Strings attached : for subjects in Haiti study, free AIDS care has a price
6 juin 1999 (New York Times)
PORT-AU-PRINCE, 6 June 1999 (New York Times)
A special report by NINA BERNSTEIN
The impoverished patients who step from the dirt sidewalk into the modern AIDS research clinic run by Cornell Medical College in Port-au-Prince, Haiti, are offered a seemingly simple arrangement.
"We would like to test your blood because you live in an area where AIDS may be common," the English version of the clinic’s consent form reads. "We will provide you with medicine if you fall sick and cannot afford such care."
But the transaction is not as straightforward as it sounds. Many Haitians who visit the clinic are at once patients and subjects of United States-financed medical research, and circumstances that are bad for their health are sometimes best for research results.
That conflict is especially true in Cornell’s most tantalizing research in Haiti, a study of sex partners, only one of whom is infected with the AIDS virus. Researchers, seeking clues to developing a vaccine, study the blood of both partners, particularly the uninfected ones who continue to be exposed to the virus through unprotected sex. They are trying to find out whether some people have natural protections against infection with the AIDS virus that could be replicated in a vaccine.
The Haitians are ideal research subjects, largely because they are not receiving the kind of care now standard in the world’s developed countries. Condom use is low in Haiti, for cultural and other reasons. Anti-retroviral drugs that are successful at suppressing the virus are unavailable except to the very wealthy, and are not included in Cornell’s promise to provide medicine.
Nearly 20 years after Cornell opened the clinic, it provides some of the best AIDS treatment available in a country devastated by the epidemic, fighting the myriad illnesses that result from AIDS. But that is a lower standard of care than patients receive routinely at American institutions, including the hospital affiliated with Cornell in New York City.
If the research were done in the United States, experts agree, the physicians would be obligated to prescribe the anti-retrovirals and deliver the most effective possible counseling against unprotected sex.
The ethical questions posed by Cornell’s work among Haiti’s poor are at the heart of a global debate about AIDS research that is roiling international health organizations from Geneva to Thailand, challenging ethics formulations established decades ago.
"It’s really like a Faustian bargain," said Marc Fleisher, a member of the committee at Cornell that reviews research on humans. "It’s like, since we’re making this a better place, we’re going to exploit it in a way we could never get away with in the United States," said Mr. Fleisher, the outside member on a board made up mostly of university employees who are doctors.
Cornell doctors defended the couples study as vitally important and stressed that its subjects receive the same counseling about the dangers of AIDS and the same care as other patients at the Haitian clinic.
United States standards for research on humans were strongly influenced by outrage over the Tuskegee syphilis study earlier this century, which misled impoverished black subjects for years while tracking their disease, and withheld treatment even after penicillin was discovered.
Today’s subjects are not to be pressured to participate in research, according to Federal regulations. They are to be fully informed about the research’s purposes and risks. They must receive the best available therapy for their illnesses and be told about any findings relevant to their health.
In theory, the same rules apply to federally financed studies overseas. But an examination of 15 years of records related to the Haiti couples research shows that it has received scant scrutiny from Government officials in Washington.
And the Government’s rules barely address the moral ambiguities of AIDS research in indigent countries.
Should participants receive the best treatment available in the United States or in Haiti, one of the poorest countries on earth ? How forcefully should researchers who are documenting the progress of the AIDS virus warn subjects about the dangers of rejecting condoms ?
Dr. Warren D. Johnson, the chief of international medicine and infectious diseases at Cornell, called the couples study "a very high priority," though he said it had been temporarily suspended while the university concentrated on other research in Haiti. "This is the critical group in the world — couples — that’s where the war is to be fought," he said.
At least 97 couples have been enrolled in the blood study since 1991, records show, but Dr. Johnson said only 30 couples are still being followed. The study will be expanded to new couples early next year, he said, and coordinated with AIDS vaccine trials, which are expected to start in Haiti this fall using similar couples as subjects.
Cornell’s clinic in Haiti offers strong inducements to subjects. It is the only center in the country providing free screening and treatment for H.I.V., venereal disease and tuberculosis, a common complication of AIDS. The thousands who flock to it are too poor to buy food, let alone the simple medicines and vitamins that serve as "a powerful incentive for study participation," in the words of one Cornell grant report.
The head of the clinic, Dr. Jean William Pape, is a Haiti native and Cornell professor who has studied AIDS in Haiti for two decades. Dr. Pape, who trained at Cornell, defended the treatment of research subjects in the couples study, saying they benefited from the same counseling and free condoms available to everyone who visits the clinic.
Dr. Pape said that offering the life-saving drugs to the handful of research subjects would be an unethical lure to participate. Treating all H.I.V.-infected citizens, he said, would cost 10 times Haiti’s health budget.
If the research on couples succeeds, he said, it could help lead to a vaccine against AIDS. "You have to take into account people who mean well for their country and not impose on them things that you feel are good for Western ideas," he said.
The Research : Tracking the Path Of an Epidemic
Cornell’s presence in Haiti dates from 1979, when Dr. Pape returned to his native land and took a job at a pediatric hospital where 40 percent of the babies were dying of endemic diarrhea.
"A man would come to pick up the bodies three times a day, with a big bag," he recalled, bending his tall frame in a scooping gesture. "The noise of the skulls in that bag was unbearable."
Using the latest treatment, oral rehydration, Dr. Pape cut the death rate to 1 percent. But the next year his Haitian colleagues asked him to help fight an enemy that would prove far more formidable.
Adults were mysteriously falling ill with persistent diarrhea, harbinger of a new, deadly disease. Suddenly, Dr. Pape and Cornell found themselves on the front lines in the fight against a global epidemic : acquired immunodeficiency syndrome, or AIDS.
Dr. Pape had the credentials to lead the effort. Part of an elite Haitian family long prominent in medicine, he had received an undergraduate degree from Columbia University and a medical education from Cornell. Supervised by Dr. Johnson, his Cornell mentor, Dr. Pape set up a local group to study the new disease and soon won Federal financing. In 1985, Cornell was awarded a major Federal grant to conduct a study, "The Natural History of H.I.V. Infection in Haiti." A succession of these five-year grants eventually brought Cornell more than $7 million in research money and hundreds of thousands more in related training grants.
The studies produced some important early findings. Researchers dispelled an early theory that Haitians were unusually vulnerable to the disease. They also helped show that AIDS could be transmitted through heterosexual contact.
AIDS testing at the research clinic followed the United States model of the mid-1980’s. Haitian patients with the virus, mostly heterosexual men, were offered condoms and counseling. It was left up to patients to inform their sexual partners, and at least 60 percent never did so, researchers said.
The hope was to get Haitians to practice protected sex, but by the early 1990’s it appeared this approach was not working. Dr. Pape said the data persuaded him that only a vaccine could stem Haiti’s epidemic, then speeding from high-risk men to women whose only risk was an unfaithful partner.
Looking closer at several hundred couples in which only one partner was infected, he found that AIDS was transmitted annually in about 7 percent of the couples having unprotected sex. That was about twice the rate of similar couples in the United States and Europe, but even so, it suggested an unexplained resistance to infection.
The Haitians were valuable for another reason. Unlike AIDS patients in the United States and Europe, they were not receiving the anti-retroviral drugs that proved effective in halting the disease’s progress.
The lack of those drugs "may allow identification of novel findings not easily studied in the U.S.A.," Dr. John L. Ho, a Cornell immunologist, wrote in an application for Federal funds. In 1995, the Federal Government awarded Cornell an extra $60,000 to expand this part of the Haitian couples study.
Grant records show that by 1996, 5 of the 31 previously uninfected partners studied most closely by Cornell tested positive for the AIDS virus. But Cornell’s blood tests found something to ponder : In two of the cases there was a substantial delay between transmission of the virus and actual infection — 11 and 49 months. And among those who still tested negative, it seemed in several cases that a version of infection had occurred but that the virus had disappeared again, at least temporarily.
Cornell researchers called these results, similar to findings by scientists elsewhere, "tantalizing" and "intriguing." They hypothesized that certain levels of sexual exposure to H.I.V. might be triggering an infection that blocked transmission, aborted infection or at least weakened the effects of disease — all clues to vaccine development.
Research plans approved last year include further study of 19 high-risk Haitian partners who still test negative for H.I.V. but show intermittent signs of the virus in their blood samples. Cornell researchers estimated that over five years, at least 36 partners would contract the virus. One report to the National Institutes of Health anticipated that 15 to 20 H.I.V.-infected women from the study would become pregnant each year. Those children, Cornell officials wrote, could be subjects for another study examining the high mortality rate of H.I.V.-infected infants.
The Subjects : Offering Counseling Of Its Own Design
Outside the gates of the research clinic at 33 Truman Boulevard, the dirt sidewalk is crammed with people by midmorning. Charcoal smoke, flies and sewage stench mix with cooking smells as vendors sell beans by the scoop to waiting patients.
Thousands of men and women have made their way to the clinic over the years, many desperate for relief from sickness, others sent by lovers to be tested for venereal disease and the AIDS virus.
All are potential research subjects. But the most interesting to science are patients like the couple identified in clinic records as No. 1986, a man with AIDS, and No. 1986C, his uninfected, pregnant wife.
Ethical standards for Federally financed studies require that patients be told why researchers want to study them. But the written consent form approved at Cornell and read aloud in Creole to each potential subject does not mention that the study focuses on couples in which one sexual partner has tested positive for H.I.V.
The form tells subjects their blood is being tested because "you live in an area where AIDS may be common." It promises all patients that H.I.V. test results will be kept confidential.
Dr. Pape said that in the case of the couples study, the clinic makes a practice of disclosing results of AIDS tests to the uninfected partners. He said they are informed orally by a doctor at the clinic that their spouse or lover has H.I.V.
Research subjects, Dr. Pape said, are given the same counseling about the dangers of AIDS as other patients. The clinic offers free condoms, and videos about protected sex are shown in the crowded waiting room.
Those who contracted the virus while being studied by Cornell "have no one to blame but themselves, because they were provided with everything," he said.
Researchers in Europe, the United States and Africa said consent forms and research outlines in comparable studies typically spell out detailed procedures for informing partners and dealing with the clashes that might arise. A joint consent form used as early as 1988 in Zambia, for example, specifies : "One of you is infected with the virus and the other is not," adding, "It is possible that during the study, the partner who was uninfected will become infected with the AIDS virus. This is distressing and can cause depression, anger and marital problems."
A review of Cornell’s materials found no written procedures for disclosing a partner’s infection, or for forcefully counseling partners as a couple about the dangers of their situation. Dr. Pape said study subjects choose to reject condoms even though they are fully informed of the risks. To demonstrate, he provided a one-page questionnaire dated Dec. 3, 1992. It belonged to patient No. 1986C, then three months pregnant.
"Are you still sexually active with your partner ?" it begins. The only record of the woman’s replies are a clinic worker’s check marks and scribbled notations. Yes, said the woman, she planned to continue having sex with her husband. No, they were not using condoms. No, she did not want a free supply. The reason was scrawled in English : "He does not like it and she’s afraid of condom."
The document, administered at three-month intervals to subjects gathered from their shantytowns by social workers paid by the United States, did not contain the word AIDS or H.I.V. It asked, "When have you been aware of the infection of your sex partner ?" The answering notation : "At entry into the study."
After reviewing clinic materials, Marie Saint Cyr, a native of Haiti who now directs an AIDS program for women in Harlem, said there was a "clear conflict of interest" between the desire to collect information from research subjects and the obligation to effectively warn patients at risk.
"If you know somebody is positive and is having sex with a partner who is negative, you have a life and death situation in front of you," she said. "You have to do individualized counseling to really tap into what those people value in life, to confront them with the reality of H.I.V. and AIDS. This in no way addresses those serious things."
The World Debate : Balancing Sickness And Science
When Cornell researchers came to Haiti to collect blood, they stayed high above the swarming slums of Port-au-Prince, at a colonial, gingerbread-style hotel called the Kinam, where purple bougainvillea spills over a sunlit swimming pool.
At a conference at the hotel in April 1998, the president of the National AIDS Council of France challenged Dr. Pape to rethink the way the disease is treated in Haiti, particularly in patients who are research subjects.
The French official, Dr. Alain Sobel, said the French Government could provide anti-retroviral drugs to Haiti, as it does already for nearby French islands like Martinique and Guadeloupe.
Dr. Pape, according to both men, replied that the multiple drug cocktail that had been so effective in treating the disease in developed countries could not be feasibly used in Haiti. The country’s health care system, he insisted, was not organized enough to properly distribute the drugs or make sure that patients too poor to eat regularly take a pill before or after certain meals, as the demanding regimen requires.
Dr. Sobel did not disagree. But he argued that Dr. Pape’s clinic, with thousands of patients enrolled in various long-term studies, was the obvious place to make a start.
"They are really the only institution that can do this in Haiti," Dr. Sobel said later in a telephone interview from Paris. He said that since Cornell’s patients are participating in research, "they deserve to be treated."
Dr. Pape disagreed. Asked about this argument in an interview, he said offering such treatment to clinic patients would be "an inducement to become infected." He questioned how long a foreign government’s commitment to provide such expensive drugs — about $15,000 yearly per person — would endure in an economic or political downturn.
The clash between Dr. Pape and Dr. Sobel reflects a larger international debate over clinical trials in third world nations, which has intensified in the era of AIDS.
In 1997, The New England Journal of Medicine sharply criticized research in Thailand and Africa that gave placebos to pregnant women infected with H.I.V. as part of a search for a cheaper way to stop transmission of the virus to newborns.
The placebo trials were halted in February 1998, when one of the studies in Thailand showed that transmission could be prevented with a short course of the drug AZT costing as little as $50.
The finding came at a price. Pregnant women pass on AIDS to their children in about 35 percent of cases, and in the studies, half the women were given dummy pills, the others given much less AZT than in the proven regimen used in the developed world.
Dr. Marcia Angell, the editor of The New England Journal, had likened the trials to the Tuskegee study of syphilis, in which public health officials withheld effective treatment from a cadre of black men for 40 years.
Many research scientists defended the placebo trials as a shortcut to giving poor nations a new weapon against AIDS.
More recently, world health officials have clashed over how to test AIDS vaccines whose effectiveness is best assessed with subjects exposed to the disease and not treated with anti-retrovirals because of poverty.
"If in Malawi, why not Appalachia ?" asked Dr. David Rothman, a professor of social medicine at the Columbia College of Physicians and Surgeons. "You have serious investigators trying to do good, trying to save hundreds of thousands of lives, but I consider it ultimately destructive of the investigator’s integrity and the well-being of all of us to have an ethic of human experimentation that changes as it travels."
Dr. Pape said decisions about treating third world patients can be unusually complicated. For example, he was critical of a proposal by a United Nations group to give pregnant women at the Haitian State Hospital AZT last year.
That proposal, he said, did not address the problem of H.I.V. transmission through breast-feeding. The danger, he said, is that infected Haitian women who are told of the risks to their children will not nurse their infants. In a country where safe formula is a relative rarity, he said, this could put children at an even greater risk of death.
"The ethical issues sometimes are torturing me," he said.
Dr. Sobel attributed Dr. Pape’s lack of enthusiasm for anti-retrovirals at least in part to his commitment to developing an H.I.V. vaccine. In 1998, Dr. Pape became the principal investigator in a $619,000 Federal contract to prepare for preliminary vaccine trials in Haiti as early as this year.
"I told him this was completely utopic, since the vaccine is not ready and will not be ready for many years," Dr. Sobel said.
The experimental vaccines, which have been developed elsewhere, are at best only partially protective, many scientists say. Even so, Dr. Pape said he considers it crucial for Haitians to be among the first in line to test them to establish Haiti’s moral claim to an affordable supply of an effective vaccine when — or if — one is developed.
Dr. Frantz Large, the vice president of the Haitian Medical Association, which is collaborating on the plans for vaccine trials, called Dr. Pape a great patriot.
"He would never do anything unethical," Dr. Large said. "But if he had to choose between the survival of 10 people and the survival of a nation, he would probably choose the survival of a nation, and I would, too."
Oversight Agencies Give Program Scant Review
Cornell’s research in Haiti, like all Federally funded studies, is subject to extensive Government rules intended to protect patients from abuse.
Overseas projects are to be reviewed by two independent boards, one in the United States at the sponsoring university, the other in the country where the research is taking place. The boards, in turn, are overseen by the Office of Protection from Research Risk, which is part of the United States Department of Health and Human Services, as well as by Federal program officials who award the research grants.
But according to documents and interviews, Cornell’s research on couples in which one partner has AIDS has received scant scrutiny.
The review board at Cornell, for example, appears to have taken only a cursory look at the research procedures it renewed year after year for the couples studies. When Marc Fleisher, the outside member on a Cornell board made up mainly of university employees, was read the statement used at the university’s Port-au-Prince clinic to inform subjects about the study, he derided it as ’’doublespeak’’ and ’’just a lie.’’ He was unaware that he himself had twice approved the statement last year in board votes.
The impartiality of the local board in Haiti is in question. Documents show that its members include the husband of Dr. Marie-Marcelle Deschamps, one of the study investigators ; the mother of Dr. Jacques Boncy, who heads the research clinic’s lab, and Dr. Gladys Taverne, the psychologist who originally designed the clinic’s H.I.V. counseling.
Dr. Jean William Pape, the Cornell professor directing the research in Haiti, said there was no conflict of interest. But Dr. Tom Puglisi, a director in the Office of Protection from Research Risk, which approved the composition of the board, disagrees. ’’We would consider it a conflict of interest for a family member of an investigator to sit on the I.R.B.,’’ he said, referring to the Haitian institutional review board. ’’If that’s in there and we missed that, that’s something we should have caught.’’
Federal documents show that the Government failed to follow up when officials did discover flaws in Cornell’s research arrangements. Dr. Puglisi’s office demanded in 1996 that the clinic change the statement read to patients, making explicit that participation was voluntary and that counseling was available. Dr. Warren D. Johnson, the chief of international medicine and infectious diseases at the medical school, wrote back that the changes had been made. But because of what he called a paperwork oversight, this was not done.
No one noticed. The National Institutes of Health renewed Cornell’s overall Haitian research grant, now more than $786,000 a year, every year from 1985 through 1999. And in 1995, when Dr. Pape and Dr. John L. Ho of Cornell applied to the institutes’ Fogarty International Center to add money for expanded couples research to a $600,000 medical training grant, it was approved without conditions.
In March 1998, Dr. Rodney Hoff, a program official in the institutes’ Division of AIDS, raised questions about the consent procedures. Unaware that the expanded project was already under way, he barred Cornell from the research on human subjects until it revised the consent form. Since the revision, Cornell has suspended the research again, but Dr. Johnson said there were plans to resume and expand the study next year.
Should doctors sacrifice one life to save many ?
To the Editor :
Re "For Subjects in Haiti Study, Free AIDS Care Has a Price" (front page, June 6) :
You quote a Haitian Medical Association official’s description of the AIDS researcher Dr. Jean William Pape : "If he had to choose between the survival of 10 people and the survival of a nation, he would probably choose the survival of a nation." This statement is a measure of our medical and public health establishment’s failure to provide a grounding in the ethics of research. The fact that it was meant to praise Dr. Pape demonstrates how abject that failure has been.
Presumably, Dr. Pape and his Cornell Medical College colleagues all once worked for the survival of individuals, not nations.
We have failed if doctors and researchers can no longer recognize that their wagers on a future AIDS vaccine are covered with the lives of real people.
Bronx, June 8, 1999
Copyright (c) 2001 The New York Times Company
Cornell University : Dr. Jean Pape, Cornell Professor and Fighter Against AIDS in Haiti, Honored at the United Nations
New York, NY (Nov. 6, 2000) — Dr. Jean William Pape, a 1975 graduate of Cornell University Medical College and a Professor of Medicine at Weill Cornell Medical College (as it is now called), has been honored by United Nations Secretary-General Kofi A. Annan at a special ceremony in the General Assembly Hall. Mr. Annan, noting that he was "honoring heroes whose actions and courage makes the world a better place," praised Dr. Pape’s "achievements, courage, and inspiration in contributing to breaking the silence on HIV/AIDS."
Dr. Pape, who is also a professor at the State University of Haiti, has worked in his native Haiti since the onset of the AIDS epidemic in 1980. He is a founder of GHESKIO (Groupe Haitien d’Etude du Sarcome de Kaposi and des Infections Opportunistes), which has championed education, health care, and HIV research, and which has worked closely with Weill Cornell since its inception. He also directs, in concert with Weill Cornell’s Division of International Medicine and Infectious Diseases, a National Institutes of Health training and research program that focuses on HIV/AIDS, tuberculosis, and diarrheal illness. He is the lead investigator for an HIV vaccine trial that will be initiated later this year in Haiti.
"Among many other accomplishments, Jean Pape has mentored our medical students for invaluable clinical training in Port-au-Prince," said Dr. Warren Johnson, Director of Weill Cornell’s Division of International Medicine and Infectious Diseases. "No one could be more deserving than he is of this recognition at the U.N."
Dr. Pape was also honored in May of this year by the Haitian-Canadian Cator Foundation as one of 10 Haitians who have made outstanding contributions to the country. In 1996, GHESKIO and Dr. Pape received a special commendation, Dr. Leon Audain’s Prize, from the Haitian Medical Society for their work in the prevention and control of HIV/AIDS.
Honouree : Jean William Pape
Dr. Jean William Pape has taken on the challenge of HIV/AIDS in Haiti, where the Ministry of Health estimates that 5.4 percent of adults are currently HIV-positive and that by the end of 2000, AIDS will leave over 200,000 Haitian children orphans.
In 1980, after graduating from Cornell Medical College in the US, Dr. Pape returned to Haiti to set up Cornell’s unit at Hopital de l’Universite d’Etat d’Haiti. A trained scientist, Dr. Pape was asked to consult on new cases of adults with intractable diarrhea. These cases turned out to be the first recognized AIDS patients in Haiti. In 1982, Dr. Pape, in collaboration with several other health care professionals, founded GHESKIO, the first institution in developing countries, the second in the world, dedicated to the care of AIDS patients.
GHESKIO is the only institution in Haiti providing health care workers with post-graduate training in HIV/AIDS care, treatment and prevention while also providing research and study on tuberculosis and diarrheal diseases and offering patients counseling and reproductive health services. Beyond the medical community, more than 2000 social workers, religious and community leaders have received training through the center. Under D. Pape’s leadership, the centres provide integrated systems of care to more than 100,000 patients each year. To deliver equitable services to all sectors of the population, GHESKIO does not charge for either care or medications.