Scientific American, 7/98, Tim Beardslay (staff writer), page 86
Coping with HIVs Ethical Dilemmas
The issues are many and thorny
AIDS has challenged ethical precepts from the earliest days of the pandemic, and it
continues to pose agonizing dilemmas in countries rich and poor. AIDS patients and others
infected with HIV, the AIDS virus, face discrimination of various sorts the world over,
and the high cost and long-term nature of treatment aggravate quandaries that occur to a
lesser degree in other serious diseases. Major battles revolve, in particular, around
ensuring access to therapies and testing new ones in an ethical manner.
Fear of contagion has sometimes led to discrimination against HIV infected people not only by the public but also by medical personnel, and some related legal struggles from the early days of the epidemic continue. This summer the U.S. Supreme Court should rule on an appeal from a dentist who refused to treat an HIV infected woman in his office. She successfully sued, alleging discrimination under the Americans with Disabilities Act. The case could change the legal interpretation of disability.
Yet discrimination is only one of the ethical issues that HIV has raised for medical professionals and society. The best available therapy, which usually combines three drugs that suppress viral replication, must be continued indefinitely and costs more than $10,000 a year. Although states have instituted assistance programs to provide anti-HIV drugs to those who would otherwise be unable to get them, the funds are limited, and so the poor have less access than those with good insurance policies.
Money is not the only obstacle to equitable care. Triple therapy involves taking a minimum of eight HIV fighting pills (and frequently many more) a day on an often complex schedule, in addition to any other medicines the individual might need. Patients who fail to follow the directions risk encouraging the proliferation of drug-resistant virus in the body, making subsequent treatment more difficult and increasing the risk that the patient will pass resistant virus to others. Physicians therefore sometimes advise against triple therapy for patients who seem unlikely to adhere to the regimen dutifully "Compromises are made," says Douglas D. Richman of the University of California at San Diego School of Medicine, an expert on drug resistance in HIV
Advances in therapy in the past two years have also raised ethical issues that are now affecting the conduct of clinical trials. Physicians have learned that no anti-HIV drug works for long by itself and that solo use of a drug promotes resistance to it. Therefore, biomedical ethicists agree it is no longer appropriate to conduct long-term trials of any single drug in HIV infected patients in the U.S. The need to maintain high ethical standards has thus greatly increased the complexity-and cost-of new trials: Ethical agreement has been impossible to find in a bitter argument over the propriety of rich countries sponsoring in poor countries studies that would be unethical at home. The controversy erupted in 1997, when Peter Lurie and Sidney M. Wolfe of Public Citizen's Health Research Group insisted that certain research being sponsored in developing countries by the Centers for Disease Control and Prevention and the National Institutes of Health, as well as the Joint United Nations Program on HIV/AIDS, was unethical and exploitative. The studies were aimed at learning whether a short course of the drug zidovudine (AZT) or various other inexpensive therapies could prevent the transmission of HIV from infected women to their babies in several countries in Africa and Asia.
Lurie and Wolfe objected to the studies because scientists knew even before they started that zidovudine reduces transmission of HIV by about two thirds if the drug is administered in a regimen known as ACTG 076 (so called because a trial with this designation proved the regimen's value). In this protocol the drug is administered during the last 26 weeks of pregnancy, during delivery (by intravenous drip) and to the baby for six weeks after birth. But the regimen, which costs about $800, is too expensive for wide use in developing countries.
The disputed studies sought to determine whether a much less expensive course of zidovudine or other medication, given only during the last three to four weeks of pregnancy and costing no more than a tenth as much as the ACTG 076 protocol, could still achieve a worthwhile reduction in HIV transmission. Lurie and Wolfe objected to the decision to place some mothers in a control group in which they received only fake medicine that was of no value to their babies. They argued that instead of comparing a short course of medication with a placebo, the investigators should have compared the short course with the full ACTG 076 protocol to see how closely the two were equivalent.
Defenders of the trials, notably Harold E. Varmus, director of the NIH, and U.S. Surgeon General David Satcher, argued that by including placebos investigators could learn more-and more quickly-about the value of inexpensive treatments in reducing transmission. The placebos were necessary to learn the baseline transmission rates without treatment, because these rates vary in different parts of the world, for reasons that are largely obscure.
Moreover the defenders asserted, placebos would help identify any important toxicity of the drugs studied-not an insignificant concern, as anemia, one of the known side effects of zidovudine, is much more common in undernourished populations than in the U.S. The trials did no harm, Varmus and others pointed out, because the placebo-no treatment-was the standard of care in the countries under study. "Research does not create an entitlement," concurs Robert J. Levine of Yale University.
Lurie and Wolfe and their supporters were not satisfied. No foreseeable toxicity from zidovudine or other therapy could counterbalance the babies' lives that might have been saved by using the ACTG 076 protocol in the comparisons, they maintained. Other critics believe certain participants in the trials may not have given true informed consent.
Wendy K. Mariner of Boston University holds that trials such as the disputed ones can be ethical only if there is a plan at the outset to make the treatment available to the local population if it proves to be effective. In fact, there was no plan to provide it at the time the studies got under way, Mariner says. Yohana J. S. Mashalla, vice president of the Medical Association of Tanzania, faults the studies as exploitative, for setting out to demonstrate in developing countries the value of a therapy that might then be adopted in developed ones.
Right or wrong, one of the studies sponsored by the CDC, which took place in Thailand, did show in February that a three- to four-week course of zidovudine reduced transmission significantly-though not as much as the ACTG 076 protocol. Over the following weeks, agencies started supplying the short course of the drug to women in studies around the world who had previously received only a placebo. The manufacturer of zidovudine, Glaxo Wellcome, then announced that it would cut prices of the drug for developing countries. But as of May, it was unclear how many women who needed the medicine would gain access to it.
The question of when to use placebos represents a "genuine conflict" between getting the fastest answers to critical questions and the interests of today's patients, says bioethicist Arthur L. Caplan of the University of Pennsylvania. But in his opinion, as a researcher "you owe something to your subjects-you owe them the best options."
One "underused tool" that could provide patients with better options is wider application of innovative statistical designs, according to Christopher R. Palmer of the University of Cambridge. Mathematically rigorous data-dependent designs for studies can, in some cases, provide firm information on the effectiveness of a therapy while exposing fewer patients to suboptimal treatment than a conventional trial would. During a data-dependent study, the health of the participants is continually analyzed. The accumulating evidence about the different treatments modifies the odds used to select which therapy the next participant will receive.
Data-dependent designs are as yet little used, partly because many medical statisticians are unfamiliar with the specialized math involved. But they are often ethically attractive for late-stage studies on serious diseases, Paliner notes.
The dilemmas of research on HIV will become especially acute when candidate HIV vaccines become available for large-scale trials. Because triple therapy is the standard of care in the industrial nations, some, including Lawrence O. Gostin, law editor of the Journal o f the American Medical Association, say researchers have an obligation to provide it to all participants in vaccine trials who become infected. Vaccine manufacturers, though, may well blanch at the cost of supplying triple therapy even temporarily for thousands of enrollees.
HIV will continue to tax society's conscience until inexpensive, highly effective therapies and vaccines are available for all. And that day can come only through more research. Meanwhile the desperate souls who sign up for a trial of a new drug or vaccine must do so knowing they are taking a risk-but perhaps a reasonable one that may benefit humanity's collective future.