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.