Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study)

Abstract

Background: In vitro, animal, biological and observational clinical studies suggest that some hormonal methods, particularly depot medroxyprogesterone acetate – DMPA, may increase women’s risk of HIV acquisition. DMPA is the most common contraceptive used in many countries worst affected by the HIV epidemic. To provide robust evidence for contraceptive decision-making among women, clinicians and planners, we are conducting the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study in four countries with high HIV incidence and DMPA use: Kenya, South Africa, Swaziland, and Zambia (Clinical Trials.gov identifier NCT02550067). Study design: We randomized HIV negative, sexually active women 16-35 years old requesting effective contraception and agreeing to participate to either DMPA, the copper T 380A intrauterine device or levonorgestrel implant. Participants attend a contraception support visit after 1 month and quarterly visits thereafter for 12 to 18 months. Participants receive a standard HIV prevention package and contraceptive side-effect management at each visit. The primary outcome is HIV seroconversion. Secondary outcomes include pregnancy, serious adverse events and method discontinuation. The sample size of 7800 women provides 80% power to detect a 50% difference in HIV risk between any of the three method pairs, assuming 250 incident infections per comparison. Ethical considerations: Several WHO consultations have concluded that current evidence on HIV risk associated with DMPA is inconclusive and that a randomized trial is needed to guide policy, counselling and choice. Previous studies suggest that women without a specific contraceptive preference are willing to accept randomization to different contraceptive methods. Stringent performance standards are monitored by an independent data and safety monitoring board approximately every 6 months. The study has been conducted with extensive stakeholder engagement. Conclusions: The ECHO study is designed to provide robust evidence on the relative risks (HIV acquisition) and benefits (pregnancy prevention) between three effective contraceptive methods.

Self-administration of injectable contraception: a systematic review and meta-analysis

“…Recent evidence, although mixed, suggests DMPA may be associated with an increased risk of HIV acquisition19; based on this evidence, the WHO recently changed their guidance for women who are at high individual risk for HIV acquisition, moving progestogen-only injectable contraceptives from a category 1 (no restriction for use) to a category 2 (benefits outweigh risks) 20. Results from the Evidence for Contraceptive Options and HIV Outcomes trial—the first randomised trial to examine the effect of different contraceptive methods, including DMPA-IM, on HIV incidence—are expected in mid-2019, which will provide stronger information on whether DMPA is associated with a greater risk of HIV acquisition compared with the implant and copper intrauterine device 21. On the release of these results, WHO will convene a Guideline Development Group to review the updated body of evidence and will issue guidance following WHO’s requirements for guideline development22 through an expedited process.…”

Integrating oral PrEP delivery among African women in a large HIV endpoint‐driven clinical trial

“…Incident HIV infection was the primary study endpoint. Rapid HIV testing was done at baseline, quarterly and if clinically indicated or requested by a participant [11]. Participants signed written informed consent.…”

“…The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial was an open‐label, randomized clinical trial testing the relative effects of three effective contraceptive methods on HIV acquisition risk, with incident HIV as the primary study endpoint [11]. The ECHO Trial protocol called for a comprehensive HIV prevention package to be provided to all participants, including PrEP as it became a part of national prevention policies in the host countries and as national recommendations for PrEP emerged during the trial period.…”

What impact could DMPA use have had in South Africa and how might its continued use affect the future of the HIV epidemic?

“…However, we also incorporate the body of observational evidence that suggests that such an association does exist. The ECHO trial was powered to detect a relative increase in risk of 1.5 and therefore the HR distribution represents a plausible range of values that may not have been detected by the ECHO trial.…”