Three different therapies are successful in delaying an initial bout of Pneumocystis carinii pneumonia (PCP), the most common, life threatening opportunistic infection (OI) in people with HIV, according to results from a National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial.
Samuel A Bozzette, M.D., of the University of California at San Diego, plans to present the data at the First National Conference on Human Retroviruses and Related Infections in Washington D.C., on Dec. 15.
The study, AIDS Clinical Trials Group (ACTG) 081, compared the ability of three therapeutic regimens combining zidovudine (AZT) with other drugs to prevent PCP, toxoplasmosis and serious bacterial infections among patients with advanced HIV infection. The participants, who had never had PCP, had fewer than 200 CD4+ T cells, the crucial immune system cell targeted by HIV.
Up to 80 percent of AIDS patients would develop PCP without preventative therapy. Toxoplasmosis, caused by a protozoa, is a common brain infection among AIDS patients. Bacterial infections, such as pneumonia or those of the bloodstream, also affect many HIV-infected people.
When we began this trial, no one knew which of these therapies would prove successful in delaying an initial episode of PCP," says Richard Hafner, M.D., of NIAID's Division of AIDS, and medical officer of the study. "The trial has shown that each of these therapies can delay that first case of PCP and will provide important information to use in choosing the best preventive therapy for individual patients."
Begun in May 1989, the trial followed 842 patients randomly assigned to receive 500 mg of AZT daily combined with trimethoprim/sulfamethoxazole (TMP/SMX) twice a day, with 300 mg of aerosolized pentamidine (AP) every four weeks or with 50 mg of dapsone twice a day. The trial closed to accrual in June 1990, and investigators followed the participants through June 30, 1993. As the study progressed, patients were allowed to switch from AZT to didanosine or zalcitabine.
During the trial, participants who became intolerant to the assigned therapy switched to another treatment arm. Patients also could switch if they developed PCP. For all treatment comparisons, investigators categorized patients by their initial treatment assignment, regardless of compliance, switching or discontinuation.
Patients who could not tolerate TMP/SMX or dapsone first changed to the other therapy before being assigned to the AP regimen. Patients who could not tolerate AP initially switched to TMP/SMX and then later to dapsone, if necessary.
Dr. Bozzette notes that 50.7 percent of the patients assigned to TMP/SMX had to switch to another treatment regimen during the study. Most PCP episodes in these patients occurred after switching therapies. Of the patients assigned to dapsone, 41.3 percent became intolerant and switched. Of patients assigned to dapsone, 25 percent developed PCP after switching to another regimen. Of the patients assigned to AP therapies, only 12 percent changed therapies and all but one of the PCP episodes occurred while on AP.
During the trial, 137 (16.3 percent) of the patients developed PCP. Among all patients, investigators noted no significant differences between the three treatment groups. However, for patients who began the study with fewer than 100 CD4+ T cells, TMP/SMX and dapsone were substantially more effective than AP in delaying an initial episode of PCP. Coupled with the results of ACTG 021, which demonstrated that TMP/SMX was more effective than AP for preventing recurrent PCP episodes, this data provides further evidence that the risk of developing PCP changes with time and with CD4+ T cell counts, Dr. Bozzette notes. Preventive therapy regimens should be chosen on an individual patient's risk, he adds.
Among the participants, 24 developed toxoplasmosis, and investigators noted no significant differences among the assigned treatment groups.
Death rates in the three treatment groups were not significantly different. Of all the patients, 403 (47.9 percent) have died. Investigators estimate that during a two-year period, the death rate was 19.7 percent for those taking TMP/SMX, while it was 23.3 percent for AP and for dapsone patients.
The three treatment groups were similar with respect to the occurrence of most symptoms and liver abnormalities. However, patients on AP experienced significantly lower rates of severely reduced number of the white blood cells called neutrophils, which are important in warding off infections. Also, patients on TMP/SMX and dapsone, compared to AP patients, had a significantly higher proportion of severe fever and rash.
For the trial, Stephen Spector, M.D., of the University of California at San Diego and Dr. Bozzette served as protocol cochairs.
NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.