HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial
Women represent more than half of the 37 million people worldwide currently living with HIV, most of whom reside in sub-Saharan Africa, and more than 600 000 new infections occur each year among African women. Modern contraceptive methods are used by more than 700 million women worldwide, including more than 58 million African women. Use of these methods substantially improves maternal and child health by averting unintended pregnancy and sequelae, and it contributes to women's empowerment and to economic and social development. Unfortunately, 47% of women in Africa who do not want to become pregnant (more than 50 million women) have an unmet need for modern contraception. Injectable contraceptive use has increased substantially over the past few decades in Africa, with large increases in west Africa (eg, Mali and Sierra Leone), central Africa (eg, Chad), and east Africa (eg, Ethiopia, Kenya, and Uganda), in addition to high prevalence of use in South Africa and other countries in southern Africa. In many settings in Africa where HIV incidence is high, the intramuscular injectable progestin depot medroxyprogesterone acetate (DMPA-IM) is the predominant contraceptive used. Epidemiological, clinical, and laboratory studies have suggested that use of DMPA-IM might increase a woman's susceptibility to HIV, with meta-analyses finding a 40–50% increased risk. However, all of these studies have important limitations, including an observational design and variable quality. Results have been inconsistent, with some studies finding no increase in HIV incidence among DMPA-IM users.In 2017, WHO advised that women choosing injectable progestin-only contraceptive methods and at high risk of HIV should be informed about evidence suggesting heightened HIV risk but also about the uncertainty of a causal relationship. Use of other highly effective contraceptive methods, including long-acting, reversible methods such as intrauterine devices (IUDs) and hormonal implants, is rapidly increasing in Africa, but related data on HIV risk are sparse.
Injectable, intrauterine, and implantable contraceptives have been prioritised for programmatic delivery because of high contraceptive efficacy and safety. Robust evidence on the relative risks, particularly HIV susceptibility, and benefits of these contraceptive methods is important to inform women's decision making, provider counselling, and policy maker and regulatory decisions. Our primary objective was to compare HIV incidence among women using DMPA-IM, a copper IUD, or a levonorgestrel (LNG) implant.The LNG implant was chosen over the etonogestrel implant because it is more widely used in Africa, is widely used in oral contraceptive pills, and some data suggest that LNG has fewer glucocorticoid effects and is less hypo-oestrogenic than etonogestrel. We included the copper IUD to have a highly effective non-hormonal comparator. Secondary and tertiary objectives included comparison of incidence of pregnancy, serious adverse events and adverse events leading to method discontinuation, and contraceptive method continuation by randomised method, and whether age or herpes simplex virus type 2 (HSV-2) serostatus modified the association between contraceptive method and HIV acquisition. The trial was overseen by the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium comprising leadership from Africa, the USA, and WHO. Bill & Melinda Gates Foundation, US Agency for International Development and the President's Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council, and UN Population Fund provided funding. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development.
Between Dec 14, 2015, and Sept 12, 2017, 7830 women were enrolled and 7829 were randomly assigned to the DMPA-IM group (n=2609), the copper IUD group (n=2607), or the LNG implant group (n=2613). 7715 (99%) participants were included in the modified intention-to-treat population (2556 in the DMPA-IM group, 2571 in the copper IUD group, and 2588 in the LNG implant group), and women used their assigned method for 9567 (92%) of 10 409 woman-years of follow-up time. 397 HIV infections occurred (incidence 3·81 per 100 woman-years [95% CI 3·45–4·21]): 143 (36%; 4·19 per 100 woman-years [3·54–4·94]) in the DMPA-IM group, 138 (35%: 3·94 per 100 woman-years [3·31–4·66]) in the copper IUD group, and 116 (29%; 3·31 per 100 woman-years [2·74–3·98]) in the LNG implant group. In the modified intention-to-treat analysis, the hazard ratios for HIV acquisition were 1·04 (96% CI 0·82–1·33, p=0·72) for DMPA-IM compared with copper IUD, 1·23 (0·95–1·59, p=0·097) for DMPA-IM compared with LNG implant, and 1·18 (0·91–1·53, p=0·19) for copper IUD compared with LNG implant. 12 women died during the study: six in the DMPA-IM group, five in the copper IUD group, and one in the LNG implant group. Serious adverse events occurred in 49 (2%) of 2609 participants in the DMPA-IM group, 92 (4%) of 2607 participants in the copper IUD group, and 78 (3%) of 2613 participants in the LNG implant group. Adverse events resulting in discontinuation of the randomly assigned method occurred in 109 (4%) women in the DMPA-IM group, 218 (8%) women in the copper IUD group, and 226 (9%) women in the LNG implant group (p<0·0001 for DMPA-IM vs copper IUD and for DMPA-IM vsLNG implant). 255 pregnancies occurred: 61 (24%) in the DMPA-IM group, 116 (45%) in the copper IUD group, and 78 (31%) in the LNG implant group. 181 (71%) pregnancies occurred after discontinuation of randomly assigned method.
We did not find a substantial difference in HIV risk among the methods evaluated, and all methods were safe and highly effective. HIV incidence was high in this population of women seeking pregnancy prevention, emphasising the need for integration of HIV prevention within contraceptive services for African women. These results support continued and increased access to these three contraceptive methods.