A landmark study evaluating HIV risk and hormonal contraception is under fire, with critics arguing the trial was ethically flawed from the start and that its results may limit already narrow birth-control options for African women.
The trial, called the Evidence for Contraceptive Options and HIV Outcomes (ECHO), was led by the World Health Organization (WHO), the Wits Reproductive Health and HIV Institute in South Africa, the University of Washington in the United States, and the nonprofit FHI 360.
The ECHO trial was prompted by observational data implying a greater HIV acquisition risk among women who use the injectable hormonal contraceptive depot-medroxyprogesterone acetate (DMPA-IM) -- the most common birth control method available in sub-Saharan Africa.
To help answer this question, the ECHO trial enrolled 7,829 women in eSwatini, Kenya, South Africa, and Zambia from 2015 to 2018, randomly assigning them to receive either DMPA-IM, a copper intrauterine device (IUD), or a hormonal contraceptive implant.
At the end of the study, researchers concluded that the women who received DMPA-IM were not significantly more likely to acquire HIV than the women who received the other two contraceptive methods. The results were so profound that the WHO promptly scheduled a meeting to review its recommendations for contraceptive methods among women at risk of contracting HIV.
But in the days leading up to the WHO's meeting in late July, two separate critiques raised serious questions about the ECHO trial. The first, published in the peer-reviewed journal Global Public Health, argued that ECHO violated medical ethics guidelines set out by the Helsinki declaration of 1964.
The second, an open letter signed by African doctors and advocates, argued that the ECHO results should not be used to perpetuate near-exclusive use of DMPA-IM in Africa, where the hormone shot has been misused as an instrument of social control -- most notoriously as part of a forced contraception program in apartheid South Africa.
In the wake of these critiques, ECHO investigators were swift come to the trial's defense, with WHO's James N. Kiarie, MBBCh, MMed, M.P.H., asserting "the highest global standards for research ethics, human subjects protection, and rigorous clinical trial conduct" and that any pending recommendations will be "grounded upon internationally agreed human rights principles and statutes."
Yet ECHO investigators also acknowledged that the trial has been a lightning rod from the start, because it sits at the nexus of two critically important public-health issues among African women: contraception and HIV.
"ECHO itself as a trial was extraordinarily challenging to propose and then execute," said Jared Baeten, M.D., professor of global health at the University of Washington and one of the lead investigators of the ECHO trial. "There were many critiques before the study started that it could not be done … and then, of course, there were questions of whether it should be done.
"To imagine that all of those challenges would dissipate completely when the study was over," he said, "I think no one could imagine that there would be no continued questions."
Open Letter Questions ECHO Implications, WHO Response
The open letter, published on July 25 and signed by sexual and reproductive health advocates from 12 African countries, cautioned the WHO against jumping to the conclusion that DMPA-IM is unequivocally safe.
"The letter was inspired by our concern that the trial was supposed to be some form of finality to the question of whether HIV acquisition is increased by the use of this hormonal contraceptive," said said Tlaleng Mofokeng, M.D., sexual and reproductive health and rights expert and the lead signatory of the open letter. "The WHO mustn't rush into a reclassification based on ECHO."
According to Kiarie, the WHO's recommendations will consider "all new evidence published since 2016 on possible association of HIV acquisition with hormonal contraception and intrauterine devices and HIV."
The open letter also questioned the study's methodology and why investigators chose to use certain thresholds to indicate "significant" HIV risk. But mostly, it argued that African women deserve to be informed of the risks and be given greater agency when it comes to contraception options.
"My concerns around [DMPA-IM] go beyond the study," said Mofokeng. She and the co-signers worry that the results of the study will be used to sweep ongoing, serious concerns about DMPA-IM under the rug.
Women in South Africa are not properly informed about the risks of DMPA-IM, and they are not given other options, Mofokeng said. In fact, women simply refer to the contraceptive method by its nickname -- "three months" -- because women are not told what the shot is actually called or how it works, only that they need to come back to the clinic every three months for an injection.
Mofokeng also noted that among doctors and patients in local communities, there is an overwhelming sense that the global public health community prioritizes pregnancy prevention over HIV infection prevention. She explained that many women feel that HIV prevention options are sparse, while DMPA-IM is foisted upon them.
Baeten says that ultimately, he and Mofokeng want the same thing: more contraceptive and HIV prevention choices for women, and better information about the risks associated with each of those options at the community level.
"My biggest fear coming out of ECHO is that the status quo remains," said Mitchell Warren, executive director of AVAC, an HIV prevention and reproductive health advocacy organization. "Everybody coming into family planning clinics in those countries should be offered oral PrEP [pre-exposure prophylaxis]," he said.
Global Public Health Article Questions ECHO's Ethical Conduct
On June 24 -- eleven days after the ECHO study results were published in the Lancet -- a scathing critique of the ECHO study was published in Global Public Health. The article was written by C. Sathyamala, Ph.D., a public-health physician and epidemiologist with the International Institute of Social Studies, Erasmus University Rotterdam, Netherlands.
The main thrust of Sathyamala's critique was that the ECHO trial lacked clinical equipoise, an ethical principle stating that investigators should only assign patients to different treatment arms randomly if it's unclear which arm will have worse outcomes. Sathyamala pointed out that ECHO investigators already suspected that women in the DMPA-IM would be more likely to acquire HIV, yet the informed-consent documents explained to volunteers that "the main goal of the ECHO study is to see if the risk of getting HIV is different with three different contraceptives."
Sathyamala wrote, "it cannot be denied that one-third of the trial participants who received Depo-Provera were knowingly subjected to a drug with potentially fatal outcome." She also took issue with the recruitment methods, alleging that the incentives used as part of the recruitment strategy amounted to coercion.
The ECHO investigators disputed these allegations in the strongest possible terms. Sathyamala declined an interview request.
"This article, frankly, did surprise us," said Helen Rees, M.D., executive director of the Wits Reproductive Health and HIV Institute and one of the lead investigators of the ECHO trial.
From the start, ECHO investigators were careful to solicit input on the study design from the community, according to Dázon Dixon Diallo, D.H.L., M.P.H., founder and president of SisterLove.
"What the ECHO trial did that hadn't been done before was [solicit] a deep level of community engagement," she said. "A large part of that trial design was inspired by women who are in the HIV community and women who are on contraception."
Rees and Baeten said that women who participated in the ECHO study were more thoroughly informed and consented than Sathyamala implied.
Kiarie added that a data safety and monitoring board (DSMB) met four separate times during the course of the study, noting that "if metrics had suggested lack of equipoise, the DSMB would have recommended that the study cease."
"Serious scientists from Africa, the U.S., and the WHO probably put more thought into the design of this study -- the ethics of it -- probably than ever before," said Rees. "Both Jared and I have been researchers for many years. When something is going wrong, people do report it. We didn't have a single report from any site."
Beyond the Backlash
Although these two critiques of the ECHO study hail from different corners of the advocacy world, they are united by the "red hot" context in which the ECHO trial takes place, said Warren.
"What's common about both of these is that this trial has been shrouded in controversy -- not because of the trial, but because of the issues," Warren said, noting women in Africa are facing assault from multiple fronts -- the coercive use of DMPA-IM and the unacceptably high rate of HIV infection.
The history of DMPA-IM has been so traumatic that, counterintuitively, some reproductive health advocates hoped ECHO would show an increased risk of HIV -- data that might disqualify DMPA-IM as a feasible contraceptive option moving forward, Dixon Diallo said.
"What they found is that it is equal to the others," she said, in terms of its HIV risk. "That is actually good news for women's reproductive rights advocates." Now, advocates have evidence to argue that women should be offered multiple contraception options "and allow them to choose what's best."