Elsevier

The Lancet HIV

Volume 2, Issue 11, November 2015, Pages e474-e482
The Lancet HIV

Articles
Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study

https://doi.org/10.1016/S2352-3018(15)00184-8Get rights and content

Summary

Background

Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens.

Methods

We did this retrospective cohort study of HIV-positive women aged 15–45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations.

Findings

24 560 women contributed 37 635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1·1 per 100 person-years (95% CI 0·72–1·5) for nevirapine-based ART users and 3·3 per 100 person-years (1·8–4·8) for efavirenz-based ART users (adjusted incidence rate ratio [IRR] 3·0, 95% CI 1·3–4·6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4·5 per 100 person-years (95% CI 3·7–5·2) for nevirapine-based ART users and 5·4 per 100 person-years (4·0–6·8) for efavirenz-based ART users (adjusted IRR 1·2, 95% CI 0·91–1·5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3·1–4·1 higher rates of pregnancy than did those using implants, with 1·6–2·8 higher rates in women using efavirenz-based ART.

Interpretation

Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other contraceptive methods except for intrauterine devices and permanent methods. Guidelines for contraceptive and ART combinations should balance the failure rates for each contraceptive method and ART regimen combination against the high effectiveness of implants.

Funding

None.

Introduction

Unintended pregnancies in HIV-positive women can have significant consequences for HIV-related maternal morbidity1 and vertical transmission of HIV.2 Effective contraception can prevent unintended pregnancies, but potential interactions between antiretroviral therapy (ART) and hormonal contraception, particularly between efavirenz-based ART and subdermal implants, might compromise contraceptive efficacy. This issue is particularly important to the nearly 13 million women living with HIV in sub-Saharan Africa.3 First, efavirenz-based ART is increasingly used as the first-line regimen, enabled by its availability as a fixed-dose combination pill.4 Second, there is increasing access over time to hormonal contraceptives for family planning in sub-Saharan Africa, including implants, which are used by up to 14% of HIV-positive women in the region.5, 6, 7 Implants prevent pregnancies by gradually releasing synthetic forms of progesterone (etonogestrel or levonorgestrel) into the serum, thereby suppressing ovulation, increasing cervical mucus viscosity, and altering the endometrium. The two types of implants commonly used in sub-Saharan Africa contain etonogestrel (68 mg per rod) and levonorgestrel (two 75 mg rods). The contraceptive failure rate with implants is less than 1%,8, 9 making them the most effective reversible contraceptive method available.

Because of pharmacokinetic data showing potential drug interactions between ART and certain hormonal contraceptives, national guidelines often advise dual use of condoms or alternative contraceptive methods.10, 11, 12 Hormonal contraceptives, including etonogestrel and levonorgestrel, are metabolised by hepatic cytochrome P450 (CYP450) enzymes, specifically CYP3A4.13 Antiretrovirals, including protease inhibitors; non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine and efavirenz; and cobicistat-boosted drugs, affect the activity of CYP3A4 and 2B6 enzymes.13 NNRTIs are specifically implicated in CYP3A4 induction. Two pharmacokinetic studies14, 15 reported reduced etonogestrel or levonorgestrel concentrations in women using implants and efavirenz-based ART.

Research in context

Evidence before this study

We searched PubMed for articles published in English between Jan 1, 1950, and Aug 18, 2015, with a combination of the terms “efavirenz”, “antiretrovirals”, “antiretroviral therapy”, “contraceptive implants”, “implants”, and “contraceptive failure”. We identified four case reports, two pharmacokinetic studies, and three clinical studies. The case reports were of six women who had contraceptive implants then initiated efavirenz-based antiretroviral therapy (ART) and had unintended pregnancies. In the two pharmacokinetic studies, the implant hormone serum concentrations were about 40–60% lower in women using efavirenz-based ART than in those not using ART. In one of the two studies, three women became pregnant within the first 48 weeks of follow-up while using efavirenz-based ART and implants. In the first clinical study from Brazil, 79 HIV-positive women were given an etonogestrel implant and followed up for 3 years, during which time no pregnancies occurred. Investigators of the second clinical study from Swaziland did a retrospective chart review of 332 levonorgestrel implant and ART users and recorded that 15 (12%) of 121 of the women using efavirenz-based ART became pregnant. The last clinical study combined data from three longitudinal studies in Africa and showed that, in women using implants, no pregnancies occurred in those using nevirapine-based ART, one pregnancy occurred in those using efavirenz-based ART (6·0 pregnancies per 100 person-years), and seven pregnancies occurred in those not using ART (1·4 pregnancies per 100 person-years).

Added value of this study

In this large cohort analysis, we showed that, in women who use implants, those who take efavirenz-based ART had three-times higher pregnancy rates than did those who take nevirapine-based ART. However, in women who take efavirenz-based ART, those who use other contraceptive methods, except for intrauterine devices and permanent methods, had up to three-times higher pregnancy rates than did those who use implants.

Implications of all the available evidence

Although our study supports the growing evidence that efavirenz-based ART might reduce the effectiveness of contraceptive implants, implants remain the most effective and readily available form of reversible contraception in resource-limited settings, including in combination with efavirenz-based ART. HIV programmes, providers, and ministries of health should continue to offer HIV-positive women the choice of selecting concomitant implants and efavirenz-based ART until better contraceptive and ART alternatives are shown to be more effective and become readily available.

The ultimate significance of any drug interactions between ART and hormonal contraceptives is unclear because few studies have examined contraceptive failure rates with efavirenz and implant use. Some case reports,16, 17, 18, 19 two retrospective studies,20, 21 and a pharmacokinetic study from Uganda22 show contraceptive failures in women who used efavirenz-based ART and implants; however, in another study from Brazil, there were no pregnancies in women who used implants and ART.23 In view of the little scientific literature and the debate about implant use in women receiving efavirenz-based ART, we aimed to investigate whether pregnancy rates differ with various combinations of contraceptive methods and ART regimens. For women using implants, we postulated that pregnancy rates would not differ significantly with nevirapine-based and efavirenz-based ART.

Section snippets

Study design and patients

We did this retrospective, longitudinal cohort study of HIV-positive women aged 15–45 years enrolled at 19 HIV health facilities supported by Family AIDS Care and Education Services (FACES) in Kisumu, Homabay, and Migori counties in western Kenya. FACES is a programme sponsored by the President's Emergency Plan for AIDS Relief and jointly managed by the University of California San Francisco (UCSF) and the Kenya Medical Research Institute (KEMRI).24 The appendix provides additional information

Results

24 560 women contributed 94 162 observations to the analysis (table 1; appendix, p 2), representing 37 635 person-years of observation. We could not determine the date of probable conception for 303 (9%) of 3337 pregnancies; the imputed median time of documented clinical pregnancy to the date of likely conception derived from the remainder of the cohort was 4·2 months (2·6–5·8). Women were assumed not to be pregnant for 8847 (9%) of 94 162 observations missing pregnancy status.

Overall, 3337

Discussion

In women using either etonogestrel or levnorgestrel implants, adjusted pregnancy rates were three-times higher with efavirenz-based ART than with nevirapine-based ART. However, even in women who use efavirenz-based ART, implant use was associated with lower pregnancy rates than were alternative contraceptive methods, except intrauterine devices and permanent methods.

Implants are among the most effective forms of contraception available,29 and the most readily available, reversible, and

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