Tests of a new drug for a lung infection that is the most common cause of death in AIDS patients suggest that the experimental treatment is at least as effective as current therapies and has far fewer side effects, according to a report published today.
Trimetrexate, an experimental drug previously evaluated as a cancer therapy, was used to treat 49 AIDS patients suffering lung infections with Pneumocystis carinii pneumonia, or PCP, by researchers at the National Institutes of Health and George Washington University Medical Center.
The encouraging results of the preliminary trial, published in today's New England Journal of Medicine, have led to plans for a national study later this month of 370 AIDS patients with the infection that will compare trimetrexate with trimethoprim-sulfamethoxazole, the combination antibiotic most often used to treat PCP.
Once a rare infection seen only in patients whose immune systems were damaged by cancer or medications, PCP has become more common as a result of the acquired immune deficiency syndrome epidemic.
As many as 80 percent of AIDS patients suffer at least one episode of PCP, according to Dr. Carmen J. Allegra, the principal author of the new study. In 58 percent of the 24,412 reported AIDS deaths in the United States, PCP was the cause, according to the most recent figures from the federal Centers for Disease Control.
Episodes of PCP can be cured about 75 percent of the time with currently available drugs, which include trimethoprim-sulfamethoxazole and pentamidine isethionate, Allegra said. But AIDS patients frequently suffer multiple episodes, and the cure rate in patients with a second or third episode falls to between 40 and 60 percent, according to the report.
Both the standard drugs frequently cause serious side effects in AIDS patients, such as dangerously low blood counts and allergic reactions.
"Up to 50 percent of people will have side effects severe enough to cause the physician to stop therapy," Allegra said.
The rationale for trying trimetrexate in PCP was similar to the use of a related drug, methotrexate, in cancer patients, Allegra said. Trimetrexate blocks the activity of a chemical enzyme in cells needed to manufacture folic acid, a vitamin critical to cellular function. Given intravenously, trimetrexate is taken up by both the Pneumocystis organisms and by the patient's cells.
To prevent the drug from poisoning the patient's cells, doctors administer a second "rescue" drug called leucovorin, a form of folic acid that enters human cells but not Pneumocystis organisms. Thanks to leucovorin, the infecting organisms are killed by trimetrexate but the patient's cells are unharmed.
Allegra emphasized that the preliminary results must be confirmed and expanded in a large, randomized study comparing trimetrexate to standard therapy. But he noted that the most encouraging finding was the rarity of side effects with trimetrexate.
Although 12 patients experienced temporary lowering of blood counts, none suffered bleeding or infection because of low blood counts, a common side effect with the standard drugs. Four patients had temporary abnormalities in liver function detected on laboratory tests. Only one patient, who developed a rash, had to stop taking the drug.
Trimetrexate was first synthesized in 1969 by a researcher at the Warner-Lambert Co. in Morris Plains, N.J., which holds the patent. A spokesman said the company will provide the drug free of charge for a national study of trimetrexate, scheduled to begin this month at the 19 AIDS treatment evaluation units funded by the National Institute of Allergy and Infectious Diseases.