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CLINICAL SCIENCE: CONCISE COMMUNICATIONS

Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study

Palanee-Phillips, Theslaa; Brown, Elizabeth R.b,c; Szydlo, Danielb; Matovu Kiweewa, Flaviad; Pather, Arendevie; Harkoo, Ishanaf; Nair, Gonasagrieg; Soto-Torres, Lydiah; Hillier, Sharon L.c,i; Baeten, Jared M.c for the MTN-020/ASPIRE Study Team

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doi: 10.1097/QAD.0000000000002260
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Abstract

Introduction

Whether the use of certain forms of contraception increases the risk of HIV-1 acquisition in women is a question of global public health importance, particularly for African settings where HIV-1 prevalence and unmet family planning needs are high. A recent meta-analysis of observational studies concluded that, compared with use of no contraception, women using intramuscular depot medroxyprogesterone acetate (DMPA-IM) had a 40% increase in HIV-1 acquisition risk [1]. Limited data are available to assess HIV-1 risk for other contraceptive methods, including the alternative injectable norethisterone enanthate (NET-EN), intrauterine devices (IUDs), and hormonal implants. IUDs and implants are long-acting reversible contraceptives which have recently been prioritized for global programmatic delivery due to their high contraceptive efficacy and high rates of continuation.

In eastern and southern Africa, where HIV-1 is prevalent, injectable contraceptives are the most commonly used method [2]. In South Africa, the country with the largest HIV-1 epidemic in the world, half of the women using contraception use injectable progestin methods, and use is up to 90% in some areas [3]. The two most commonly used injectables are DMPA-IM (150 mg per injection), a progesterone derivative used every 3 months [4], and NET-EN (200 mg per injection), a first-generation synthetic progestin used every 2 months [5,6]. Both DMPA-IM and NET-EN are highly effective, available in the public sector [7], have the same medical eligibility criteria (MEC) and are treated similarly in policy guidance [8,9]. Some observational data from South Africa suggest that NET-EN may pose lower HIV-1 risk than DMPA-IM [10].

In light of findings that suggest potential increased HIV-1 infection risk in women who use DMPA-IM, in 2017, the WHO recommended that women considering progestogen-only injectables, including both DMPA-IM and NET-EN, should be advised about data suggesting heightened HIV-1 risk, about the uncertainty over a causal relationship, and about how to minimize their risk of acquiring HIV-1 by using condoms [9]. If DMPA-IM use increases HIV-1 infection risk, understanding whether alternative contraceptive methods are safer is imperative, so that women can make informed choices weighing HIV-1 risk against other aspects of contraceptive decision-making.

Methods

We analysed prospective data collected during the MTN-020/ASPIRE trial, a phase 3 randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, among 2629 women aged 18–45 years (ClinicalTrials.gov number NCT01617096) [11].

ASPIRE was conducted from August 2012 through June 2015 at 15 clinical trial sites in Malawi, South Africa, Uganda and Zimbabwe. Women were eligible for study participation if HIV-1 seronegative, sexually active (defined as at least one sexual act in the 3 months prior to screening), nonpregnant, had no untreated curable genitourinary infection, and willing to use effective contraception (i.e., a hormonal method, IUD or surgical sterilization). Women who were breastfeeding or had abnormal renal, hepatic, or hematologic function were excluded. Women were randomized in a 1 : 1 fashion to either a silicone elastomer vaginal matrix ring containing 25 mg of dapivirine or a placebo vaginal ring, to be worn continuously and changed monthly.

Women attended monthly visits for study product provision, completion of standardized questionnaires regarding sexual behaviour, and testing for pregnancy and HIV-1 infection status. At these follow-up visits, procedures included HIV-1 serologic testing, safety monitoring, and individualized adherence counselling. All participants received a package of HIV-1 prevention services, including counselling with respect to HIV-1 risk reduction, partner HIV-1 testing, treatment of sexually transmitted infections in participants and partners, and free condoms. Contraceptive use was documented monthly, and all sites provided multiple methods on-site; for women who received contraception from off-site clinics, current method was transcribed from family planning clinic cards. Women were tested monthly for pregnancy, and the study ring was withheld from women who became pregnant; they resumed use of the study ring when no longer pregnant or lactating. Screening for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis was performed at baseline, every 6 months, at the final study visit, and additionally when clinically indicated (e.g., symptoms, or reported partner symptoms).

The primary endpoint for the present analysis was HIV-1 infection, identified with the use of a standard seroconversion algorithm, including two rapid HIV-1 serologic tests done in parallel at each study visit and then confirmatory testing in the event of a positive rapid result, including HIV-1 RNA [11]. Among the 2629 women who were enrolled, 168 HIV-1 infections occurred; the incidence of HIV-1 infection in the dapivirine group was lower by 27% [95% confidence interval (CI), 1–46, P = 0.05] than that in the placebo group and by more than 50% in subgroups with evidence of greater adherence [11].

The ASPIRE study was approved by local regulatory authorities and annually by the Institutional Review Boards at each of the participating sites, and was overseen by the regulatory infrastructure of the US National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Participants provided their written informed consent prior to study participation.

Data were analysed using SAS, version 9.4. (SAS Institute Inc., Cary, North Carolina, USA). We compared risk of HIV-1 acquisition among women using different contraceptive methods – specifically, DMPA-IM, NET-EN, hormonal-containing implants, and the copper IUD – among women enrolled in South African sites only. The at-risk population was women who were exposed to any of these contraceptive methods during the specified visit interval. Follow-up time was censored after HIV-1 seroconversion. To account for contraceptive method switching the exposure was treated as time-varying, by splitting participant records into distinct observations when contraceptive method was switched. In cases of concurrent contraceptive exposure, we defined the primary method of contraception to be that which a woman was currently using and had been on for the longest duration during that interval. Time was censored when not using one of the four contraceptive methods under investigation.

The association between hormonal contraception use and risk of HIV-1 was estimated using Cox proportional hazards models adjusted for the following confounders: trial randomization arm (dapivirine vs. placebo), age (18–21, 22–25, ≥26 years, baseline), condom use (yes/no, time-varying), menstrual bleeding (yes/no, time-varying), number of sexual partners (0–1 vs. >1, time-varying), sexually transmitted infections (C. trachomatis, N. gonorrhoeae, T. vaginalis, time-varying). Copper IUD was chosen as the primary reference category so that the hormonal methods could be compared against a nonhormonal method; in a sensitivity analysis, NET-EN was chosen as an alternate referent.

Results

In total, 2629 women were enrolled and followed in ASPIRE, including 1426 from South Africa, of whom 1136 contributed to this analysis. The median age was 24 years [interquartile range (IQR) 21–29], 75 (7%) were married, and 368 (32%) indicated use of a condom at the last sex act at baseline. The median follow-up was 1.6 years (IQR 1.0–2.5) with over 35% of participants contributing more than 2 years of follow-up. At some time during follow-up, 725 (64%) used DMPA-IM, 455 (40%) NET-EN, 257 (23%) contraceptive implants, and 219 (19%) copper IUDs.

A total of 95 incident HIV-1 infections were observed over 22 293 follow-up visits, for an overall HIV-1 incidence of 5.6 per 100 woman-years. In unadjusted analyses, HIV-1 incidence was lowest among women using implants (1.93 per 100 woman years) and highest among those using NET-EN (6.22 per 100 person years) (Table 1). In multivariable models, there were no statistically significant differences between contraceptive methods in the risk of HIV-1 acquisition; however, compared with the IUD, DMPA-IM (hazard ratio 0.91, 95% CI 0.44–1.87) and NET-EN (hazard ratio 1.02, 95% CI 0.49–2.12) had point estimates near 1 while the implant had risk that was approximately half that of the IUD (hazard ratio 0.46, 95% CI 0.13–1.70). When the three hormonal methods were combined, their relative risk compared with the IUD was near 1 (hazard ratio 0.90, 95% CI 0.45–1.76). Similarly, when NET-EN was chosen as the reference, none of the other methods was statistically different.

T1-9
Table 1:
HIV-1 incidence across different contraceptive methods, among South African women.

Discussion

HIV-1 incidence was high in this population of young South African women, emphasizing the importance of the question of whether contraceptive method choice influences HIV-1 susceptibility. Our results are limited by the sample size and observational nature of the data, but they provide one of the only head-to-head comparisons with date of HIV-1 incidence across contraceptive methods, particularly for IUDs and implants. We found no statistically significant differences in HIV-1 incidence by contraceptive method. Implants had the lowest point estimate for HIV-1 incidence, and IUDs had the risk comparable with injectable methods in multivariate models whether the reference category was the IUD or NET-EN. These results emphasize that robust, prospective studies, are needed to better define the relative HIV-1 risks across different contraceptive methods, an urgent priority for women and policymakers.

Providing clarity about the safety of hormonal contraceptive methods for women at risk of HIV-1 is a public health priority [12]. The WHO publishes the MEC for contraceptive use, an evidence-based guideline informed by a continuous review of evidence, that provides recommendations on the safety of contraceptive methods for women with various medical conditions or personal characteristics, including recommendations for use of various contraceptive methods by women at high risk of HIV, women living with HIV, and women using antiretroviral therapy [13,14]. In December 2016, WHO convened an expert review of available data on use of hormonal contraception and risk of HIV-1 acquisition in women, and the MEC recommendation for progestogen-only injectable use among women at high risk of HIV changed from a category 1 (meaning that the method can be used without restriction) with a clarification (stating that women should be informed that progestogen-only injectables may or may not increase risk of HIV acquisition) to a category 2 (meaning that advantages of using the method generally outweigh potential risks) with an updated clarification. The clarification highlights that women interested in, or using, these methods should be advised of the concern regarding a link between use of these methods and potential increased risk of HIV-1, about the uncertainty over whether the link is causal and about how to minimize HIV-1 risk [14]. It is also noted that, provided with informed choice, women at high risk of HIV-1 infection who still wish to use injectable contraceptives should not be denied access to them. The ongoing Evidence for Contraceptive Options and HIV Outcomes trial is directly testing the relative risks (particularly HIV-1 acquisition) and benefits (e.g., pregnancy prevention) between DMPA-IM, the levonorgestrel implant, and the copper IUD using a randomized design [15].

Research gaps and programmatic priorities remain highly pertinent in light of continued uncertainty regarding progestogen-only injectable contraceptive use and risk of HIV-1 acquisition in women [12]. Policies, programmes and communications must keep women, and their priorities and rights, at the centre of decision-making. Programmes should recommit to informed choice through offering multiple contraceptive methods and clear information so women can choose and use a method based on their preferences. This commitment should emphasize integration of joint protection against unintended pregnancy and HIV-1.

Acknowledgements

The study was funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096. Supported by grants (UM1AI068633, UM1AI068615, and UM1AI106707) from the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

contraceptive methods; HIV-1 risk; South African women

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