DDI EARLY RESULTS

Two separate reports of small trials of ddI appeared in the May 10 New England Journal of Medicine. These papers are unrelated to the current trials of ddI, and to the expanded access program under which several thousand people have been treated with the drug. Instead these papers describe earlier "phase I" studies: one at New York University, the University of Rochester, and the National Institutes of Health, the other at two medical centers in Boston (in order to distinguish, we will call them "the New York study" and "the Boston study" in this article).
The results of these studies have already been used (before they were formally published) in the design of the current phase II trials and the expanded access program; therefore there are no big surprises. But some of the information now published may be useful to persons taking or considering ddI.
In the same issue of the Journal, an editorial by Anthony Fauci, M. D., director of the National Institute of Allergy and Infectious Diseases (NIAID), compares and evaluates the studies. Both of them reported a number of different indications that the drug was working: T-helper increases, p24 antigen decreases, improved hematological measures, and substantial weight gain and energy level increases. In the Boston study, which used less ddI and gave the drug only once a day, 11 patients had had mild peripheral neuropathy before they started the ddI; this symptom resolved for eight of the 11 while they were using the drug. (Since peripheral neuropathy can be a side effect of ddI, it is interesting that peripheral neuropathy due to HIV infection would improve during treatment with the drug.) P24 and T-helper improvements were seen even at the lowest doses -- adding to the increasing suspicion that the doses of ddI now generally used (in the clinical trials and in the expanded-access program) might be
too high.
The most serious side effect of ddI is pancreatitis, which has caused several deaths among the several thousand patients who have used the drug. In the New York study, which gave the larger total doses of ddI, five of 37 patients developed pancreatitis. In the Boston study, only two of 34 developed pancreatitis. But the New York study had better p24 results. Dr. Fauci speculated that since the active form of ddI inside the cells has a half-life of 12 hours, the best regimen might be lower doses twice a day; but he noted that more trials are necessary to determine if this is true.
Both studies were short-term, giving ddI for a mean of 17 weeks in New York and 15.8 weeks in Boston -- another reason why the ongoing trials are necessary.

Symptoms of Toxicity

Some of the descriptions of the more common side effects published in the report of the New York study might help patients who are using ddI recognize them if they occur. It is very important to notify one's physician immediately in case of side effects, so that the dose can be reduced or the drug discontinued. In the latter case, it is often possible to restart later, at a lower dose.
The neuropathy "consisted of a tingling, burning, or aching in the lower extremities, particularly in the soles of the feet. The pain was particularly prominent at night but was also present throughout the day. Initially, the discomfort was noted in walking, but in more advanced cases pain interfered with sleep and routine daily activities... The onset of neuropathy occurred from 55 to 201 days after the initiation of therapy."
Pancreatitis was "manifested by abdominal pain and elevated amylase levels. The episodes began with vague abdominal pain, nausea, and vomiting and progressed to moderate or severe epigastric pain, which required narcotic analgesics in three of the five patients... The symptoms resolved within one to three weeks after the cessation of ddI therapy."
There have also been other side effects, such as seizures in a few patients. Physicians who are using ddI under the expanded-access program receive updates from the sponsor, Bristol-Myers Squibb Co., and from other doctors, as new information becomes available.
Some patients in the expanded-access program have decided to reduce their doses of ddI, often by taking only one of the two daily doses. There is some confusion on whether it is possible to do this with the knowledge of Bristol-Myers, or whether the drug would be cut off in such a case. We do not know the answer. In order to assure the accuracy of the safety information being collected from the expanded-access program, Bristol-Myers should make it clear that patients can reduce their doses and report that fact, without threatening access to the drug which some have found to be a lifeline.