Many of the first AIDS patients treated with a widely publicized test drug experienced severe nerve pains and had to discontinue the therapy, according to physicians who are testing the medication.
As a result, the researchers are reassessing the use of the new drug, called DDC or dideoxycytidine, which they had hoped would be more effective and less toxic than other anti-AIDS medications.
For example, they are reducing the dosage of DDC or are alternating the drug with doses of AZT, the only drug that has been shown to prolong the lives of some patients with AIDS--acquired immune deficiency syndrome.
Suppresses Virus Growth
The new strategies are designed to take advantage of DDC's apparent effectiveness in suppressing the replication of the AIDS virus.
The nervous-system disorder is a potentially serious complication in AIDS patients. However, it is not life-threatening, like the AIDS virus infection itself.
A substantial number of patients who received the higher doses of DDC suffered from "a peripheral neuralgia, which causes pain, primarily in the feet," according to Dr. Samuel E. Broder of the National Cancer Institute, who developed the drug for use in AIDS patients. In most patients, the pain went away after the drug was stopped but sometimes not for "a month or more," he said.
In a telephone interview, Broder said it is too soon to say what effect, if any, the unexpected neuralgia side effect will have on DDC's eventual role in AIDS therapy.
"When a drug is given to human beings for the first time, the most important thing is to determine what will be the limiting toxicity of the drug," he said.
Broder said the next step is to try to find a "safe zone" in which DDC blocks the replication of the AIDS virus but does not cause the nervous system toxicity. Only after such a safe-dosage zone is established can larger tests be conducted to determine the effectiveness of the drug in prolonging the lives of AIDS patients or in reducing their suffering.
"It is not surprising with any new drug that toxicities appear," said Dr. Martin S. Hirsch of Harvard Medical School, who is testing DDC on AIDS patients at Massachusetts General Hospital in Boston. "The early results in the laboratory did not suggest that this was a very toxic drug. But you can't be sure with any agent until you check it in patients."
The researchers do not know why DDC can cause nerve symptoms. But AIDS patients may be predisposed to such a complication because they frequently experience problems with the nerves of their arms and legs as a consequence of the AIDS virus infection.
In a recent study, about 35% of a random sample of AIDS patients in San Francisco showed evidence of neurological disorders, according to Dr. Dale E. Bredesen, an assistant professor of neurology at the UC San Francisco Medical Center. About half had discomfort, such as tingling in their feet, but only about one in 10 experienced severe pain, he said.
Asked about the reports of DDC-associated neuropathy, Bredesen, who is not involved in testing DDC, speculated that the drug might be "bringing to light" sub-symptomatic nerve abnormalities in affected patients.
Broder said that one encouraging aspect of the early trials was the accumulation of "very strong data that DDC suppresses the (human immunodeficiency) virus at doses that are lower that we would have predicted."
This finding may make it more feasible for the researchers to avoid or minimize the neuropathy side effect in further tests, according to Dr. Thomas C. Merigan of Stanford University Medical Center, another leading DDC investigator.
So far, DDC has been tested on about 70 AIDS patients, according to a spokeswoman for Hoffman-LaRoche Inc. of Nutley, N.J., which was granted an exclusive license to develop the pill by the federal government in May. The ongoing clinical trials are being conducted at Stanford, UC San Diego, Johns Hopkins Medical Center, Massachusetts General, the University of Miami and the National Cancer Institute in Bethesda, Md.
AZT, or azidothymidine, was shown to prolong the lives of some AIDS patients in a large national study completed last year. However, serious side effects, including severe anemia, frequently require doctors to reduce the dosage levels or to stop the drug altogether.