The oral drug trimethoprim-sulfamethoxazole (TMP/SMX) is better than aerosolized pentamidine for preventing a second episode of Pneumocystis carinii pneumonia (PCP) in people with AIDS who can tolerate both drugs, according to a study supported by the National Institute of Allergy and Infectious diseases (NIAID) and reported in the Dec. 24 issue of The New England Journal of Medicine.
PCP is the most common life-threatening opportunistic infection affecting people with AIDS. Without preventive therapy, recurrent PCP develops in about 65 percent of patients taking zidovudine (AZT) who survive an initial episode of PCP.
The study included patients at 23 sites of NIAID's AIDS Clinical Trials Group (ACTG), a nationwide network of AIDS clinical research centers. Robert Holzman, M.D., of New York University School of Medicine, and W. David Hardy, M.D., of the University of California at Los Angeles, served as co- principal investigators for the clinical trial, known as ACTG 021.
According to the trial results, patients on AZT who receive preventive aerosolized pentamidine run a 3.25 greater risk of developing a second bout of PCP than patients taking AZT plus prophylactic TMP/SMX (trade names, Bactrim or Septra). Patients in the two study groups demonstrated no major differences in blood or liver toxicities or rates of survival.
On Aug. 28, 1991, NIAID's Data and Safety Monitoring Board conducted an interim review of the study. The clinical and laboratory data appeared to show the TMP/SMX regimen to be more effective. This finding prompted the board to recommend the study be stopped on Aug. 30, 1991, nine months earlier than originally scheduled.
On Sept. 6 1991, NIAID issued a press release to bring the information to public attention. On Oct. 11, 1991, after further analysis of the data, NIAID issued a Note to Physicians with a detailed description of the study to help doctors make treatment decisions pending the study's publication.
Drs. Holzman and Hardy emphasize that the trial results apply primarily to those people with AIDS who have significantly compromised immune systems, and that caution should be used in generalizing to people who do not fit this profile. Although this study clearly indicates that TMP/SMX performs better, they note that both drugs are effective, and appropriate therapy must be determined by patients in consultation with their physicians.
The study evaluated the two treatment regimens in 310 participants enrolled between July 1988 and November 1990. All had been treated for an initial bout of PCP within 10 weeks prior to their enrollment.
By random assignment, participants received either a double-strength tablet of TMP/SMX [160 milligrams (mg) TMP/800 mg SMX] daily or 300 mg aerosolized pentamidine every four weeks. In addition, all took 1200 mg AZT daily before March 1990 and 600 mg daily thereafter, based on revised labeling and dosage recommendations. Patients who became intolerant to AZT switched to ddC. Patient follow-up lasted an average of 17.1 months.
The study participants, 94 percent men, included 185 whites, 67 African-Americans, 53 Hispanics and five of unknown background. They averaged 36 years of age. Overall, they had very low CD4+ T-cell levels--the median count at entry was 56 cells per cubic millimeter--indicative of advanced HIV infection. CD4+ T cells, a key target of HIV, are white blood cells that orchestrate the immune response.
Fifty participants had PCP recur during the study: 14 (9 percent) in the TMP/SMX group and 36(23 percent) in the pentamidine group. After one year, the researchers estimated the PCP recurrence rate as 3.5 percent for patients receiving TMP/SMX versus 18.5 percent for those receiving aerosolized pentamidine. After 18 months, the rates rose to 11.4 percent and 27.6 percent, respectively.
As of July 1, 1991, 90 deaths had occurred among the study participants. However, only five deaths--three among those taking TMP/SMX and two among those taking pentamidine-- were attributable to PCP.
TMP/SMX reduced recurrent PCP more effectively, but Drs. Holzman and Hardy say these results do not mean that TMP/SMX is the best choice for all patients. During the study, 27 percent of patients on TMP/SMX versus 4 percent of those on aerosolized pentamidine switched to the other therapy because of side effects presumed related to the study medications. The study design itself, however, which made it easier to switch from TMP/SMX to aerosolized pentamidine, in part accounted for the greater number of crossovers in the TMP/SMX group.