A global health controversy erupted this summer when the prominent scientific journal Nature ran an article entitled “HIV trial attacked.” Within, commentators squared off over whether a huge ongoing study provides suboptimal and thus unethical treatment options to mothers with HIV in the developing world.
The multinational PROMISE study (for Promoting Maternal and Infant Survival Everywhere) is enrolling thousands of pregnant women with HIV in hopes of comparing mortality and other clinical outcomes between mothers who receive lifelong HIV therapy to mothers who receive shorter treatment durations if they have less advanced HIV disease.
Changing HIV Treatment Guidelines
When first designed, the PROMISE study answered a critical question: Do HIV-infected mothers with intact immune systems need treatment after they deliver their babies? Yet subsequent changes to HIV treatment guidelines from the World Health Organization have made at least some global health experts reconsider whether the question can still be asked and answered.
Two years ago, the World Health Organization (WHO) recommended that all pregnant mothers with HIV receive lifelong HIV therapy. While this recommendation aligns with United States treatment guidelines, which urge lifelong HIV therapy for all adults, it is more aggressive than the approach in most developing world countries where HIV therapy is reserved for patients with advanced disease.
Since the PROMISE study includes short-term HIV treatments for some mothers with HIV, countries in the developing world that are scaling up to meet the new WHO guidelines are asking a logical question: Is it ethical to provide mothers with HIV in a research study therapies that are not recommended by the WHO or in newly revised national HIV treatment guidelines?
From Dartmouth’s Geisel School of Medicine (where I see patients and conduct research), Dr. Paul Palumbo has shaped HIV treatment policy worldwide. A pediatrician, researcher, and leader in the IMPAACT clinical trials network that funds the PROMISE study, Palumbo believes the safety and efficacy of immediate and lifelong HIV therapy for new mothers are still unproven, and thus that the PROMISE study is important to complete. Palumbo is optimistic the PROMISE study – which is being conducted in the United States, too – will enroll its last subject by fall 2014, meaning PROMISE may yield important results before most developing countries are able to put the new WHO guidelines into effect.
By contrast, Professor Eligius Lyamuya, an ethicist and researcher at the Muhimbili University of Health and Allied Sciences in Dar es Salaam, Tanzania, told me that because the WHO has recommended immediate lifelong therapy as the standard option, “it would be difficult to justify [other approaches] ethically.” Lyamuya believes the fiscal and logistical challenges of delivering lifelong intensive therapy to African mothers do not justify restricting developed world-style HIV therapy to mothers in one arm of a research study.
These divergent viewpoints show how quickly HIV treatment is changing on the ground in Africa. A few years ago when the PROMISE study was first planned, the provision of lifelong HIV therapy to all mothers seemed impossibly ambitious, the WHO had not yet recommended immediate and lifelong therapy for all mothers with HIV.
Dr. Palumbo says the multinational PROMISE study has been evaluated and approved by dozens of country-specific community advisory boards. Each local community advisory group continues to oversee the study, says Palumbo, and can discontinue the study if it no longer matches local priorities and values. This is important in part because different developing countries have different national HIV treatment guidelines in response to different local feasibility of delivering HIV treatment to the people who need it.
“Engaging with the community is of critical importance,” says Dr. Rachel Vreeman, assistant professor at Indiana University School of Medicine and lead researcher for the massive AMPATH HIV treatment program in Kenya. Vreeman, who has studied community engagement in research in the developing world, says collaboration with local leaders is critical. She thinks PROMISE is an important study and that “honest, open, mutually respectful community engagement” is key to informing local reactions to the study.
Professor Mecky Matee of the Tanzanian National Ethics Review Committee agrees that local collaboration and oversight are critical. In light of ongoing efforts in Tanzania to provide lifelong HIV therapy to all mothers in accordance with WHO recommendations, the committee “was not in favor” of continuing the PROMISE study in Tanzania because local authorities felt the alternate treatment approaches assessed in PROMISE – that is, shorter treatment for those with less advanced disease – were “inferior.”
This situation is a great example of the complexity of global health research in a changing environment. To me, this kind of ethical complexity, which changes to a degree from place to place and from time to time, should turn us away from one-size-fits-all ethical pronouncements. Rather, a case-by-case, locally specific, informed conversation is the right way forward. Each country should decide on its own whether the PROMISE study meets local ethical and scientific standards. Tanzania may drop the PROMISE study, for instance, while another country like Zimbabwe may elect to proceed.
We should remember, too, the bad and good reasons why PROMISE became controversial. The bad reasons are that access to HIV treatments are still massively constrained in developing world countries compared to the United States and Europe, and millions of people die unnecessarily every year because of it. Without this egregious global health disparity, the controversy would not exist. Yet, progress in delivery of HIV care to developing world countries is driving change, and that good circumstance also contributes to the changing conversation about what is and what is not ethical in the developing world.
What is uncontroversial is that we all dream of a future in which effective HIV therapy is available to everyone who needs it, most particularly mothers with HIV and the babies they are so excited to see.