AZT trials in the Third World: Tuskegee redux or cheap shot?

The zidovudine (AZT) regimen used in the United States to prevent mother-to-infant transmission of HIV has not been feasible in the Third World because of its complexity and cost. But a U.S.-backed research initiative to test a simpler, less expensive regimen last year touched off a sharp debate about the ethical standards for clinical trials, particularly those in the Third World. The controversy centered on whether dire circumstances could justify putting the good of the community ahead of the welfare of individual patients--in this case whether the limited resources of the Third World justified the inclusion of a placebo control group in the AZT study of pregnant women with HIV.

Critics of the study design charged that the many infants whose pregnant mothers received placebos would die and that this amounted to another Tuskegee--the notorious government study of syphilis in which poor African-American men were denied treatment for their disease, even after the discovery of penicillin. Supporters of the study, on the other hand, argued that the trials had been requested by the host countries and vetted by review boards at every step. Given that the price tag of the proven AZT regimen (roughly $800 per person) put it out of reach of developing countries, the need for a less costly alternative was urgent. Supporters believed that only controlled trials could provide reliable and informative answers. Explains Dr. Louise Kuhn, assistant professor of public health at Columbia: If instead of a placebo every trial group received some dose of AZT, researchers would not know whether the transmission rates they found were actually lower than if the women had gotten no drug at all. Likewise, says Dr. Jane Pitt, Columbia associate professor of clinical pediatrics, results obtained using "historical controls" (basically records of untreated infected mothers in the past) would prove untrustworthy, primarily because HIV transmission rates have fluctuated considerably over time.

How did this complex issue fare in the media? The main wave of coverage began after the Sept. 18, 1997, New England Journal of Medicine published an editorial by executive editor Dr. Marcia Angell, who held up the AZT tests as a "retreat from ethical principles" and "not...very far from Tuskegee." The apparent double standard for poor people of color, the "sacrifice" of innocent babies, and the seeming arrogance of big Western medicine set off an outpouring of commentary. In the Washington Post, columnist William Raspberry, himself an African-American, seemed to see the Tuskegee allusion as part of a cautionary tale: "It is devilishly easy for good people with the best of intentions to slip into doing less than their ethical best--particularly when reputations and funding are at stake." Ellen Goodman, in her syndicated column for the Boston Globe, asked rhetorically: "Now I wonder, did we shut down Tuskegee? Or did we export it?" And in one of the bluntest indictments of the trials, Gracie Bonds Staples of the Fort Worth Star-Telegram, while admitting she didn't fully grasp their rationale, didn't hesitate to call their consequences "murder."

Defenders of the protocols were at a double disadvantage in the press, observes Dr. Ronald Bayer, professor of public health at Columbia. On the one hand, the suggestion that the trials were exploiting people of color "is an easy thing for the media to pick up"; on the other hand, the idea that there might be a good reason for "doing research in another part of the world that would be unacceptable in the U.S. is very difficult to convey."

Several Columbia professors interviewed condemned Dr. Angell's use of the Tuskegee analogy, calling it "irresponsible" or "inflammatory," but they appreciated its impact on the media. "The New England Journal is so highly regarded that if a senior editor like Dr. Angell publishes a strong and controversial view such as this, many in the press are likely to report on it as something to take very seriously, if not as actual gospel," says Dr. Allan Rosenfield, dean of Columbia's Mailman School of Public Health and DeLamar professor of public health and of obstetrics/gynecology.

Dr. Rosenfield notes that news stories triggered by the resignation of two prominent members of NEJM's editorial board in protest against not being informed beforehand of Dr. Angell's editorial helped call the public's attention to the respectability of the opposing view. In fact, one of them, Dr. David Ho, director of the Aaron Diamond AIDS Research Center and Time's 1996 Man of the Year, wrote an essay for that magazine in which he said the Tuskegee comparison was "unfair, and could make a desperate situation even worse." One can debate the decisions made about this study, says Dr. Rosenfield, but they were made in good faith, and the analogy to Tuskegee was simply inappropriate.

Dr. David J. Rothman, Schoenberg professor of social medicine at Columbia's College of Physicians & Surgeons, who describes himself as generally critical of the design of the trials, sees a positive result from the media's role. "The issues were very complicated, very messy," he observes. "The news stories I saw, with a handful of exceptions, were informative, although they didn't always take you in depth into the detail of the protocols." Nonetheless, the attention generated by these stories and the many editorials helped "force a reconsideration of the ethics of the trials. Moreover, without all the press coverage I don't think we would have seen drug companies...changing their pricing policies," as one major manufacturer has done. "In the end, the press did its job well."

As a practical matter, in February of this year the placebo debate became moot: In response to promising data from a study in Thailand, the CDC ordered that U.S. government-sponsored trials to eliminate the placebo arms and give all participants some dose of AZT. Even supporters of the original trials are now looking forward to this next stage of research. They want it understood that their position on placebo use recognized the realities of Africa. Yet, they say, that does not mean that they ever simply accepted as immutable fact the vast disparity between rich and poor countries, whereby many babies are doomed while the more fortunate are spared by prophylactic treatment. On the contrary, they insist, it is all the more imperative that as alternative therapies are shown to be effective, Western countries--and pharmaceutical companies in particular--pledge to make treatment broadly available in the Third World. That, all parties agree, was the goal from the start. --Kim Dalton

Related links...

KIM DALTON is a health editor and free-lance writer in New York City.

Photo CreditsPhoto: AP/Wide World Photos