To the Editors:
In his interesting article, “The Shame of Medical Research” [NYR, November 30, 2000], Dr. David Rothman stakes out the ethical high ground concerning the conduct of clinical trials in third world countries, notably Africa and Asia, insisting that no research be carried out unless it includes “the best proven therapeutic method” (i.e., standard highly active antiretroviral agents as used in America). While admitting that the subject “has become a bitterly debated question,” Dr. Rothman doesn’t yield an inch of contested moral territory in his rebuttal to a letter from Dr. Barry Bloom [NYR, March 8, 2001], who raised some important practical issues, including the facts that 95 percent of the victims of HIV/AIDS live in the third world, and that Rothman’s idealism not only delays acquisition of important knowledge but forestalls provision of much-needed medical care.
A personal experience may shed some light on the debate, bearing the grim statistics in mind: over 20 million people have died since the beginning of the pandemic, and at the end of the year 2000, 36 million people in the world were living with HIV/ AIDS; moreover, nearly three quarters of this burden has decimated the impoverished countries of sub-Saharan Africa. From March 29–31, 2000, I co-chaired a consultation sponsored by UNAIDS and the World Health Organization in Harare, Zimbabwe, to consider the potential benefits of giving an antibiotic called cotrimoxazole to prevent certain complications of HIV/ AIDS that are common in Africa. Fifty-two representatives from fifteen countries, including experienced health professionals from the most heavily afflicted sub-Saharan African countries, attended the meeting. After three days of thorough discussion, the group unanimously approved and UNAIDS/ WHO posted on their Web site the recommendation that “cotrimoxazole should be used for prophylaxis in adults and children living with HIV/AIDS in Africa as part of a minimum package of care” (official publication is pending). The recommendation was based chiefly on the results of two placebo-controlled trials in Abidjan, Ivory Coast. Everyone at the consultation realized that generalizing findings from one city in one country to all of sub-Saharan Africa was somewhat tenuous, but generalize we did and for good reason. In recognition of the scant information available, the recommendation also called for “Monitoring and Evaluation” and “Further Research.”
UNAIDS/WHO and the African health care professionals are not deliberately withholding the “best therapeutic method”; they are trying to offer a stopgap, something that might benefit sick people until antiretroviral agents became available—in a setting where no treatment is the norm. During the closing session, I told the group that I would encourage use of the resources of the International Union Against Tuberculosis and Lung Disease (the world’s oldest and leading NGO in global tuberculosis control), which I as a past president was representing, to identify persons with HIV/ AIDS from among the tens of thousands of persons with tuberculosis in the African countries where the Union has programs or trials. (In most southern African countries, at least 50 percent of all patients with tuberculosis are coinfected with HIV; so half or more of the people with tuberculosis might profit from also receiving cotrimoxazole. But which half? HIV testing is necessary.) Since then, the Union has applied for funds to undertake the task of identifying those persons who are also HIV-infected and treating all of them with cotrimoxazole, including the costs of keeping careful track of these people to determine if it is beneficial or harmful—“research.” An important part of the proposal is to study whether increased use of the antibiotic in HIV-infected people affects its usefulness in those without HIV infection. Many experts fear that additional treatment with cotrimoxazole, which is already widely used in Africa, may diminish its effectiveness (or that of related drugs) against bacterial respiratory and diarrheal infections and malaria.
There is no doubt that this study could not be carried out in the United States, where cotrimoxazole is already the standard of care for the prophylaxis of Pneumocystis carinii pneumonia and other infections in selected persons with HIV/AIDS. Dr. Rothman and other purists will counter with their belief that anything less than the best is unethical. But the best is also unattainable; a year’s worth of proprietary antiretroviral drugs for a single patient costs around $12,000, and even if ongoing negotiations with the pharmaceutical industry are successful, they will still be much too expensive for the desperately poor African countries that need them the most, or for international aid agencies like the Union. The much-cheaper generic substitutes from Brazil and India are attractive, but they are a source of considerable and as yet unresolved controversy, and it remains to be seen if the United States and other rich countries, which are going to have to foot much of the bill, will undercut their own drug manufacturers. Meanwhile, cotrimoxazole costs less than $25 per person per year; in addition, a system needs to be established for identifying persons living with HIV/AIDS and treating them with, first, cotrimoxazole and, then, antiretroviral agents as soon as they become available. Why not start now? Preventing needed research on the basis of high-minded moral principles that impede urgent medical care raises important ethical issues of its own.
John F. Murray, M.D.
Professor Emeritus of Medicine
University of California–San Francisco
San Francisco, California
David J. Rothman replies:
Upon first reading Dr. Murray’s letter, I suspected that the initiative he hopes to carry out in southern Africa involves treatment, not research. A subsequent conversation with him confirmed that impression. Essentially, he and his collaborating organizations, working in countries like Malawi and Mozambique, want to test patients already diagnosed with tuberculosis for HIV disease; and all who test positive will receive prophylactic doses of cotrimoxazole, an antibiotic commonly known as bactrim. The team will then conduct surveys to learn whether bactrim is as effective in Southern Africa as it is elsewhere in preventing complications of AIDS and whether the widespread use of the drug increases antibiotic resistance to a dangerous level.
Dr. Murray’s proposal presents no challenge to the views I offered or to the Declaration of Helsinki. He will not be conducting a trial that compares a group of patients receiving bactrim with a group receiving a placebo. Although he may well believe that a trial which gave one group the antibiotic and the other a placebo would answer the questions more quickly, he is not prepared to follow such a design in light of bactrim’s known efficacy. His intervention closely resembles the post-marketing research that pharmaceutical companies sometimes conduct after a drug is approved and is being widely used. To be sure, Dr. Murray will not be bringing antiretroviral drugs to the entire TB and AIDS population in southern Africa. But no one would argue that because he does not supply antiretrovirals, he may not deliver antibiotics.
Dr. Murray notes the recent efforts by companies in Brazil and India to sell generic versions of antiretroviral drugs at far below prevailing prices and in violation of the intellectual property rights of the original drug manufacturers. The annual per patient cost of these generics will drop from the US price of $16,000 to around $500. Several American drug companies have already reduced their prices and are likely to make even more significant cuts in the immediate future. As a result of all these changes, which reflect both humanitarian and self-interested motives, as well as those of AIDS activists and humanitarian medical organizations like Doctors Without Borders, therapies that heretofore were available exclusively in the first world may now be used in the third world. Researchers will no longer be able to claim that placebo-based trials of new cures for AIDS are ethical because advanced therapies are not available or affordable in developing countries. The status quo will not justify withholding known effective treatments. Thus, in practice if not in theory, we may be on the verge of making the ethical design of AIDS research universal.
May 17, 2001