The safety of hormonal contraceptives for women living with HIV and their sexual partners

Transcription

1 Contraception 93 (2016) Review article The safety of hormonal contraceptives for women living with HIV and their sexual partners Sharon J. Phillips a, Chelsea B. Polis b, Kathryn M. Curtis c a Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland b Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA c Division of Reproductive Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA Received 12 October 2015; accepted 13 October 2015 Abstract 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 femaleto-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] ] or injectables (adj HR 0.72, CI ). 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 Published by Elsevier Inc. Keywords: Hormonal contraception; HIV; injectable contraceptives; oral contraceptives 1. Introduction Ensuring that women living with HIV (WLHIV) who wish to prevent pregnancy can access safe, effective contraception is critical to their health and prevents vertical HIV transmission [1]. WLHIV may be concerned about the effect of a contraceptive method on progression of their disease or on HIV transmissibility to sexual partners. Systematic reviews on HIV disease progression and on female-to-male HIV transmission were prepared for the World Health Organization (WHO) meeting on the safety of hormonal contraception (HC) for WLHIV in January 2012 and published in 2013 [2,3]. We updated these reviews for the 2014 WHO meeting to update the Medical Eligibility Criteria for Contraceptive Use [4] and included additional studies published through the end of The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the World Health Organization or US Centers for Disease Control and Prevention. 2. Methods We searched Pubmed from December 15, 2011 (the end date of the previous reviews), to December 15, 2014, and EMBASE from 2011 to 2014 using the same search strategy employed for the prior reviews [Appendix A]. We contacted one author for additional pertinent data [5]. For HIV disease progression, we included primary reports of WLHIV that evaluated the effects of HC use on measures of disease progression but excluded studies of women on antiretroviral therapy (ART) at study initiation, as we considered these noninformative for our outcome of interest. No such studies were identified prior to For female-to-male HIV transmission (hereafter referred to as HIV transmission), we included primary reports in which HIV-negative male partners of WLHIV using HC were followed for incident infection. Studies that measured proxy markers of infectivity in women (plasma HIV viral load or cervicovaginal viral shedding) were considered indirect evidence. An explanation of the data abstraction process and assessment of study quality where applicable can be found in the previously published reviews / 2016 Published by Elsevier Inc.

2 12 S.J. Phillips et al. / Contraception 93 (2016) Results We identified 233 new references: 10 were selected for full text review and 4 were included [5 8]. One newly included article addressed HIV progression [5]. Three new articles addressed HIV transmission [6 8]; one reported on a direct outcome (HIV transmission in serodiscordant couples) [8] and two on an indirect outcome (cervicovaginal HIV shedding [6]) HIV disease progression The new study included data from 2269 WLHIV who participated in a randomized clinical trial (RCT) of acyclovir for HIV prevention in serodiscordant couples [5]. The primary outcome was a composite measure of HIV disease progression, defined as initiation of ART, CD4 count falling below 200 or nontraumatic death. Use of injectable contraceptives (norethisterone enanthate (NET-EN) or depot medroxyprogesterone acetate (DMPA), not disaggregated) was associated with a significantly lower likelihood of the composite progression outcome [adjusted (adj) hazard ratio (HR) 0.72, confidence interval (CI) ], while use of oral contraceptives (OCs) was not associated with any significant difference (adj HR 0.83, CI ) HIV transmission Direct evidence One study reported on HIV transmission among serodiscordant couples from a Ugandan community cohort [8] (Table 1). To reduce potential confounding by differential condom use between HC users and nonusers, the investigators restricted the study to intervals in which no condom use was reported. Among 159 couples assessed, there were no significant differences in HIV transmission for women using OCs (adj IRR 2.52, CI ) or DMPA (adj IRR 0.57, CI ). Given the long intersurvey interval (12 16 months), exposure misclassification is possible. A sensitivity analysis assessing transmission only within couples reporting using the same contraceptive method during sequential survey intervals found no association with HIV transmission and OCs (adj IRR 2.56, 95% CI ) or DMPA (adj IRR 0.45, 95% CI ). The wide CIs make these results difficult to interpret. A case control subanalysis adjusting for viral load, similarly problematic due to lack of power, also found no association between use of DMPA (adj OR 1.40, 95% CI ) or OCs (adj OR 2.11, 95% CI ) and HIV transmission Indirect evidence Two new studies assessed the indirect outcome of genital HIV shedding (Table 2). One followed 199 sex workers in Burkina Faso using ART [7] to assess qualitative detection of HIV RNA on polymerase chain reaction of cervicovaginal lavage specimens. The study found no statistically significant association between use of either DMPA (adj OR 1.32, CI ) or OCs (adj OR 1.57, CI ) and detection of HIV RNA (nor with a quantitative measure of cervicovaginal HIV RNA) after adjusting for plasma viral load. A new report of longer from a study included in the previous review [9] assessed 102 women initiating ART in Kenya and found no association between DMPA exposure and qualitative detection of cervical RNA (adj OR 1.41, CI ) or plasma RNA (adj OR 0.81, CI ) [6]. 4. Conclusions The newly identified study regarding disease progression [10] reported significantly reduced hazards of disease progression or death in women using injectables, and no association with OC use, as compared to women not using a method of HC. This is consistent with findings from the prior systematic review; no observational study has shown accelerated HIV progression associated with use of any HC method [3,11 13]. One RCT suggested an increased risk of progression or death among users of HC versus users of an IUD, but severe methodological shortcomings (i.e., high rates of crossover and dropout) rendered these findings difficult to interpret [14] (Fig. 1). Regarding HIV transmission, one direct study in the previous review found significantly increased transmission among injectable users; a newly identified direct study adds little information due to very wide CIs. Among indirect studies of HIV transmission, the prior review showed mixed results; among the eight studies, some suggested increased shedding, while others found no difference. The two newly identified indirect studies found no evidence of significantly increased HIV transmission with use of any HC method studied. In 2014, the WHO Expert Working Group reviewed this evidence (with the exception of one article [6] that was published later) to evaluate medical eligibility criteria for the use of HC among WLHIV. The Expert Working Group recommended that WLHIV can use all hormonal contraceptives (WHO Category 1), although special consideration may be required for women using antiretroviral therapy [4]. Acknowledgments We would like to thank Renee Heffron for providing unpublished data from her study. This review was supported by the World Health Organization and the US Centers for Disease Control and Prevention. Appendix A. Search strategies. PubMed: (((hormonal AND contracepti*) OR ( hormonal methods )) OR ((progestin* OR progestins[mesh] OR Progesterone[MeSH] OR progestogen* OR progestagen*) AND contracept*) OR (oral contracept*) OR ((((depo OR depot) AND medroxyprogesterone) OR depomedroxyprogesterone OR

3 Table 1 HIV disease progression Primary author, year, funding Heffron 2013 [5] NIH, Bill & Melinda Gates Foundation Study design, location Study population Contraceptive method/ comparison group/outcome Prospective cohort (from an RCT assessing the effect of suppressive acyclovir on HIV transmission among serodiscordant couples), median 1.7 years of Prevalent cases 7 Eastern/Southern African countries 2269 women who were both HIV and HSV positive Excluded women with CD4 b250, on ART or with history of AIDS-defining illness Injectables (n=324) Oral contraceptives (n=95) Nonhormonal (hysterectomy, tubal ligation, condoms or no method) (n=1817) IUD/Implant users excluded from analysis due to small numbers Initiation of ART, CD4 decline to b200, or nontraumatic death (composite outcome); CD4 decline to b350 among those with CD4 N 350 at enrolment ART: Antiretroviral therapy; OC: Oral contraceptives; HC: Hormonal contraceptives; GUD: Genital ulcer disease Results [adj HR (95% CI) unless otherwise noted] Composite outcome Inj vs no HC 0.72 ( ) OC vs no HC 0.83 ( ) Indicators considered separately (adj HR) Progression to CD4 b200 HC vs no HC 0.87 (p=.4) ART initiation HC vs no HC 1.03 (p=.9) Death HC vs no HC 0.45 (p=.1) CD4 decline to b350 HC vs no HC 0.78 (p=.03) The following disaggregated estimates are unpublished data provided by the author: Progression to CD4 b200 Inj vs no HC 0.82 ( ) OC vs no HC 0.96 ( ) ART initiation Inj vs no HC 1.07 ( ) OC vs no HC 0.84 ( ) Death Inj vs no HC 0.59 ( ) OC vs no HC: no events Strengths Weaknesses Quality Frequent (monthly) collection of data on contraceptive use Large sample size Analysis of ART treatment-naive population Accounted for switching of methods Prevalent cases with control for baseline characteristics Controlled for time-varying characteristics No data collected on type of OC or injectable Relatively short (1.7 years average) II-2, fair S.J. Phillips et al. / Contraception 93 (2016)

4 Table 2 Female to male HIV transmission Direct evidence Study, publication date, location, study description, funding source Lutalo 2013 [8] Uganda Serodiscordant couples enrolled in a community cohort study in Rakai, Uganda, , who reported no condom use NIAID, NICHD, The Henry M. Jackson Foundation; The Fogarty Foundation; The Bill and Melinda Gates Institute for Population and Reproductive Health at Johns Hopkins University No. seroconverted/ person-years, no. seroconverters with partners using HC/ person-years 26/358.4 p-y total No HC:21/285.5 p-y OC: 2/12.1 p-y DMPA: 3/60.8 p-y Referent group Overall proportion of condom use in population Frequency of study visits No use of hormonal contraceptive method Only condom nonusers were included Intersurvey interval months HC/non-HC differences noted at baseline or? No differences noted on baseline variables Multivariate analysis controlled for Male partner's age, time-varying number of sex partners, alcohol use with sex, GUD in the previous 12 months Results Summary of strengths Summary of weaknesses No HC Incidence rate 7.4/100 pys OC Incidence rate 16.5/100 pys Adj IRR: 2.52 ( ) DMPA Incidence rate 4.9/100 pys Adj IRR: 0.57 ( ) Sensitivity analysis excluding method switchers OC Adj IRR: 2.56 ( ) DMPA Adj IRR: 0.45 ( ) Case control sub-analysis adjusting for HIV viral load OC: adj OR 2.11 ( ) DMPA: adj OR 1.40 ( ) Note: This analysis included some condom users; adjusting for condom use did not change results Analysis of serodiscordant couples increases likelihood that participants equally exposed to sexual activity with an HIV-positive partner. Exclusion of condom users may reduce an important source of confounding Multivariate analysis controlled for variables previously shown to be associated with HIV transmission in the same population Infrequent (12 16 months) Infections not genetically linked Limited statistical power and precision. 14 S.J. Phillips et al. / Contraception 93 (2016) 11 16

5 Indirect evidence Study, publication year, location, design, funding Outcome, technique, site Technique for specimen collection N, population Follow-up Multivariate analysis? (covariates considered) Important confounders addressed? Description of results Strengths and weaknesses Low 2014 [7] Burkina Faso Prospective cohort Agence Nationale de Recherches sur le SIDA et les Hepatites (ANRS), The Wellcome Trust, DFID Day 2014 [6] Kenya Prospective cohort NIH Follow-up from previously included study [9] RNA (cervicovaginal) RNA (cervical and plasma) Cervicovaginal lavage Cervical swab 199 female sex workers using ART 102 women initiating ART, 99 with Mean 3.4 years Median 34 months Yes (plasma viral load, adherence to ART, which ART used, blood in sample, abnormal discharge; contraception and pregnancy considered but had no effect); however, results of multivariate analysis for contraceptives not reported Yes (baseline plasma viral load, concurrent CD4, self-reported adherence, plasma viral load at time of sample collection) ART:yes Blood contamination:yes Partner contamination:yes (however, confounders not included in analysis for DMPA/OCs) ART:yes Blood contamination:yes (women rescheduled if menstruating) Partner contamination: yes (sensitivity analysis removing visits where sperm was detected visually) Detection of HIV RNA DMPA: adj OR 1.32 (CI ) OC: adj OR 1.57 (CI ) (adjusted for plasma viral load) Reference: no HC Quantity of HIV RNA (in periods when detectable- adjusted regression coefficient) DMPA: 0.15 ( 0.51, 0.21) OC: 0.04 ( 0.18, 0.26) (adjusted for plasma viral load) Reference: No HC Detection of HIV RNA: Cervical DMPA exposure past 70 days: adj OR 1.41 (CI ) (adjusted for all covariates considered) Reference: no HC Detection of HIV RNA: plasma DMPA exposure past 70 days: adj OR 0.81 (CI ) (adjusted for all covariates considered) Reference: no HC Strengths -Standardized collection and processing of CVL for RNA -Controlled for plasma viral load Weaknesses -Multivariate analysis accounting for potential important confounders performed. but results for HC not reported Strengths -Multivariate analyses performed -Long Weaknesses -Power analysis done post hoc -Blood contamination addressed only by not measuring during menses -Partner contamination addressedonlyby visual inspection S.J. Phillips et al. / Contraception 93 (2016)

6 16 S.J. Phillips et al. / Contraception 93 (2016) Fig. 1. Composite outcome, adjusted HR: progression to AIDS, ART initiation, or death. Actual use analysis, adjusted HR. depo OR depot OR dmpa OR net en OR net-en OR norethisterone enanthate OR norethisterone-enanthate OR Medroxyprogesterone 17-Acetate[MeSH]) AND (contracept* OR inject*)) OR (((levonorgestrel OR etonogestrel) AND implant) OR (uniplant OR jadelle OR implanon OR norplant OR norplant2 OR sino-implant)) OR (contraceptives, postcoital[mesh] OR (contracept* AND (emergency OR postcoital OR post coital )) OR ulipristal acetate OR Plan B OR mifepristone) OR ((levonorgestrel AND (intrauterine devices[mesh] OR iud OR iucd OR ius OR intrauterine system OR intra-uterine system OR intrauterine device OR intra-uterine device )) OR mirena) OR ((combin* AND inject* AND contracept*) OR (( once a month OR monthly) AND inject* AND contracept*) OR (cyclofem OR lunelle OR mesigyna OR cyclo provera OR cycloprovera)) OR ((((contraceptive devices[mesh] OR contraceptive agents[mesh]) AND ring) OR nuvaring OR nuva ring )) OR ((((contraceptive devices[mesh] OR contraceptive agents[mesh]) AND patch) OR ortho evra OR orthoevra)) AND ( HIV Seropositivity [MeSH] OR HIV [MeSH] OR HIV Infections [MeSH] OR Acquired Immunodeficiency Syndrome [MeSH] OR HIV progression OR HIV disease progression OR HIV shedding OR viral shedding OR HIV transmission OR Virus Shedding [MeSH]) AND Humans[MeSH]). Embase: ( Hormonal contraception ) AND HIV. References [1] Wilcher R, Petruney T, Cates W. The role of family planning in elimination of new pediatric HIV infection. Curr Opin HIV AIDS 2013;8: [2] Polis CB, Phillips SJ, Curtis KM. Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence. AIDS 2013;27: [3] Phillips SJ, Curtis KM, Polis CB. Effect of hormonal contraceptive methods on HIV disease progression: a systematic review. AIDS 2013;27: [4] World Health Organization. Hormonal contraceptive methods for women at high risk of HIV and living with HIV: 2014 guidance statement. Geneva: World Health Organization; [5] Heffron R, Mugo N, Ngure K, Celum C, Donnell D, Were E, et al. Hormonal contraceptive use and risk of HIV-1 disease progression. AIDS 2013;27: [6] Day S, Graham SM, Masese LN, Richardson BA, Kiarie JN, Jaoko W, et al. 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. J Acquir Immune Defic Syndr 2014;66: [7] Low AJ, Konate I, Nagot N, Weiss HA, Kania D, Vickerman P, et al. Cervicovaginal HIV-1 shedding in women taking antiretroviral therapy in Burkina Faso: a longitudinal study. J Acquir Immune Defic Syndr 2014;65: [8] Lutalo T, Musoke R, Kong X, Makumbi F, Serwadda D, Nalugoda F, et al. Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples. AIDS 2013;27(Suppl 1):S [9] Graham SM, Masese L, Gitau R, Jalalian-Lechak Z, Richardson BA, Peshu N, et al. Antiretroviral adherence and development of drug resistance are the strongest predictors of genital HIV-1 shedding among women initiating treatment. J Infect Dis 2010;202: [10] Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis 2012;12: [11] Morrison CS, Chen PL, Nankya I, Rinaldi A, Van Der Pol B, Ma YR, et al. Hormonal contraceptive use and HIV disease progression among women in Uganda and Zimbabwe. J Acquir Immune Defic Syndr 2011;57: [12] Polis CB, Wawer MJ, Kiwanuka N, Laeyendecker O, Kagaayi J, Lutalo T, et al. Effect of hormonal contraceptive use on HIV progression in female HIV seroconverters in rakai, Uganda. AIDS 2010;24: [13] Stringer EM, Giganti M, Carter RJ, El-Sadr W, Abrams EJ, Stringer JS. Hormonal contraception and HIV disease progression: a multicountry cohort analysis of the MTCT-plus initiative. AIDS 2009;23(Suppl 1):S [14] Stringer EM, Levy J, Sinkala M, Chi BH, Matongo I, Chintu N, et al. HIV disease progression by hormonal contraceptive method: secondary analysis of a randomized trial. AIDS 2009;23: