two women experienced HIV-1 disease progression during 3242 years of follow-up (incidence rate = 11.5 events per 100 person-years). Rates of HIV-1 disease progression among women who were currently using and not using hormonal contraception were 8.54 and 12.31 per 100 person-years, respectively (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.98, P = 0.04). Rates were 8.58 and 8.39 per 100 person-years for the subsets using injectable and oral contraception (adjusted hazard ratio = 0.72, P = 0.04 for injectable users and adjusted hazard ratio = 0.83, P = 0.5 for oral users compared to women not using hormonal contraception). Sensitivity analyses assessing enrollment or cumulative contraceptive use during the study demonstrated risk estimates closer to 1.0 with no evidence for accelerated disease progression.
CONCLUSION:
Among African women with chronic HIV-1 infection, use of hormonal contraception was not associated with deleterious consequences for HIV-1 disease progression.
Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms - Huijbregts, R. P., Helton, E. S., Michel, K. G., Sabbaj, S., Richter, H. E., Goepfert, P. A., & Hel, Z.
Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.
Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples - Lutalo, T., Musoke, R., Kong, X., Makumbi, F., Serwadda, D., Nalugoda, F., … Wawer, M.
BACKGROUND:
The risk of HIV associated with hormonal contraceptives is controversial. We assessed hormonal contraceptive use and HIV incidence in HIV-discordant couples in Rakai, Uganda.
METHODS:
HIV-discordant couples were retrospectively identified from a cohort between 1999 and 2009. Hormonal contraception included oral contraception, depomedroxyprogesterone acetate (DMPA), and implants (Norplant). Poisson regression estimated adjusted incidence rate ratios (adjIRRs) associated with hormonal contraceptive methods. A case-control subanalysis estimated odds ratios (ORs) of HIV associated with hormonal contraceptive, adjusted for viral load and age.
RESULTS:
We identified 190 male HIV-positive/female HIV-negative (M+F-) and 159 male HIV- negative/female HIV-positive (M-F+) couples not using antiretroviral therapy or condoms. Female HIV incidence was 5.8/100 person-years (py) among nonhormonal contraceptive users, 12.0/100 py among oral contraceptive users [adjIRR 2.65, 95% confidence interval (CI) 0.82-8.60], 4.5 among Norplant users (adjIRR: 0.89, 95% CI 0.11-7.10), and 7.5/100 py among DMPA users (adjIRR 1.42, 95% CI 0.60-3.36). Male HIV incidence was 7.4/100 py during nonhormonal contraceptive use, 16.5/100 py during female oral contraceptive use (adjIRR 2.52, 95% CI 0.49-12.95), and 4.9/100 py with DMPA use (adjIRR 0.57, 95% CI 0.19-1.70). The number of female seroconverters was three among oral contraceptive users, one among Norplant users, and seven among DMPA users. Male seroconverters were two during female oral contraceptive use, none with Norplant use, and three with DMPA use. In a nested case-control analysis after adjustment for HIV viral load, the adjOR associated with oral contraceptive use was 1.59 (95% CI 0.32-97.85) for M+F- and 2.11 (95% CI 0.18-25.26) for M-F+ couples. For DMPA use, the adjOR was 1.44 (95% CI 0.46-4.51) for M+F- and 1.40 (95% CI 0.30-6.49) for M-F+ couples.
CONCLUSION:
We did not observe significant risk of HIV acquisition or transmission with oral contraceptives or DMPA use in HIV discordant couples, but several point estimates were above 1.0 and statistical power was limited.
Hormonal contraception and HIV/AIDS transmission: challenges for Zimbabwe’s reproductive health service providers in promoting informed contraception choices - Mafuva, C., & Marima-Matarira, H. T.
None-barrier methods are the most predominant contraceptive methods of choice among Zimbabwean women, with the contraceptive pill being the most popular. The spread of HIV/AIDS is most prevalent in sub-Saharan African countries, Zimbabwe included. The prevalent mode of transmission is unprotected heterosexual sex. Although Zimbabwe boasts of a high literacy rate some women may still be vulnerable like in other parts of the world, as they may not understand the role of the Zimbabwe National Family Planning Council (ZNFPC) and other reproductive health service providers. This is because some women at risk may expose themselves to unprotected sex while they are on hormonal contraceptives. This paper seeks to infer into pros and cons of hormonal contraceptive use among Zimbabwean women. There is also need to discuss the effectiveness of providers (ZNFPC clinics and the Ministry of Health) in educating women about the risk of HIV transmission, which may be associated with some non-barrier methods of contraception. An understanding of women's attitudes towards the different forms of contraception is of paramount importance as is that of the factors that could contribute to women in different social settings resorting to uninformed contraceptive choices.
Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa - McCoy, S. I., Zheng, W., Montgomery, E. T., Blanchard, K., van Der Straten, A., de Bruyn, G., & Padian, N. S.
OBJECTIVE:
To evaluate the effect of oral and injectable hormonal contraception on the risk of HIV acquisition among women in South Africa and Zimbabwe.
DESIGN:
Secondary data analysis of 4913 sexually active women aged 18-49 years followed for up to 24 months in the Methods for Improving Reproductive Health in Africa (MIRA) phase III effectiveness trial of the diaphragm and lubricant gel for HIV prevention.
METHODS:
Participants were interviewed quarterly about contraception and sexual behavior and were tested for pregnancy, HIV, and other sexually transmitted infections. We used a Cox proportional hazards marginal structural model, weighted by the inverse probability of hormonal contraception use, to compare the risk of HIV acquisition among nonpregnant women reporting use of combined oral contraceptive pills (COC), progestin-only pills (POP), and/or injectable hormonal contraception to women not using these methods.
RESULTS:
During the study, 283 participants seroconverted. Use of oral contraceptives (POP or COC) was not associated with HIV risk [adjusted hazard ratio (HRa) = 0.86, 95% confidence interval (CI) 0.32, 1.78]. Injectable hormonal contraception was associated with a small nonsignificant risk of HIV infection (HR(a) = 1.34, 95% CI 0.75, 2.37). The effect of injectable hormonal contraception was similar in the unweighted site-adjusted only (HR(a) = 1.32, 95% CI 1.00, 1.74) and baseline factor adjusted models (HR(a) = 1.27, 95% CI 0.94, 1.72).
CONCLUSIONS:
In this study, oral contraceptives were not associated with HIV acquisition. There is substantial uncertainty in the effect of injectable hormonal contraception on HIV risk. These findings underscore the importance of dual protection with condoms and the need for diverse contraceptive options for women at risk of HIV infection.
Effect of hormonal contraceptive methods on HIV disease progression: a systematic review - Phillips, S. J., Curtis, K. M., & Polis, C. B.
OBJECTIVE:
Systematically assess from the literature whether women living with HIV who use hormonal contraception are at increased risk of HIV-disease progression compared with those who do not use hormonal contraception.
METHODS:
We searched PUBMED and EMBASE for articles published in peer-reviewed journals through December 15, 2011 for evidence relevant to all hormonal contraceptive methods and HIV-disease progression.
RESULTS:
Twelve reports of 11 studies met inclusion criteria. One randomized controlled trial (RCT) found increased risk for the composite outcome of a reduced CD4 cell count or death among hormonal contraceptive users when compared with copper intrauterine device (IUD) users. Ten cohort studies reported no increased risk for HIV disease progression (as measured by mortality, time to a CD4 cell count below 200, time to initiation of antiretroviral therapy, an increase in HIV-RNA viral load, or a decrease in CD4 count) among women who used hormonal contraception compared with those who did not.
CONCLUSION:
The preponderance of evidence indicates that HIV-positive women can use hormonal contraceptive methods without concerns related to HIV-disease progression. Cohort studies consistently found no association between hormonal contraceptive use and HIV-disease progression compared with nonuse of hormonal contraceptives. One RCT found that hormonal contraceptive use was associated with increased risk of HIV-disease progression when compared with IUD use, but this study had important methodological shortcomings. Prevention of unintended pregnancy among women living with HIV remains a public health priority to safeguard women's and infants' health and to prevent vertical transmission of HIV.
Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence - Polis, C. B., & Curtis, K. M.
OBJECTIVE AND DESIGN:
Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.
METHODS:
We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception.
RESULTS:
We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4.
CONCLUSION:
Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.
Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence - Polis, C. B., Phillips, S. J., & Curtis, K. M.
OBJECTIVE:
To systematically review epidemiologic evidence assessing whether hormonal contraception alters the risk of HIV transmission from an HIV-positive woman to an HIV-negative male partner.
DESIGN:
Systematic review.
METHODS:
We included articles published or in press through December 15, 2011. We assessed studies with direct evidence on hormonal contraception use and HIV transmission, and summarized studies with indirect evidence related to genital or plasma viral load.
RESULTS:
: One study provided direct evidence on oral contraceptive pills (OCPs) or injectable contraception and female-to-male HIV transmission; both injectables [Cox-adjusted hazard ratio (adjHR) 1.95, 95% confidence interval (CI) 1.06-3.58; marginal structural model (MSM) adjusted odds ratio (adjOR) 3.01, 95% CI 1.47-6.16] and OCPs (Cox adjHR 2.09, 95% CI 0.75-5.84; MSM adjOR 2.35, 95% CI 0.79-6.95) generated elevated point estimates, but only estimates for injectables were significant. Findings from 11 indirect studies assessing various hormonal contraception methods and viral genital shedding or setpoint were mixed, and seven of eight studies indicated no adverse effect of various hormonal contraception methods on plasma viral load.
CONCLUSION:
The only direct study on OCPs or injectable contraception and female-to-male HIV transmission suggests increased risk with the use of injectables. Given the potential for confounding in observational data, the paucity of direct evidence on this subject, and mixed indirect evidence, additional evidence is needed.
Hormonal contraception and HIV: the methods have confused the message - Schwartz, S. R., Pettifor, A., Stuart, G. S., & Cohen, M. S.
OBJECTIVE:
To examine different scenarios through which confounding by condom use may lead to inaccurate conclusions about the effect of hormonal contraception on HIV acquisition in women.
DESIGN AND METHODS:
Scenario analyses were conducted to evaluate the impact of coarse adjustment for condom use and condom misreporting on adjusted relative risk estimates for HIV acquisition in injectable hormonal contraception (IHC) users vs. nonusers.
RESULTS:
Analyses crudely accounting for condom use through a binary variable result in biased hormonal contraception-related risk estimates if condoms are used during follow-up periods in which any unprotected sex is reported and condom use differs by hormonal contraception use. We found that over-reporting of condom use is plausible in at least one recent study, as demonstrated by high pregnancy rates given, reported IHC and condom use. Over-reporting of condom use also biases estimates, typically leading to underestimation of IHC-related risk if over-reporting is the same among IHC and non-hormonal contraception users, and overestimation of IHC-related risk if condom misreporting is differential by IHC use. The impact of misreported condom use is most pronounced in study populations with high condom uptake.
CONCLUSIONS:
Discrepant findings in hormonal contraception-HIV-related research may result from inadequate measurement or adjustment for confounding by condom use. Future studies should precisely account for condom use in statistical analyses. Studies should aim to quantify the degree of condom use misreporting, by comparing reported condom use to pregnancy, HIV or other sexually transmitted infection rates, and if possible, testing stored genital swabs for prostate-specific antigen or Y chromosome.
Hormonal contraceptive continuation and switching in South Africa: Implications for evaluating the association of injectable hormonal contraceptive use and HIV - Smit, J. A., & Beksinska, M. E.
Investigating the association between hormonal contraception and HIV is challenging due to high discontinuation rates among users. This secondary analysis of 262 South African adolescent new users of hormonal contraception found continuation rates after 1 year for depot medroxyprogesterone acetate, norethisterone enanthate, or combined oral contraceptives of 40.4%, 64.4%, and 64.6%, respectively. Implications for studies evaluating the association between injectable hormonal contraceptive use and HIV are discussed.
2012
Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study - Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al.
BACKGROUND:
Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners.
METHODS:
In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk.
FINDINGS:
Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6-24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06-3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8-24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12-3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression.
INTERPRETATION:
Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1.
Hormonal contraception and the risk of HIV acquisition among women in South Africa - Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M, et al.
OBJECTIVES:
To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa.
DESIGN/METHODS:
We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular.
RESULTS:
Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users.
CONCLUSIONS:
In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.
Living with uncertainty: acting in the best interests of women - Gollub, Erica and Stein, Zena
A recent multi-country study on hormonal contraceptives (HC) and HIV acquisition and transmission among African HIV-serodiscordant couples reported a statistically significant doubling of risk for HIV acquisition among women as well as transmission from women to men for injectable contraceptives. Together with a prior cohort study on African women seeking health services, these data are the strongest yet to appear on the HC-HIV risk. This paper will briefly review the Heffron study strengths and relevant biological and epidemiologic evidence; address the futility of further trials; and propose instead an alternative framework for next steps. The weight of the evidence calls for a discontinuation of progestin-dominant methods. We propose here five types of productive activities: (1) scaling injectable hormones down and out of the contraceptive mix; (2) strengthening and introducing public health strategies with proven potential to reduce HIV spread; (3) providing maximal choice to reduce unplanned pregnancy, starting with quality sexuality education through to safe abortion access; (4) expanding provider training, end-user counseling and access to male and female barriers, with a special renewed focus on female condom; (5) initiating a serious research agenda to determine anti-STI/HIV potential of the contraceptive cervical cap. Trusting women to make informed choices is critical to achieve real progress in dual protection.
Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy - Robinson, J. A., Jamshidi, R., & Burke, A. E.
BACKGROUND:
Preventing unintended pregnancy in HIV-positive women can significantly reduce maternal-to-child HIV transmission as well as improve the woman's overall health. Hormonal contraceptives are safe and effective means to avoid unintended pregnancy, but there is concern that coadministration of antiretroviral drugs may alter contraceptive efficacy.
MATERIALS AND METHODS:
We performed a literature search of PubMed and Ovid databases of articles published between January 1980 and February 2012 to identify English-language reports of drug-drug interactions between hormonal contraceptives (HCs) and antiretroviral drugs (ARVs). We also reviewed the FDA prescribing information of contraceptive hormone preparations and antiretrovirals for additional data and recommendations.
RESULTS:
Twenty peer-reviewed publications and 42 pharmaceutical package labels were reviewed. Several studies of combined oral contraceptive pills (COCs) identified decreased serum estrogen and progestin levels when coadministered with certain ARVs. The contraceptive efficacy of injectable depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) were largely unaffected by ARVs, while data on the contraceptive patch, ring, and implant were lacking.
CONCLUSIONS:
HIV-positive women should be offered a full range of hormonal contraceptive options, with conscientious counseling about possible reduced efficacy of COCs and the contraceptive implant when taken with ARVs. DMPA and the LNG-IUS maintain their contraceptive efficacy when taken with ARVs.
Evaluating the competing risks of HIV acquisition and maternal mortality in Africa: a decision analysis - Rodriguez, M. I., Reeves, M. F., & Caughey, A. B.
OBJECTIVE:
To model the risk of HIV acquisition and maternal mortality for women in four African countries in the light of previous data on risk of HIV acquisition and hormonal contraceptive use.
DESIGN:
Decision analysis.
SETTING:
Chad, Kenya, South Africa and Uganda.
POPULATION:
Women of reproductive age, at risk of HIV, who do not desire pregnancy.
METHODS:
A decision analysis model was built to compare the consequences of removing progestin injectables from use, assuming an increased risk of HIV acquisition. Three scenarios were considered in four African countries: replacement of progestin injectables with no method, with combined oral contraceptives (COC) or with an intrauterine device (IUD). Health outcomes measured include: life-years, maternal mortality, HIV acquisition and unsafe abortion. Sensitivity analysis, including Monte Carlo simulation, was performed around all variables.
MAIN OUTCOME MEASURES:
HIV acquisition, maternal mortality and life-years.
RESULTS:
If progestin injectables are removed from use, without a minimum of 70-100% of women switching to an IUD or COCs, up to nine additional maternal deaths will occur for every case of HIV averted. Sensitivity analysis demonstrated that this finding persisted across a broad range of variables.
CONCLUSIONS:
Contraception is critical to preserving life for women in Africa. In the absence of clear evidence regarding hormonal contraception and HIV acquisition, policy decisions must not overlook the very real risk of maternal mortality.
The effects of injectable hormonal contraceptives on HIV seroconversion and on sexually transmitted infections - Wand H, Ramjee G.
OBJECTIVES:
To investigate the association between hormonal contraceptives and risk of HIV-1 seroconversion and prevalence of other sexually transmitted infections.
DESIGN:
Prospective cohort.
METHODS:
The study population was 2,236 HIV-negative women who were screened in a biomedical intervention trial in Durban, South Africa. The association between the use of hormonal contraceptives and risk of HIV-1 seroconversion was modeled using Cox proportional hazards regression analysis. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections were assessed using logistic regression models.
RESULTS:
Hormonal injectables were the most common method of contraceptives (46.47%) followed by condom use (28.04%). Overall, compared with women who reported using condoms or other methods as their preferred form of contraceptive, those who reported using hormonal contraceptives (injectables and oral pills) were less likely to use condoms in their last sexual act. Using hormonal injectables during the study was significantly associated with increased risk for HIV-1 infection [adjusted hazard ratio 1.72, 95% confidence interval (CI) 1.19-2.49, P = 0.005]; hormonal injectables were also significantly associated with higher prevalent of C. trachomatis infections (adjusted odds ratio 2.46, 95% CI 1.52-3.97, P < 0.001).
CONCLUSION:
Hormonal injectables are highly effective and well tolerated family planning methods and have played an important role in reducing unplanned pregnancies and maternal and infant mortality. However, they do not protect against HIV-1 and other sexually transmitted infections. This study reinforces the importance of comprehensive contraceptive counseling to women about the importance of dual protection, such as male condoms and hormonal contraceptives use.
2011
Hormonal contraception and HIV: an unanswered question - Morrison, C. S., & Nanda, K.
Most of the 16 million women currently living with HIV are in sub-Saharan Africa, where 60% of HIV infections occur in women. A high proportion of women in this region also use hormonal contraception, especially injectable depot-medroxyprogesterone acetate (DMPA). Since the first report of increased HIV acquisition in women taking oral contraceptives, whether hormonal contraception increases the risk of HIV acquisition remains a crucial unanswered question.
2010
Hormonal Contraception and HIV‐1 Transmission - Blish, CA, & Baeten, JM
Safe and effective contraceptive choices are essential for women with HIV-1 infection and at risk for HIV-1 infection. Epidemiological and laboratory-based studies suggest that hormonal contraception may influence HIV-1 transmission. Several large studies in high-risk populations indicate that hormonal contraceptive use may modestly increase the risk of HIV-1 acquisition. In addition, HIV-1-infected users of hormonal contraceptives may be more infectious to their uninfected partners, although no studies have directly measured HIV-1 transmission risk from women to men. However, several studies failed to demonstrate a link between contraceptive use and HIV-1 acquisition or transmission, and interpretation of many studies limited by methodological considerations, such as infrequent measurements of contraceptive exposure and HIV-1 status. As a result, many questions remain, and high-quality studies remain needed. It is clear that hormonal contraceptives are not protective against HIV-1 infection, and that dual protection with condoms should be the goal for women using hormonal contraception.
Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling - Morrison CS, Chen PL, Kwok C, Richardson BA, Chipato T, Mugerwa R, et al.
Hormonal contraceptives are used widely worldwide; their effect on HIV acquisition remains unresolved. We reanalyzed data from the Hormonal Contraception and HIV Study using marginal structural modeling to reduce selection bias due to time-dependent confounding. Replicating our original analysis closely, we found that depo-medroxyprogesterone acetate (DMPA) but not combined oral contraceptive (COC) was associated with increased HIV acquisition. Also, young (18-24 years) but not older women who used DMPA and COCs were at increased HIV risk.
2009
Risk factors for HIV incidence in women participating in an HSV suppressive treatment trial in Tanzania - Watson-Jones D, Baisley K, Weiss HA, Tanton C, Changalucha J, Everett D, et al.
OBJECTIVES:
A randomized, double-blind, placebo-controlled trial (RCT) of herpes simplex virus type 2 suppressive therapy with acyclovir 400 mg twice daily conducted among women in northwestern Tanzania reported a similar rate of HIV acquisition in both trial arms (Current Controlled Trials number ISRCTN35385041). Risk factors for HIV incidence were examined in the context of 3-monthly follow-up visits offering both voluntary counselling and testing and care for sexually transmitted infections.
DESIGN:
Prospective cohort analysis of trial participants enrolled and followed for up to 30 months.
METHODS:
Risk factors for HIV acquisition were analysed using Cox regression.
RESULTS:
Overall, 821 herpes simplex virus type 2 seropositive, HIV seronegative women were randomized; 400 randomized to acyclovir and 421 to placebo; 659 (80.3%) completed follow-up. HIV incidence was 4.27 per 100 person-years. There was no overall impact of acyclovir on HIV incidence [hazard ratio = 1.01; 95% confidence interval (CI) 0.61-1.66]. HIV acquisition was independently associated with younger age at enrolment (age 16-19 vs. 30-35: hazard ratio = 4.02; 95% CI 1.67-9.68), alcohol consumption at enrolment (> or =30 drinks/week vs. none: hazard ratio = 4.39, 95% CI 1.70-11.33), having paid sex within the previous 3 months (hazard ratio = 1.82, 95% CI 1.09-3.05), recent infection with gonorrhoea (hazard ratio = 3.62, 95% CI 1.62-8.08) and injections in the previous 3 months (hazard ratio = 3.45, 95% CI 1.62-7.34). There was some evidence of an association between HIV incidence and living in the recruitment community for less than 2 years (hazard ratio = 1.75, 95% CI 0.98-3.10) and exposure to hormonal contraception (hazard ratio = 1.60, 95% CI 0.93-2.76).
CONCLUSION:
A high incidence of HIV was observed in this trial cohort, especially in young women. Interventions are needed to address the risk associated with alcohol use and to sustain control of other sexually transmitted infections.
2008
HIV-1 incidence among women of reproductive age in Malawi - Kumwenda NI, Kumwenda J, Kafulafula G, Makanani B, Taulo F, Nkhoma C, et al.
The aim of this study was to determine HIV-1 incidence among women of reproductive age in Malawi. A prospective study design was followed. HIV-1 uninfected women were followed up for nine visits during a period of 12 months. At baseline, women received HIV-1 counselling and testing. At each visit, venous blood was collected for HIV-1 testing. Incidence rate for HIV-1 was estimated using person-years of follow up (PYFU). Risk factors for HIV acquisition were assessed using Cox proportional hazard models. A total of 842 HIV-1 negative women were enrolled in the study. Of these, 787 had subsequent HIV testing and 31 were found HIV-1 infected; an overall incidence rate of 4.51 (95% confidence interval: 2.96-6.06) per 100 PYFU was obtained. Young age, using hormonal injectable contraceptives and bacterial vaginosis were the main predictors of HIV acquisition. The incidence of HIV continues to be high among women in Malawi, and young women appear to be at higher risk.
2007
Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women - Baeten JM, Benki S, Chohan V, Lavreys L, McClelland RS, Mandaliya K, et al.
BACKGROUND:
Studies of the effect of hormonal contraceptive use on the risk of HIV-1 acquisition have generated conflicting results. A recent study from Uganda and Zimbabwe found that women using hormonal contraception were at increased risk for HIV-1 if they were seronegative for herpes simplex virus type 2 (HSV-2), but not if they were HSV-2 seropositive.
OBJECTIVE:
To explore the effect of HSV-2 infection on the relationship between hormonal contraception and HIV-1 in a high-risk population. Hormonal contraception has previously been associated with increased HIV-1 risk in this population.
METHODS:
Data were from a prospective cohort study of 1206 HIV-1 seronegative sex workers from Mombasa, Kenya who were followed monthly. Multivariate Cox proportional hazards analyses were used to adjust for demographic and behavioral measures and incident sexually transmitted diseases.
RESULTS:
Two hundred and thirty-three women acquired HIV-1 (8.7/100 person-years). HSV-2 prevalence (81%) and incidence (25.4/100 person-years) were high. In multivariate analysis, including adjustment for HSV-2, HIV-1 acquisition was associated with use of oral contraceptive pills [adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 1.00-2.13] and depot medroxyprogesterone acetate (adjusted HR, 1.73; 95% CI, 1.28-2.34). The effect of contraception on HIV-1 susceptibility did not differ significantly between HSV-2 seronegative versus seropositive women. HSV-2 infection was associated with elevated HIV-1 risk (adjusted HR, 3.58; 95% CI, 1.64-7.82).
CONCLUSIONS:
In this group of high-risk African women, hormonal contraception and HSV-2 infection were both associated with increased risk for HIV-1 acquisition. HIV-1 risk associated with hormonal contraceptive use was not related to HSV-2 serostatus.
Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort - Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B, et al.
OBJECTIVE:
To investigate whether the incidence of HIV infection is higher among sexually active women using depot medroxyprogesterone acetate (DMPA) or noresthisterone enanthate (NET-EN) injections for contraception than among women using nonhormonal or no contraception.
METHODS:
Five hundred and fifty-one initially HIV-negative women were followed up for a total of 491 person-years. Participants were interviewed, counselled, examined, tested for HIV and other STIs, and treated, at three monthly intervals for 1 year.
RESULTS:
There was no significant association between progestin contraceptive use and HIV infection (rate ratio 1.1, 95% CI 0.5 to 2.8; log-rank test, p=.73). In proportional hazards regression, the only significant hazard ratios for HIV acquisition were prevalent Neisseria gonorrhoea (5.2; 95% CI 1.1 to 23.7, p=.035) and Trichomonas vaginalis (4.8; 95% CI 1.0 to 22.8, p=.049); bacterial vaginosis was marginally significant (2.8; 95% CI 1.0 to 8.3, p=.057). The adjusted hazard ratios for NET-EN and DMPA were 1.76 (95% CI 0.64 to 4.84) and 0.46 (95% CI 0.06 to 3.79), respectively, relative to nonuse. Five hundred and twelve of 551 women had one or more confirmed STIs during the study.
CONCLUSIONS:
There is no evidence of an association between HIV infection and injectable contraceptives. Due to the limited power of this study and because similar studies have not included young women using NET-EN, we recommend that further research be carried out to focus on the use of NET-EN and HIV acquisition in high risk groups.
Prospective study of hormonal contraception and women's risk of HIV infection in South Africa - Myer L, Denny L, Wright TC, Kuhn L.
BACKGROUND:
Many women using hormonal contraceptives are also at risk of sexually transmitted HIV infection, but data are mixed on whether hormonal contraception increases women’s risk of HIV. We investigated associations between HIV incidence and use of combined oral contraceptives (COC), norethindrone enanthate (NET-EN) or depot medroxyprogesterone acetate (DMPA) in a cohort of South African women.
METHODS:
Participants were 4200 HIV-negative women aged 35-49 years enrolled into a cervical cancer screening trial. At enrollment, women were tested for sexually transmitted infections and reported on their sexual behaviour and contraceptive use. During the 24 months of follow-up, women reported on their sexual behaviours and contraceptive use and underwent repeat HIV testing.
RESULTS:
During the 5010 person-years of follow-up, 111 incident HIV infections were observed (HIV incidence, 2.2 infections/100 person-years). At enrollment, 21% of women reported using hormonalcontraception, primarily DMPA (14% of all women) or NET-EN (5%). After adjusting for sexual risk behaviours and sexually transmitted infections, the incidence of HIV was similar among women using COC, NET-EN or DMPA compared with women not using any hormonal method [incidence rate ratios and 95% confidence intervals, 0.65, 0.16-2.66; 0.79, 0.31-2.02 and 0.96, 0.58-1.59, respectively]. There was also no association between increased duration of DMPA use and HIV incidence (P-value for trend, 0.51).
CONCLUSIONS:
These findings contribute to the evidence from general population cohorts of women that hormonal contraceptive use is not associated with increased risk of HIV acquisition. Nonetheless, family planning services are an important venue for HIV prevention activities.
2003
Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda - Kiddugavu M, Makumbi F, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al.
BACKGROUND:
Hormonal contraceptives have been associated with increased risk of HIV acquisition.
METHODS:
The association between hormonal contraception use and HIV acquisition was assessed in a rural community-based cohort in Rakai District, Uganda. A group of 5117 sexually active HIV-negative women were surveyed at 10 month intervals between 1994 and 1999. Information on demographic and sociobehavioral characteristics, use of hormonal contraception (pill and injectable methods), condoms and the number of sexual partners was obtained by home-based interview. HIV incidence rate ratios (IRR) and 95% confidence intervals (CI) associated with hormonal contraception were estimated by multivariate Poisson regression after adjustment for age, condom use, number of sexual partners, marital status, education and history of genital ulcer disease.
RESULTS:
At one or more interviews, 16.6% of women reported use of hormonal contraceptives and 23.0% reported condom use. HIV incidence was 2.3/100 person-years in hormonal contraceptive users compared with 1.5/100 person-years in non-hormonal contraceptive users (unadjusted IRR, 1.56; 95% CI, 1.00-2.33). After multivariate adjustment, the IRR associated with hormonal contraceptives was reduced to 0.94 (95% CI, 0.53-1.64). The adjusted IRR was 1.12 (95% CI, 0.48-2.56) with oral contraceptive use and 0.84 (95%CI, 0.41-1.72) with injectable methods.
CONCLUSION:
Use of hormonal contraception is not associated with HIV acquisition after adjustment for behavioral confounding.
1998
The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania - Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ.
OBJECTIVES:
To determine the risk factors for HIV seroconversion and assess the association between contraceptive use and HIV infection among women attending three large family planning clinics in Dar es Salaam, Tanzania.
DESIGN:
Prospective cohort study.
METHODS:
Between 1992 and 1995, 2471 HIV-negative women were followed prospectively. Information about sociodemographic characteristics, sexual behavior, contraceptive use and other risk factors was collected at recruitment and updated at follow-up visits. At the end of the study, specimens were collected for HIV testing and laboratory diagnosis of sexually transmitted diseases.
RESULTS:
The overall HIV incidence was 3.4 per 100 person-years [95% confidence interval (Cl), 2.6-4.1]. The risk of HIV seroconversion decreased with increasing age (P=0.04, test for trend). Women reporting three or more sex partners during the follow-up period had the highest risk of HIV [age-adjusted relative risk (RR), 4.89; 95% Cl, 2.61-9.17]. Having an uncircumcised husband was associated with a significantly increased risk of HIV (age-adjusted RR, 3.60; 95% Cl, 1.12-11.59). The risk of HIV was also significantly increased among women with gonorrhoea (age-adjusted RR, 3.51; 95% Cl, 1.60-7.71) and candidiasis at baseline (age-adjusted RR, 1.98; 95% Cl, 1.17-3.33) and among women reporting alcohol consumption during the follow-up period. After controlling for other risk factors, the risk of HIV infection amongst users of oral contraceptive, intrauterine device and injectable contraceptive was not significantly increased. Similarly, there was no significant trend associated with increasing duration of use of any of these contraceptive methods.
CONCLUSION:
These findings confirm that a large number of new HIV infections continue to occur in this population. Reassuringly, no significant association was observed between HIV and use of specific contraceptive methods. Interventions to reduce further spread of HIV are still urgently needed.
1996
Contraceptive use and HIV infection in Kenyan family planning clinic attenders - Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY, et al.
This pilot study aimed to determine the feasibility of a larger study of contraception and risk of HIV infection in women. We also measured risk factors for and occurrence of HIV infection in the participants. A cohort of 1537 seronegative women attending a family planning clinic in Nairobi, Kenya was enrolled and followed for up to 12 months per woman. HIV testing was done quarterly. A nested case-control analysis was done with seroconverting women (cases) and 3 matched controls per case, who had detailed interviews and received physical examinations and STD tests. The prevalence of HIV at enrollment was 6.1%; seropositive women were excluded from further analysis. The 12-month life-table cumulative incidence of HIV was 2.1 per 100 women (95% confidence interval [CI] 1.1-3.2). In the nested case-control analysis (17 cases and 51 controls), the crude odds ratio of HIV infection comparing oral contraceptive (OC) users with other women was 3.5 (95%) CI 0.8-21.5), which persisted after control for single confounders at a time. The putative association between OC use sand HIV infection is critical to public health policy, yet no study has been conducted specifically to measure it, yielding weak and conflicting evidence. We intend to conduct a larger study with a similar design as the current pilot study, which confirmed the feasibility of a more definitive project.