Feminist fears of HIV perils from long-acting contraceptives finally dawn on mainstream medicine Print E-mail
Refer 2009 Feminist Research:
Visvanathan, Nalini. Hormonal Contraception & HIV Disease Acquisition
: A Limited Review and Reassessment of Findings.
A discussion paper prepared for the Population and Development Program's Reviving Reproductive Safety Project
Hampshire College, Amherst, MA July 2009

[Scroll down to also read the October 2011 mainstream medical research report by Heffron et al.  which despite claiming to use search terms of “hormonal contraception”, “hormonal contraceptive”, “HIV-1”, and “HIV-1 acquisition or transmission” in different combinations" in their research, fails to acknowledge Dr. Visvanathan's documentation of the HIV risks faced by women using injectable hormone contraceptives back in July of 2009]

Population and Development Program, CLPP, Hampshire College, Amherst, MA 01002

Reviving Reproductive Safety:

Phone: 413-559-5506 Fax: 413-559-5826 e-mail:

~~~~~~~~~~~~~~~~~~~~~~~

Hormonal Contraception & HIV Disease Acquisition: A Limited Review and Reassessment of Findings

A discussion paper
Prepared for the Population and Development Program’s Reviving Reproductive Safety Project, Hampshire College, Amherst, MA July 2009
By Nalini Visvanathan

Summary

This paper reviews some of the key studies within the epidemiological literature that examine the relationship between hormonal contraception (HC) use, primarily depot-medroxyprogesterone acetate (DMPA) injectables, and HIV acquisition. The primary objective is to reassess the findings rather than reinterpret them; consequently, it synthesizes the findings and implications published in peer-reviewed scientific journals, and it discusses their translation into preventive actions. Recent publication of findings raises lingering questions about the role of DMPA injectables, administered once in three months, in the transmission of the virus. The vulnerability of young females to infection in the epidemic, a phenomenon as yet not fully understood, and of the women engaged in sex work makes it critical to re-examine and reassess the findings that “overall” there is no association between hormonal contraception (HC) use and HIV disease acquisition.

Emerging and persistent questions about hormonal contraception’s role in disease progression and infectivity (transmission) have also increased the urgency of gaining a fuller and more nuanced understanding of the potential hormonal contraception-HIV relationship, especially because investigators and commentators have noted limitations of their findings. The 2005 WHO Nairobi statement left the Medical Eligibility Criteria for Contraceptive Use (MEC guidelines) unchanged and appears to have sanctioned the continuing use of these contraceptives by all women living in areas where the HIV epidemic is widespread. The WHO statement has been reinforced by reassurance on the website of Family Health International (FHI), a contraceptive research and service agency, that hormonal contraception does not increase the risk of contracting HIV. In scientific publications, FHI researchers acknowledge that age could be a modifier of the association and more research is needed. The researchers’ recommendations for further research and for hormonal contraceptive users to use dual protection, however, are less likely to be mentioned when the principal finding of no “overall” association is cited.

Through synthesis of the findings from two groups of studies that each followed a cohort of women and measured changes in their status over a period of time, the paper highlights important insights and information that have to be disseminated alongside the finding of “no overall association.” It discusses the shortcomings in the HC-HIV study that precipitated the WHO statement, and their implications, and recommends that revised guidelines are instituted to protect, inform and educate all women and particularly the subgroups of women at risk when using hormonal contraception.
~~~~~~~~~~~~~~~~~~~~~~~~
Nalini Visvanathan, Ph.D., MPH is an independent researcher and public health advocate. She has served for three years on the Brigham and Women’s Hospital and Fenway Community Health joint community advisory board, where she became involved with the HIV Prevention Trials Network (HPTN) and later joined the NIH/DAIDS-sponsored working group that recommended guidelines for community involvement in HIV clinical trials. From 2005 through 2006, she was a member of the Harvard Medical and Dental Schools Joint Human Subjects Committee.

Dr Visvanathan is also the co-editor of

~~~~~~~~~~~~~~~~~~~~~~~~

Calls for new policies (see pages 19-21)

We prioritize issues for policy development based on their level of urgency for the vulnerable subgroups of women in the sub-Saharan African region that were discussed in this paper:

A. Policy formulation for immediate action: Development of guidelines for hormonal contraceptive providers and the initiation of educational campaigns in communities.
1) We need policy guidelines that will ensure that women engaged in sex work and those having greater exposure to sexual activity are fully informed and educated about the increased risk for HIV if they choose hormonal methods of contraception, wherever it may be dispensed. (Rationale: The findings of a hormonal contraceptive and HIV acquisition association in the Mombasa study have been explained in terms of the greater sexual exposure to which the women are occupationally subjected, compared to women in the general population. Because this is a biological phenomenon, the findings could have implications for sex workers in other regions of the world.)

2) Providers and counselors must follow a protocol that informs their clients about the need to use a dual protection method when they provide DMPA injectables. (The WHO statement did stress the need for dual protection, “The use of male or female condoms is recommended whenever there is any possibility of exposure to STIs, including HIV. Programmes to promote dual protection should be actively supported.”) While there has been an increase in condom use within the region, it is not clear what is being done in different local contexts.21

3) Adolescent girls and young women (15 24 years) should be counseled to adopt dual protection methods if they choose hormonal contraception. They should be educated and supported in the use of the female condom.22

B. Policy to identify issues for continuing research: Expansion of current research agenda for understanding the hormonal contraception and HIV association.
1) There should be expanded research on the association between hormonal contraception and HIV disease acquisition, progression and transmissibility in the general population of women. The research agenda framed at the 2005 meeting hosted by Gynuity (p. 5) broadly documents areas to address.
2) The research design should incorporate purposive sampling to include large enough samples from subgroups like teenage girls and young women who show marked susceptibility, in order that statistical tests can be performed for this subgroup.
3) We need more studies to explicate the relationship between hormonal contraception and the acquisition of HIV by young women, with attention to changes in the vaginal epithelium and immunity response mechanism.

C. Policies to emphasize the importance of translation research: Creation of regional scientist-lay committees to review and prioritize the scientific findings that have implications for women’s health.
1) The tendency for mass mediated communications to simplify and summarize complex and nuanced scientific findings is a pervasive problem in the translation of new knowledge and its application in clinical settings. In this instance, there seems to be a gap between the nuanced presentation of the findings in a scientific forum and its simplified interpretation in the research literature. We need to examine the diffusion of findings and the threats to the integrity of the information that is relayed both in the mass media and in scientific publications.
2) There is need to set up mechanisms for ensuring that findings with serious implications for women’s health are followed up and public education programs initiated with little loss of time.

~~~~~~~~~~~~~~~~~~~~~~~~~
To read the complete article in pdf format go HERE:


Table of Contents

Summary................................................................................................................4
PART 1: Background & Introduction.......................................................................5
Vulnerable Groups in the HIV Epidemic..................................................................6
Methodology...........................................................................................................6
DMPA, Fertility Control and HIV Transmission........................................................7
The Gynuity Meeting...............................................................................................8
The 2005 WHO Nairobi Statement.........................................................................10
PART 2: Disscussion of Key Studies....................................................................12
Mombasa Study.....................................................................................................12
HC-HIV Study / Uganda, Zimbabwe and Thailand Multi-Center Study..................13
Recent Studies......................................................................................................15
Related Issues.......................................................................................................16
Contraceptive Counseling and Dual Protection Method.........................................16
Critical Areas for Follow-up and Action................................................................17
PART 3: Recommendations for Discussion...........................................................19
Endnotes................................................................................................................21
References............................................................................................................23
Appendix: Matrix of Select Principal Studies.........................................................25

~~~~~~~~~~~~~~~~~~~~~~~~
Acknowledgements
We would like to thank the reproductive health researchers and practitioners who
contributed generously to this paper by providing detailed comments and helping us in the
research process. Since institutional policies restrict our ability to include all whose help has been invaluable, we are not listing names, but that does not diminish our sincere gratitude.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Contact us if you would like a free hard copy. < >
Nalini Visvanathan, Author
Betsy Hartmann, Director, Population and Development Program
Elizabeth Barajas-Román, Associate Director, Population and Development Program
~~~~~~~~~~~~~~~~~~~~~~~~~
 Early Online Publication, 4 October 2011

Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study

Read in pdf format HERE

Renee Heffron MPH a, Deborah Donnell PhD e f, Prof Helen Rees MBBChir g, Prof Connie Celum MD a b c, Nelly Mugo MBChB b i j, Edwin Were MBChB k, Guy de Bruyn MBBCh h, Edith Nakku-Joloba MBChB l m, Kenneth Ngure MPH i, James Kiarie MBChB b i j, Prof Robert W Coombs MD c d, Jared M Baeten MD a b c ?, for the Partners in Prevention HSV/HIV Transmission Study Team†

Summary
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 12·6­24·2] 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 1·06­3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8­24·2] 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 1·12­3·45, 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.

Funding
US National Institutes of Health and the Bill & Melinda Gates Foundation.

Introduction
Safe and effective family planning services are central to initiatives to reduce unintended pregnancies, promote economic development, and improve the health of women and children worldwide. Among women with and at-risk for HIV-1, the prevention of unintended pregnancy is a key component of strategies to reduce vertical HIV-1 transmission.1, 2

Hormonal contraceptive methods, including daily oral pills and long-acting injectables, are used by more than 140 million women worldwide.3 During the past two decades, epidemiological and laboratory studies have suggested that hormonal contraception could alter the risk of HIV-1 acquisition in women.4­8 However, results have been inconsistent.9 Only one study has addressed the effect of hormonal contraception and risk of HIV-1 transmission from women to men.10 Increased risk related to hormonal contraceptive use would be of importance to global public health because of the large number of women using such methods. WHO has called for high-quality studies to assess the potential role of hormonal contraception in increased HIV-1 risk.11, 12 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
Study design and participants
From 2004­10, we did two prospective studies of HIV-1 incidence in African HIV-1-serodiscordant couples (ie, one partner with HIV-1 infection and one partner without). The Partners in Prevention HSV/HIV Transmission Study was a randomised, placebo-controlled, trial of daily acyclovir herpes simplex virus type 2 (HSV-2) suppressive therapy given to 3408 people infected with HIV-1 and HSV-2 as an intervention to reduce HIV-1 transmission to their heterosexual HIV-1-seronegative partners (Clinicaltrials.gov #NCT00194519 ); acyclovir did not significantly reduce HIV-1 transmission.13 Couples were from seven countries in east and southern Africa (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia) and were followed for up to 24 months. In a parallel study at two of the clinical trial sites (Kampala, Uganda, and Soweto, South Africa), we enrolled an additional 485 HIV-1 serodiscordant couples into an observational study of immune correlates of HIV-1 protection and followed them for up to 12 months. For both studies, eligible participants were aged 18 years or older and sexually active, HIV-1-seropositive partners had no history of AIDS-defining disorders and were not using antiretroviral therapy (ART), the HIV-1-seropositive partners in the clinical trial had CD4 counts of 250 cells per L or higher, were seropositive for HSV-2, had no known history of adverse reactions to acyclovir, and were not pregnant. Couples were recruited through study-initiated community outreach activities and referrals from HIV-1 testing and care centres, antenatal clinics, and non-governmental organisations.14 The main reasons couples did not enrol were that they did not meet the CD4 count, HSV-2, pregnancy, or sexual activity eligibility criteria.15

HIV-1-uninfected partners were seen quarterly for HIV-1 serological testing. For HIV-1-infected partners, CD4 counts were measured every 6 months, and participants eligible for ART initiation during follow-up were referred to local HIV-1 care clinics. All participants received comprehensive HIV-1-prevention services, including individual and couples counselling, free condoms, and treatment of sexually transmitted infections. Contraceptives were offered by referral or on-site. Differences in contraceptive use occurred between sites.16, 17

We excluded enrolled patients who were subsequently reported to not have HSV-2 or HIV-1 infection and couples for whom the HIV-1 uninfected participant did not complete any follow-up visits for assessment of HIV-1 seroconversion. We also censored visits for couples for whom the HIV-1 infected partner started ART, because such treatment eliminated HIV-1 risk in the study population.18 The protocols were approved by institutional review boards at the University of Washington and collaborating institutions at each study site. Participants provided written informed consent.

Procedures
Rapid HIV-1 antibody tests were used for HIV-1 serological testing and positive results were confirmed by ELISA.13 For HIV-1 seroconverters, analysis of HIV-1 env and gag sequences from both members of a couple was used to establish whether transmission was linked within the partnership.19 Nucleic-acid-amplification testing for bacterial sexually transmitted infections (STIs) was done on samples collected from both partners at study enrolment.15 All participants were tested for HSV-2 with HerpeSelect-2 EIA (Focus Technologies, Cypress, CA, USA) or by HSV-specific western blot.20 CD4 quantification was done with standard flow cytometry. Plasma HIV-1 RNA concentrations were quantified from a sample collected at study enrolment and 6 months later with the COBAS TaqMan real-time HIV-1 RNA assay, version 1.0 (Roche Diagnostics, Indianapolis, IN, USA). Concentrations of endocervical HIV-1 were quantified with the COBAS assay of swab samples collected 6 months after enrolment from HIV-1-infected women in the clinical trial cohort, as previously detailed.21 The lower quantification limit for HIV-1 RNA testing was 240 copies.

At each quarterly study visit, women were asked about their current contraceptive method with a standard questionnaire. Women were classified as exposed to hormonal contraception for each quarterly period if they reported hormonal use at the quarterly visit. Contraceptive use was analysed as a time-dependent exposure, with women assumed to have used the same method during the 3 months that elapsed between study visits. Analyses were done for exposure to any hormonal contraception and then separately for injectable and oral contraception; the comparison group was women not using hormonal contraception, which included women who had had a hysterectomy or tubal ligation, used condoms only, or used no contraception. Visits at which women reported use of implantable hormonal methods or an intrauterine device were rare (<2% of visits) and therefore excluded. Many women reported condom use, either with or without another method for contraception; condom use was thus included in analyses as a potential confounder. HIV-1-uninfected men were classified as exposed to hormonal contraception if their HIV-1-infected female partner reported using an injectable or oral method at her corresponding study visit. For 4% of male follow-up time, missing contraceptive data from their female partners were imputed to be the method consistently reported at adjacent study visits; data were not imputed if methods during adjacent periods were inconsistent.

Statistical analysis
The primary outcome measure was HIV-1 seroconversion. We did separate analyses of the association of hormonal contraception with HIV-1 acquisition by women (male-to-female transmission) and HIV-1 transmission from women to men (female-to-male transmission). For female-to-male transmission, only genetically linked seroconversions were included as outcomes to minimise misclassification of HIV-1 transmissions from outside partners with unknown hormonal contraceptive use, and follow-up time was censored for those men at the time they acquired HIV-1 from a partner other than the HIV-1-infected partner with whom they enrolled.

We compared participant characteristics during periods of hormonal contraceptive use and non-use with generalised estimating equations. To assess the effect of contraceptive method on HIV-1 risk, we used time-dependent Cox proportional hazards regression with robust standard errors to account for within subject correlation with repeated measurements.22 Models were adjusted for variables that had confounded the contraception­HIV-1-risk relation in previous analyses7, 8­age and time-dependent pregnancy and any sex without condoms­and plasma HIV-1 concentrations in HIV-1-infected partners, a strong predictor of HIV-1 transmission.23 We also assessed several additional variables for potential confounding: region (east Africa vs southern Africa), marital status of couples and the number of children they had together, HSV-2 status of the HIV-1-uninfected partner, circumcision status of the male partner, and STI in either partner, all recorded at study enrolment, and time-dependent measures of sexual frequency (with and without condoms), sex with additional partners, CD4 count of the HIV-1-infected partner, and genital-ulcer disease in either partner. None of these additional variables substantially (>10%) changed the effect estimates and thus they were not included in the final multivariate models. For analysis of HIV-1 acquisition by women, we tested for effect modification by baseline HSV-2 status and age with a likelihood-ratio test, because previous results have shown that the hormonal contraception­HIV-1-risk relation was stronger for women who were HSV-2 seronegative or who were aged less than 25 years.24

We repeated our analyses with marginal structural modelling, a technique to adjust for time-dependent confounding.25, 26 We computed stabilised-inverse-probability weights with logistic regression to predict the probability of hormonal contraceptive use at each visit (by concentrations of plasma HIV-1, age, region, and number of children), as described by Cole and colleagues;27 the weights adjusted for time-dependent measures of pregnancy and unprotected sex. Weights for the effect of any hormonal contraception on HIV-1 risk (mean 1·00, range 0·82­1·34) were computed separately from the weights to assess the separate effects of injectable and oral contraception on HIV-1 risk (mean 1·07, range 0·19­4·56). These weights were then used in a pooled logistic-regression model of hormonal contraception versus HIV-1 risk.
Finally, we assessed the prevalence and quantity of genital HIV-1 RNA in women using hormonal contraception versus those who did not by logistic and linear regression. All analyses were done with SAS 9.2.

Role of the funding source

The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results
For most of the 3790 HIV-1-serodiscordant couples included in the analysis, the HIV-1-infected partner was female (table 1). Most couples were married with children. The median age was in the mid-30s, and 321 (24%) of 1314 uninfected women were younger than 25 years. In HIV-1-seropositive participants, the median CD4 count was 455 cells per L (IQR 337­626) and median plasma HIV-1 RNA concentration was 4·10 log10 copies per mL (IQR 3·37­4·73). More than a quarter of women were pregnant during study follow-up (table 1).


TABLE 1: Participant characteristics

27 couples enrolled in the randomised trial13 were subsequently reported not to have HSV-2 or HIV-1 infection and were excluded from the analysis, as were 76 couples in which the HIV-1-uninfected participant did not complete any follow-up visits for assessment of HIV-1 seroconversion. For 350 couples (151 with an HIV-1-uninfected woman and 199 with an HIV-1-uninfected man) in which the HIV-1-infected partner started ART, subsequent visits were censored.18

At enrolment, 194 (15%) of 1314 HIV-1-seronegative and 430 (17%) of 2476 HIV-1-seropositive women used hormonal contraception; injectable contraception was more commonly used than oral pills (477 [13%] of 3790 women used injectable vs 147 [4%] who used oral contraception). 275 (21%) of 1314 HIV-1-seronegative women and 815 (33%) of 2476 HIV-1-seropositive women used hormonal methods during study follow-up. Most women did not switch contraceptive methods during follow-up (1085 [83%] of 1314 HIV-1-seronegative women and 1909 [77%] of 2476 HIV-1-seropositive women). However, among 1321 women who ever used hormonal contraception during the study, 634 (48%; 448 [48%] of 945 HIV-1-seropositive women and 186 [49%] of 376 HIV-1 seronegative women) were not using such methods at some point during follow-up.
Median follow-up for HIV-1-seronegative women was 18·0 (IQR 12·6­24·2) months and for seronegative men was 18·7 months (IQR 12·8­24·2). Retention at 12 months for HIV-1-seronegative women was 93% (1153 of 1238 women) and for seronegative men was 90% (2098 of 2331 men). Retention at 24 months for HIV-1-seronegative women was 87% (423 of 484 women) and for seronegative men was 84% (812 of 970 men). HIV-1-seronegative partners accrued 5157·9 person-years of follow-up for assessment of HIV-1 seroincidence, during which 167 HIV-1 seroconversions occurred. Of the 73 infections in women, 62 (85%) were determined by viral sequencing to be genetically linked within the partnership, and of the 93 infections in men, 59 (63%) were linked.

During follow-up, hormonal contraceptives were used more frequently by couples with young HIV-1-uninfected partners and couples who did not experience pregnancy (table 2). Sexual behaviours did not differ for HIV-1-uninfected women during periods when they were using hormonal contraception compared with when they were not using hormonal contraception. Unprotected sex was more likely and sex with an external partner was less likely for HIV-1-uninfected men, during periods when their female partner was using hormonal contraception than it was when their partner was not taking hormonal contraception. Concentrations of plasma HIV-1 RNA and CD4 counts were similar for hormonal-contraception exposed versus unexposed periods.

TABLE 2: Participant characteristics during quarterly follow-up intervals with and without hormonal contraceptive use

Rates of HIV-1 acquisition were higher in women using hormonal contraception than in those who were not (table 3). In multivariate Cox proportional hazards analysis adjusted for age, pregnancy, unprotected sex, and concentrations of plasma HIV-1 in HIV-1-infected partners, use of hormonal contraceptives was associated with a two times increased risk of HIV-1 acquisition (adjusted hazard ratio 1·98, 95% CI 1·06­3·68). Increased risk was reported for both injectable (adjusted hazard ratio 2·05, 95% CI 1·04­4·04) and oral contraceptive use (1·80, 0·55­5·82), although the analysis of oral contraceptive use included only 50·5 person-years and was not statistically significant. The results from the marginal structural models were generally in agreement with the Cox regression models. No evidence showed that the effect of hormonal contraception on HIV-1 risk was different for HSV-2-seronegative women (195 [15%] of 1283) versus seropositive women (adjusted hazard ratio 1·56 vs 2·00, pinteraction=0·82) or for women younger than 25 years (321 [24%] of 1314) versus those 25 years or older (adjusted hazard ratio 1·96 vs 2·21, pinteraction=0·82).

TABLE 3: Hormonal contraceptive use and risk of HIV-1 acquisition by women

The rate of HIV-1 transmission from women using hormonal contraceptives to their male partners was higher than was the rate of transmission from women who did not use hormonal contraceptives (table 4). In multivariate analysis adjusted for age, pregnancy, unprotected sex, and concentrations of plasma HIV-1 in HIV-1-infected partners, men's HIV-1 risk was increased two times when their partners were using hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12­3·45; table 4). Both injectable and oral contraceptive use by female partners were associated with increased HIV-1 risk for men, although the effect was significant only for injectable contraception (table 4). The marginal structural model analyses generated similar results to the Cox proportional hazards regression.

TABLE 4: Hormonal contraceptive use and risk of HIV-1 transmission from women to men

To account for the potential persistent biological effects of hormonal contraception on HIV-1 risk when women switched contraceptive methods, we assessed the effect of extending the exposure window for 3 months after last hormonal contraceptive use (thus, women could be exposed to more than one method during one study visit window). This assessment affected 32·1 (2%) of the 1782·8 person-years and one seroconversion event for the HIV-1 acquisition analysis and 70·9 (2%) of the 3375·1 person-years and one event for the female-to-male transmission analysis. The results of these analyses were not substantially different than those shown in table 3 and table 4 (data not shown). When we limited the analysis of HIV-1 acquisition by women to those 62 outcomes that were genetically linked to their male partners, the effect estimates were not substantially changed (for any hormonal contraceptive use, Cox regression adjusted hazard ratio 2·06, 95% CI 1·05­4·03 and marginal structural model odds ratio 2·01, 95% CI 1·02­3·95). In a third sensitivity analysis, we censored observations during pregnancy and adjusted our Cox model for age, unprotected sex, and concentrations of plasma HIV-1 in HIV-1-infected partners. We did not see substantial differences in the effect estimates (Cox regression adjusted hazard ratio 1·84, 95% CI 0·97­3·49, for the association of hormonal contraception and HIV-1 acquisition among women and 1·86, 1·04­3·32, for the association of hormonal contraception and HIV-1 transmission to men) for this approach compared with our primary study models.

We measured endocervical concentrations of HIV-1 RNA from a single timepoint in 1691 HIV-1-infected women (table 5). Women using injectable contraception at the time of endocervical-sample collection were more likely to have genital HIV-1 RNA detected than were those not using hormonal contraception. Concentrations of genital HIV-1 RNA were also higher in those using injectable contraception than in those not using hormonal contraception, by an average of 0·19 log10 copies per swab, after adjustment for plasma HIV-1 concentrations and CD4 cell count (table 5). No association was identified between contraception and concentrations of plasma HIV-1 RNA collected at the same time as endocervical samples (median 3·91 log10 copies per mL [IQR 3·07­4·50] for injectable users vs 4·03 log10 copies per mL [IQR 3·22­4·65] for non-users; p=0·10), suggesting a localised effect of hormonal contraception on increased concentrations of HIV-1 in the female genital tract.

TABLE 5: Endocervical concentrations of HIV-1 RNA in HIV-1 seropositive women, by contraceptive method

Discussion
Use of hormonal contraceptives was associated with a two-times increase in the risk of HIV-1 acquisition by women and HIV-1 transmission from women to men. Injectable methods were the most common form of hormonal contraception used by our study population and subgroup analyses showed significantly increased HIV-1 risk associated with injectable use. Few women used oral contraceptives in our study; oral contraceptive use was associated with a non-significant increase in HIV-1 risk and our results are insufficient for drawing definitive conclusions about oral contraceptive use and HIV-1 risk. Our results were robust when we adjusted for multiple potential confounding factors, undertook different analytical approaches, and did sensitivity analyses.

Previous studies of HIV-1-acquisition risk related to contraceptive use have had inconsistent results, partly because of variable methodological quality.9 As a result, public health policies­targeted risk-reduction counselling and strategies to promote alternative contraceptive methods for women with or at risk of HIV-1­have not been implemented. Our findings provide new data that show that contraception might increase a woman's risk of acquiring HIV-1, and they are consistent with longitudinal studies of sex workers in Kenya and family planning attendees from Uganda and Zimbabwe.7, 24 Moreover, to our knowledge, ours is the first prospective study to show increased HIV-1 risk in male partners of HIV-1-infected women using hormonal contraception. We noted raised concentrations of HIV-1 RNA in endocervical secretions from HIV-1-infected women using injectable methods, suggesting a potential mechanism for increased risk of HIV-1 transmission. Studies of HIV-1 transmission from women to men are urgently needed to confirm or refute our findings.

Hormonal contraceptives might have physiological actions beyond pregnancy prevention, including possible risks of bone-density loss, cervical cancer, and Chlamydia trachomatis.28­30 Clinical and laboratory studies have suggested possible mechanisms by which hormonal contraception could influence HIV-1 susceptibility and infectiousness including changes to vaginal structure, cytokine regulation, CCR5 expression, and cervicovaginal HIV-1 shedding.31

Our analyses controlled for age, pregnancy, condom use, and HIV-1 concentrations in the infected partner; controlling for additional demographic, clinical, and behavioural factors did not alter our results. Only a clinical trial with random assignment of women to effective hormonal contraception versus non-hormonal contraception could definitively assess HIV-1 risk from different contraceptive methods with certainty that bias in contraceptive choice and bias due to unmeasured confounding did not influence the results. Such a study might be difficult to implement because of women's preferences for different contraceptive methods and the likelihood of contraceptive switching that could undermine randomisation.

Limitations of our study were that contraceptive use was determined by self-report­we did not gather data on adherence to contraception, and we did not record the specific brand of contraception and thus cannot comment on HIV-1 risks from specific exogenous hormones. During the study period, low-dose combination hormonal oral contraceptives and long-acting injectable depot medroxyprogesterone acetate (DMPA) were the most commonly used methods in national family planning programmes; few studies have assessed HIV-1 risk from other injectable methods (eg, norethisterone enanthate).12 Most participants in our study were participating in an HIV-1-prevention randomised trial and were recruited broadly from HIV-1 testing and care centres. Nearly all HIV-1-infected partners were co-infected with HSV-2; however, HSV-2 seroprevalence is more than 80% in HIV-1-infected people in sub-Saharan Africa.32 Thus, these factors are unlikely to limit the generality of our findings. We censored follow-up for those couples in which the HIV-1-infected partner initiated ART. Future studies with long post-ART follow-up should assess whether increased risk of HIV-1 acquisition and transmission occurs in the context of ART use.

Several observational studies have shown increased HIV-1 risk for women using hormonal contraceptives;7, 24 our findings suggest that male partners of HIV-1-infected women using hormonal contraception also face heightened HIV-1 risk. The benefits of effective hormonal contraceptive methods are unequivocal and must be balanced with the risk for HIV-1 infection. Our findings argue for policies to counsel women about the potential for increased HIV-1 risk with hormonal contraceptive use, especially injectable DMPA use, and the importance of dual protection with condoms to decrease HIV-1 risk (panel).

Panel
Research in context
Systematic review
We searched PubMed up to July, 2011, to identify studies relating use of hormonal contraceptives to HIV-1 risk, with the search terms “hormonal contraception”, “hormonal contraceptive”, “HIV-1”, and “HIV-1 acquisition or transmission” in different combinations. Additionally, systematic reviews and one meta-analysis published on this topic were reviewed.

Interpretation
Several studies show­with similar magnitude of their effect estimates­the potential for hormonal contraception to increase women's risk for acquiring HIV-1, even after controlling for sexual behaviour. Our study is the first with adequate power to assess and show the potential for hormonal contraceptive use by HIV-1-seropositive women to increase risk of transmitting the virus to their male partners. These findings have important implications for family planning and HIV-1-prevention programmes, especially in settings with high HIV-1 prevalence.

Our data do not provide estimates of HIV-1 risk related to other hormonal contraceptives, such as implants, patches, or combination injectables. Data on HIV-1 risk associated with these methods and non-hormonal contraceptive methods, such as intrauterine devices, are urgently needed, and strategies to improve the accessibility and uptake of these lower-dose and non-hormonal methods should be prioritised. Contraceptive counselling should be combined with HIV-1 counselling and testing, with joint scale-up of both approaches essential for optimisation of reproductive health and HIV-1-prevention choices for women and couples. Additionally, as national HIV-1-prevention programmes begin to incorporate antiretroviral pre-exposure prophylaxis,33­35 this new HIV-1-prevention method could be offered to women using contraceptives or their partners.

Contributors
RH, DD, and JMB designed the study and RH and DD did the analysis. RH and JMB wrote the initial draft. All authors contributed to the data collection and writing of the report and approved the final draft.

Partners in Prevention HSV/HIV Transmission Study Team
*Principal investigator. University of Washington Coordinating Center and Central Laboratories, Seattle, WA, USA: C Celum*, A Wald (protocol co-chair), J Lingappa (medical director), J M Baeten, M Campbell, L Corey, R W Coombs, J P Hughes, A Magaret, M J McElrath, R Morrow, J I Mullins. Cape Town, South Africa (University of Cape Town): D Coetzee*; Eldoret, Kenya (Moi University, Indiana University): K Fife*, E Were*; Gaborone, Botswana (Botswana Harvard Partnership): M Essex*, J Makhema*; Kampala, Uganda (Infectious Disease Institute, Makerere University): E Katabira*, A Ronald*; Kigali, Rwanda (Rwanda Zambia HIV Research Group, and Emory University): S Allen*, K Kayitenkore*, E Karita*; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): E Bukusi*, C Cohen*; Kitwe, Zambia (Rwanda Zambia HIV Research Group, and Emory University): S Allen*, W Kanweka*; Lusaka, Zambia (Rwanda Zambia HIV Research Group, and Emory University): S Allen*, B Vwalika*; Moshi, Tanzania (Kilimanjaro Christian Medical College, Harvard University): S Kapiga*, R Manongi*; Nairobi, Kenya (University of Nairobi, University of Washington): C Farquhar*, G John-Stewart*, J Kiarie*; Ndola, Zambia (Rwanda Zambia HIV Research Group, and Emory University): S Allen*, M Inambao*; Orange Farm, South Africa (Reproductive Health Research Unit, University of the Witwatersrand): S Delany-Moretlwe*, H Rees*; Soweto, South Africa (Perinatal HIV Research Unit, University of the Witwatersrand): G de Bruyn*, G Gray*, J McIntyre*; Thika, Kenya (University of Nairobi, University of Washington): N R Mugo*. Data management was provided by DF/Net Research (Seattle, USA) and site laboratory oversight was provided by Contract Lab Services (University of the Witwatersrand, Johannesburg, South Africa).

Conflicts of interest
CC has received research grant support from GlaxoSmithKline, which did not include salary support, and has served on an advisory board for this company. RWC has received research grant support from the US National Institutes of Health (AI-27757 and AI-38858) and Roche Molecular and has served as a consultant for Abbott Molecular. JMB, RH, and DD have received research support from the US National Institutes of Health. JMB, CC, GdB, RH, JK, NM, EW, and DD have received grant support from the Bill & Melinda Gates Foundation.

Acknowledgments
Funding was provided by the US National Institutes of Health(grants R03 HD068143, R01 AI083034, and P30 AI027757, and support for RH through T32 AI007140) and the Bill & Melinda Gates Foundation(grants 26469 and 41185). We thank the couples who participated in this study, the teams at the study sites, and at the University of Washington for work on data and sample collection and management; and Renee Ridzon from the Bill & Melinda Gates Foundation for study oversight.

References
1 WHO . Strategic approaches to the prevention of HIV infection in infants. http://www.who.int/hiv/pub/mtct/en/StrategicApproachesE.pdf. (accessed Dec 15, 2010).
2 Reynolds HW, Janowitz B, Wilcher R, Cates W. Contraception to prevent HIV-positive births: current contribution and potential cost savings in PEPFAR countries. Sex Transm Infect 2008; 84 (suppl 2): ii49-ii53. CrossRef | PubMed
3 Population Division, UN Department of Economic Social Affairs . World Contraceptive Use 2009. http://www.un.org/esa/population/publications/contraceptive2009/contracept2009_wallchart_front.pdf . (accessed Jan 25, 2011).
4 Plummer FA, Simonsen JN, Cameron DW, et al. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis 1991; 163: 233-239. CrossRef | PubMed
5 Kiddugavu M, Makumbi F, Wawer MJ, et al. Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda. AIDS 2003; 17: 233-240. CrossRef | PubMed
6 Kleinschmidt I, Rees H, Delany S, et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception 2007; 75: 461-467. CrossRef | PubMed
7 Baeten JM, Benki S, Chohan V, et al. Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AIDS 2007; 21: 1771-1777. CrossRef | PubMed
8 Morrison CS, Richardson BA, Mmiro F, et al. Hormonal contraception and the risk of HIV acquisition. AIDS 2007; 21: 85-95. PubMed
9 Baeten JM, Lavreys L, Overbaugh J. The influence of hormonal contraceptive use on HIV-1 transmission and disease progression. Clin Infect Dis 2007; 45: 360-369. CrossRef | PubMed
10 de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. European Study Group on Heterosexual Transmission of HIV. N Engl J Med 1994; 331: 341-346. CrossRef | PubMed
11 WHO . Hormonal contraception and HIV: science and policy. http://whqlibdoc.who.int/hq/2006/WHO_RHR_06.4_eng.pdf. (accessed Oct 16, 2010).
12 WHO . Review of priorities in research on hormonal contraception and IUDs and HIV infection. http://whqlibdoc.who.int/hq/2010/WHO_RHR_10.21_eng.pdf. (accessed June 17, 2011).
13 Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med 2010; 362: 427-439. CrossRef | PubMed
14 Lingappa JR, Lambdin B, Bukusi EA, et al. Regional differences in prevalence of HIV-1 discordance in Africa and enrollment of HIV-1 discordant couples into an HIV-1 prevention trial. PLoS One 2008; 3: e1411. CrossRef | PubMed
15 Lingappa JR, Kahle E, Mugo N, et al. Characteristics of HIV-1 discordant couples enrolled in a trial of HSV-2 suppression to reduce HIV-1 transmission: the partners study. PLoS ONE 2009; 4: e5272. CrossRef | PubMed
16 Ngure K, Heffron R, Mugo N, Irungu E, Celum C, Baeten J. Successful increase in contraceptive use among Kenyan HIV-1-serodiscordant couples enrolled in an HIV-1 prevention trial. AIDS 2009; 23 (suppl 1): S89-S95. CrossRef | PubMed
17 Heffron R, Were E, Celum C, et al. A prospective study of contraceptive use among African women in HIV-1 serodiscordant partnerships. Sex Transm Dis 2010; 37: 621-628. PubMed
18 Donnell D, Baeten J, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 2010; 375: 2092-2098. Summary | Full Text | PDF(112KB) | CrossRef | PubMed
19 Campbell MS, Mullins JI, Hughes JP, et al. Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial. PLoS One 2011; 6: e16986. CrossRef | PubMed
20 Ashley-Morrow R, Nollkamper J, Robinson NJ, Bishop N, Smith J. Performance of focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV-2 antibodies among women in ten diverse geographical locations. Clin Microbiol Infect 2004; 10: 530-536. CrossRef | PubMed
21 Baeten J, Kahle E, Lingappa J, et al. Genital HIV-1 RNA levels predict risk of heterosexual HIV-1 transmission. Sci Transl Med 2011; 3: 77ra29. PubMed
22 Kleinbaum DG, Klein M. Survival analysis: a self-learning text. New York, NY: Springer, 2005.
23 Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000; 342: 921-929. CrossRef | PubMed
24 Morrison CS, Chen PL, Kwok C, et al. Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling. AIDS 2010; 24: 1778-1781. CrossRef | PubMed
25 Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000; 11: 550-560. CrossRef | PubMed
26 Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology 2000; 11: 561-570. CrossRef | PubMed
27 Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008; 168: 656-664. CrossRef | PubMed
28 Burkman RT. Noncontraceptive effects of hormonal contraceptives: bone mass, sexually transmitted disease and pelvic inflammatory disease, cardiovascular disease, menstrual function, and future fertility. Am J Obstet Gynecol 1994; 170: 1569-1575. PubMed
29 Appleby P, Beral V, Berrington de Gonzalez A, et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370: 1609-1621. Summary | Full Text | PDF(329KB) | CrossRef | PubMed
30 US Food and Drug Administration . Black box warning added concerning long-term use of Depo-Provera Contraceptive Injection. http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html. (accessed Feb 24, 2011).
31 Hel Z, Stringer E, Mestecky J. Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection. Endocr Rev 2010; 31: 79-97. CrossRef | PubMed
32 Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis 2006; 43: 347-356. CrossRef | PubMed
33 Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587-2599. CrossRef | PubMed
34 Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329: 1168-1174. CrossRef | PubMed
35 Baeten J, Celum Con behalf of the Partners PrEP Study team. antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. International AIDS Society 2011. Italy: Rome, 2011. July 17­20, 2011. Oral abstract MOAX0106.

a Department of Epidemiology, University of Washington, Seattle, WA, USA
b Global Health, University of Washington, Seattle, WA, USA
c Medicine, University of Washington, Seattle, WA, USA
d Laboratory Medicine, University of Washington, Seattle, WA, USA
e Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
f Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
g Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa
h Perinatal Health and HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
i Department of Obstetrics and Gynaecology, Kenyatta National Hospital, Nairobi, Kenya
j Department of Obstetrics & Gynaecology, University of Nairobi, Nairobi, Kenya
k Department of Reproductive Health, Moi University, Eldoret, Kenya
l School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda
m STD Clinic, Mulago Hospital, Kampala, Uganda

Correspondence to: Dr Jared M Baeten, Department of Global Health, University of Washington, Box 359927, 325 Ninth Ave, Seattle, WA 98104, USA