6 AIDS Patient Deaths May Renew Drug Debate

Six AIDS patients taking the experimental drug DDI have died of pancreatitis, a known toxic effect of the medication, in the five months since the federal government made the drug available to thousands of patients early in the research process.

The deaths and other life-threatening DDI complications are likely to trigger renewed debate about the wisdom of providing severely ill patients suffering from AIDS, cancer or other diseases with access to promising but unproven drugs before their safety and effectiveness have been firmly established in rigorous clinical trials.

Five of the deaths have occurred among the 8,000 patients who are receiving DDI, or dideoxyinosine, as part of an unprecedented, expanded access program approved by the Food and Drug Administration, according to Bristol-Myers Squibb Co. of New York, the drug’s manufacturer. The other death occurred in one of the 700 patients participating in government-sponsored clinical trials of the drug.

“It is extremely unfortunate that anyone has gotten sick enough to die,” said Dr. Anthony S. Fauci, the director of AIDS activities for the National Institutes of Health. Fauci stressed, however, that “toxic side-effects, some of which will be serious,” were not “unexpected,” particularly in critically ill AIDS patients, when the FDA approved expanded access to DDI in September, 1989.

Clinical trials typically compare patients receiving a medication to comparable patients who either receive a different dose of the medication, another medication, or no medication. Such comparisons allow the benefits and toxicities of a new medication to be accurately determined.

The wide availability of DDI outside of such trials has been seen as a model for the federal government’s soon-to-be-launched “parallel track” program. This program is expected to further expand the availability of experimental AIDS drugs for individuals unable to participate in formal studies.

Fauci said the FDA and Bristol-Myers needed to take “a very close look” at the deaths and other life-threatening adverse reactions.

They “may want to reconsider whether expanded access for this drug is appropriate or whether it should just be distributed through formal trials,” Fauci said. But he added: “I must state clearly, I don’t know if we’re at that point with DDI.”

In a statement, the FDA said that it had been informed of the deaths and had asked Bristol-Myers to provide “in-depth information . . . as soon as possible” so that it can be determined if changes are needed “to make the ongoing (research) protocols as safe as possible.”

The FDA also said it has asked Bristol-Myers to send a “Dear Doctor” letter to physicians nationwide caring for patients receiving DDI, “providing them and their patients with the best available information about this situation and urging them to monitor their patients closely for signs of pancreatitis.” The company said it was preparing such a letter.

In total, there have been 44 reports of pancreatitis, including the six fatalities, in patients taking DDI, according to Kathryn R. Bloom, a spokeswoman for Bristol-Myers. Pancreatitis is an inflammation of the pancreas, a 5-inch-long digestive organ located in the back of the abdomen. Severe cases can lead to kidney failure, respiratory failure and death.

Two other patients receiving DDI have suffered cardiac arrests, apparently related to low concentrations of potassium or magnesium in the circulation, Bloom said. Both these patients were successfully resuscitated.

“We don’t know that these deaths have been caused by DDI,” Bloom said. “We’re not talking about a lot of patients overall” who have died or suffered adverse effects.

Nevertheless, Bloom said, “We are taking this very seriously.” She said that in addition to the informational letter for physicians, “analysis is now under way to see if this is linked to a dose level, or the length of therapy, or a drug interaction.”

Bloom added: “This is a strong drug that is fighting a strong illness. These are critically ill patients, patients who may be near death and who can’t take the only drug (AZT) that’s been approved for their condition.” The expanded access, or “Treatment IND,” program for DDI is designed to make the experimental drug available to patients with advanced cases of human immunodeficiency virus infection who are ineligible to participate in formal research studies. This includes patients who are medically unable to take AZT.

When expanded access to DDI was approved last fall, eight non-fatal cases of pancreatitis had already been reported among about 100 AIDS patients who had received the drug, according to government statistics. Many of the patients who developed pancreatitis, however, were receiving far higher doses of DDI than those approved for widespread use.

The interpretation of these and subsequent pancreatitis cases has been confounded by the fact that pancreatitis can be caused by factors unrelated to AIDS, such as excessive drinking and gallstones, as well as by medications frequently taken by AIDS patients, such as intravenous pentamidine, which is is used to treat Pneumocystis carinii pneumonia. In addition, the sicker patients become with AIDS, the more vulnerable they are to complications from any of their medications.

Other reported toxicities of DDI include severe nerve pains and numbness, seizures, confusion, diarrhea and low concentrations of minerals such as potassium and magnesium.

Dr. Robert Yarchoan, a senior investigator at the National Cancer Institute who has played a key role in testing DDI, said that pancreatitis was “a bigger concern” than other adverse reactions seen with the drug.

“I think (some of the other problems) are probably not related to the drug itself, but the pancreatitis most likely is,” Yarchoan said.

“Patients receiving DDI who develop abdominal pain (which can be the first symptom of pancreatitis) should probably stop the drug immediately and consult their physicians as soon as possible,” he said. They should also not drink alcohol and their physicians should try to avoid prescribing medications that might cause pancreatitis.

Fauci and other senior government health officials said that the DDI developments will not jeopardize the overall “parallel track” program.

Dr. James O. Mason, the assistant secretary for health in the Department of Health and Human Services, said: “That this happens is no surprise. . . . This will not affect the parallel track.”

Larry Kramer, a member of ACT UP (AIDS Coalition to Unleash Power), an activist group and a major catalyst for the recent changes in the drug regulatory process, said he was “reluctant to jump to any conclusions” about the deaths since “I have a number of friends making remarkable progress on the same drug.”

He added: “We must not forget: This is chemotherapy and people die from chemotherapy, no matter how useful the drug or how controlled the study. The choice still must be the patient’s and not the government’s, and I hope everyone remembers that.”

Marlene Cimons reported from Washington and Robert Steinbrook reported from Los Angeles