DDI RISKS: PERSPECTIVE AND PRECAUTIONS

Recently there has been much publicity about the risks of using the experimental AIDS treatment ddI. Some of the reporting has been misleading and unnecessarily frightening. But some risks are real, and experts recommend simple precautions that anyone using ddI should begin immediately.

Background

ddI is an antiviral in the same general class as AZT. It may be about equally effective, although no one knows for sure until trials are completed. There is much interest in ddI, not because it is believed to be better than AZT, but because the toxicities of the drugs are different, and also because ddI may work even after AZT has become less effective, as it does for some patients after a year or two of use. ddI is important because it provides another therapeutic option, with its own profile of risks and benefits.

Three major clinical trials (named ACTG 116, ACTG 117, and ACTG 118) are now testing ddI. In addition to these formal trials, Bristol-Myers, the company developing the drug, has made it available without charge through an expanded access programs to patients who cannot enter the formal trials and cannot use AZT -- persons with no other treatment options. At this time, about 700 people are in the formal trials, and about 8,000 additional people are receiving the drug through the expanded access program.

On March 4-7, hundreds of AIDS researchers from around the country met near Washington, DC, at a conference of the AIDS Clinical Trials Group (ACTG). This quarterly meeting is closed to the press and the public, but important news gets out. At this meeting, physicians heard the latest safety reports on the ddI trials and expanded access program, and exchanged information about their own experience with the drug. They learned that at least one patient in the formal trials and six in the expanded access program have died of pancreatitis, believed to have been caused by ddI. This death rate is about one in a thousand for both programs. (Over 30 non-fatal cases of pancreatitis have also been reported.)

The total deaths from all causes (including the pancreatitis) is 2 of the 700 in the formal trials, and 290 of the 8,000 in the expanded-access program. While the data has just begun to be analyzed, this difference in death rates between the formal trials and the expanded-access program is almost certainly caused by the fact that many of the patients receiving the drug through expanded access were more seriously ill. Patients selected for trials are usually well enough to be expected to survive the trial, whereas many enter the expanded-access program as a last resort. There is no evidence that ddI contributed to these deaths (other than those caused by pancreatitis), and no reason to believe that receiving the drug was any more risky in the expanded-access program than in the trials. The safety monitoring is similar in both programs.

Researchers suspect that ddI did contribute to the pancreatitis deaths, because the very severe and rapidly developing pancreatitis had not previously been expected with AIDS. Other drugs or diseases may also have contributed; intravenous pentamidine, for example, can also cause pancreatitis. All data from these cases will be analyzed to determine (1) if there is a dose-response relationship, with those receiving more drug per body weight at greater risk, and (2) if any cofactors, such as other drugs, were present more often in those patients who did get pancreatitis than in those who did not. If the answer to either question is yes, then ddI could be used more safely by adjusting the dose, or by stopping or not using the drug if any dangerous cofactor is present.

The much larger number of deaths from other causes will also be investigated, especially to see whether ddI may have contributed to any of them.

Precautions

The FDA has asked Bristol-Myers to write to all physicians who are using ddI, to inform them of recommended precautions. Meanwhile, the Los Angeles Times quoted Robert Yarchoan, of the U. S. National Cancer Institute, on precautions patients should take now. Dr. Yarchoan has run the longest clinical trial of ddI, at the National Cancer Institute, and is probably the world expert on use of the drug.

"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. They should also not drink alcohol, and their physicians should try to avoid prescribing medications that might cause pancreatitis." (Dr. Yarchoan, quoted in the Los Angeles Times, March 10, 1990.) Other experts have noted that anyone on ddI who
develops pneumocystis and must be treated with intravenous pentamidine should stop using ddI while on the pentamidine.

A major problem in treating the pancreatitis believed to be caused by ddI is that it can progress so rapidly that it is difficult to diagnose in time. Other researchers have recently made progress in diagnosing serious pancreatitis, for example by tesing for trypsinogen activated peptide in the urine. We do not know if this test is yet available, or if it would be useful in the ddI trials or expanded-access program.

Perspective

Before the above information about the risk of ddI was available, AIDS TREATMENT NEWS had heard both good and bad reports about the drug, but mostly good. ddI seems to have made a dramatic difference for many people; we suspect that many who are now alive would not be without it. We had also heard of a number of cases where people had to stop using this drug because of side effects.

Dr. Yarchoan told The Wall Street Journal (issue of March 12) that it was "absolutely necessary to go forward with phase 2, or effectiveness studies," the formal clinical trials mentioned above. "Only then can you put the toxicity in the context of benefits and go on."

Drug-development experts consider this finding of toxicity with ddI not at all unusual, except for the fact that this drug
trial is being conducted in a fishbowl of public attention. Initial studies gave the drug to only a few dozen people. Problems which rarely occur would not be likely to show up until later trials, when more patients are receiving the drug.

News of the deaths in the ddI program was published in the Los Angeles Times on March 10, and in The New York Times, The Wall Street Journal, and the Washington Post on March 12. These four newspapers are especially important, because most of the press follows their lead in selecting and framing the news. The coverage in The New York Times was more negative and alarming than that in the other three, and it has been widely criticized. Later articles, in The Wall Street Journal on March 13, and The New York Times on March 19 put the risks in better perspective.

Despite the new information about the risks of ddI, we still consider ddI to be one of the most important new treatment possibilities. It would be tragic to lose this drug -- or to lose the concept of parallel track or early access to treatment -- due to hasty decisions not based on careful assessment of all the facts.

Note: the related drug ddC has not been found to cause pancreatitis.