ECHO: context and limitations

We read with interest the first public report from the ECHO trial,¹ which showed no significant differences in HIV risk in women using intramuscular injection of depot medroxyprogesterone acetate (DMPA), levonorgestrel (LNG) implant, or copper intrauterine device (IUD) for contraception. This report might profoundly affect public health and family planning policies in countries where disproportionate numbers of young women live with HIV, and we feel that it is appropriate to comment on study results and conclusions that seem to generate more questions than answers.

One unexpected and inadequately addressed result is the dissimilar sexual behaviour in women randomly assigned to DMPA versus long-acting reversible contraception (LARC). Although study participants had similar behaviour at enrolment, self-report of sexual behaviour during follow-up identified more multiple and new sexual partners, and unprotected sex in women randomly assigned to the LNG implant and copper IUD groups (all p<0∙001). Despite the authors conclusion that the highly significant increase in high-risk activity in women beginning LARC use did not confound data interpretation, this behavourial change seems worth commenting on. Also worth addressing is the observation that more than 10% of women enrolled had serum MPA concentrations indicating DMPA use in the previous 3 months. Recent DMPA use was listed as an exclusion criterium in the ECHO trial, but whether data from these women were censored is unclear.

Of potential greatest impact, the inability to randomly assign women to a no contraceptive group in the ECHO study made risk factor identification dependent on a differential outcome. This requirement of study design is relevant because effects of LNG implant and copper IUD on HIV transmission are essentially unknown, and make it impossible for the ECHO trial to exclude the possibility that all three contraceptives did not comparably increase HIV susceptibility. Finally, in sub-Saharan Africa, where adolescent girls and young women represent 10% of the population but 25% of new infections,² variables that increase HIV susceptibility by less than the 30% trial threshold increase that the ECHO study was statistically powered to detect could still have devastating consequences. Therefore, concluding that trial results showed that all three contraceptive methods are safe and support increased access to contraceptive methods might be overly broad.