Atovaquone Effective, Well-Tolerated Treatment for AIDS-Related Pneumonia
The drug atovaquone is a well-tolerated treatment for a common and deadly AIDS-related pneumonia, and offers HIV-infected patients unable to tolerate the side effects of the standard therapy an effective treatment alternative, according to a study sponsored by the National Institutes of Health (NIH), Burroughs Wellcome Co., the Wellcome Foundation and the California Collaborative Treatment Group.
Reporting in the May 27 New England Journal of Medicine, the study investigators conclude that oral atovaquone is a useful treatment alternative for patients with mild to moderately severe Pneumocystis carinii pneumonia (PCP) who cannot tolerate the first-line PCP therapy, trimethoprim and sulfamethoxazole (TMP/SMX). At least 20 percent of people with AIDS-related PCP treated with TMP/SMX experience serious side effects. Another PCP drug, injectable pentamidine, also is toxic to a significant number of patients.
TMP/SMX is highly effective and remains the first line treatment for Pneumocystis carinii pneumonia. However, many patients cannot tolerate TMP/SMX and require another therapy," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). "This study demonstrates that atovaquone is a useful alternative for those unable to tolerate TMP/SMX." PCP is the most frequent and one of the most serious opportunistic infections affecting people with AIDS. The disease is caused by a common microscopic organism that rarely causes disease in persons with healthy immune systems, but devastates the lungs, and occasionally other organs, of persons whose immune systems are weakened by HIV. Early symptoms include dry cough and fever, and as the infection progresses, shortness of breath and weight loss. Untreated, PCP causes respiratory failure and almost always is fatal.
Atovaquone (formerly called 566C80) is a broad-spectrum antibiotic originally developed to treat malaria. The drug, manufactured by Burroughs Wellcome Co., was licensed in November 1992 as a second-line therapy for mild-to-moderate PCP, largely on the basis of data from the current study.
The study investigators, led by Walter T. Hughes, M.D., of St. Jude Children's Research Hospital in Memphis, compared atovaquone with TMP/SMX in the treatment of 322 AIDS patients with mild to moderate PCP. The patients enrolled at 37 study centers in the United States, Canada and Europe, including the NIH Clinical Center in Bethesda, Md., and sites of NIAID's AIDS Clinical Trials Group (ACTG).
The participants were randomly assigned to 21 days of treatment with either 750 milligrams (mg.) of atovaquone three times a day or 320 mg. of TMP and 1600 mg. of SMX three times a day. Neither the investigators nor the participants knew which drugs were given to which patients.
Although atovaquone had less therapeutic efficacy than TMP/SMX, it also had fewer side effects that required discontinuation of treatment," says Judith Falloon, M.D., of the NIAID/Clinical Center AIDS Program at NIH, a co-author of the study. "We found that overall the success rates for the two courses of therapy were similar." Therapy involving only the initial drug was successful and free of adverse events in 62 percent of patients assigned to atovaquone and 64 percent of those assigned to TMP/SMX, the investigators report.
Of 160 patients treated with atovaquone, 20 percent failed to respond to therapy, compared with 7 percent of the 162 patients treated with TMP/SMX. Seven percent of the atovaquone patients died during the treatment period or within four weeks of its end, compared to 0.6 percent in the TMP/SMX group.
Side effects that forced a change in therapy occurred in 20 percent of the TMP/SMX-treated patients and 7 percent of the atovaquone-treated patients. Higher rates of treatment-limiting side effects in the TMP/SMX group versus the atovaquone group included rash (8 percent vs. 4 percent), liver dysfunction (7 percent vs. 3 percent), vomiting (7 percent vs. 1 percent), fever (6 percent vs. less than 1 percent), nausea (5 percent vs. less than 1 percent) and a decrease in white blood cell counts (3 percent vs. 0 percent).
Overall, higher rates of nausea (44 percent vs. 20 percent) vomiting (35 percent vs. 14 percent), constipation (17 percent vs. 3 percent), dizziness (8 percent vs. 3 percent), fever (25 percent vs. 14 percent) and rash (34 percent vs. 23 percent) were reported in the TMP/SMX group than in the atovaquone group. Diarrhea during treatment occurred more frequently in the atovaquone group (19 percent) than in the TMP/SMX group (7 percent).
The researchers noted that patients with higher concentrations of atovaquone in their blood were more likely to benefit from the drug than those who absorbed the drug poorly, such as those persons who entered the study with diarrhea.
"Work in progress toward a new, improved oral formulation appears promising as does work on an intravenous preparation of atovaquone that may achieve higher plasma concentrations," the authors write. An ongoing study at the NIH Clinical Center is evaluating the safety of different doses of an oral suspension of the drug in patients with HIV infection. The study also will evaluate the action of atovaquone in the body and determine if giving atovaquone and TMP/SMX together alter the action of either drug. The Clinical Center is also a site of a multi-center trial evaluating various doses of the suspension formula of atovaquone, alone and in combination with TMP/SMX, for the treatment of PCP.
Drs. Hughes' and Falloon's co-authors include Henry Masur, M.D., of the NIH Critical Care Medicine Department; Gifford Leoung, M.D., of Davies Medical Center, San Francisco; Francoise Kramer, M.D., and Fred Sattler, M.D., of Los Angeles County Hospital and University of Southern California; Samuel A. Bozzette, M.D., of the University of California, San Diego; Peter Frame, M.D., of the University of Cincinnati; Nathan Clumeck, M.D., of St. Pierre University Hospital, Brussels, Belgium; Danny Lancaster, M.D., of the Regional Medical Center, University of Tennessee, Memphis; Charles Chan, M.D., of the Wellesley Hospital, Toronto; James Lavelle, M.D., of Georgetown University Medical Center; Sharon Safrin, M.D., of San Francisco General Hospital and the University of California, San Francisco; Joel Rosentock, M.D., M.P.H., of the Infectious Diseases Research Consortium of Georgia; Judith Feinberg, M.D., of the Johns Hopkins Hospital; and Stephen LaFon, M.Sc., and Michael Rogers, Ph.D., of Burroughs Wellcome Co.
NIAID, a component of NIH, supports research on allergy, immunology and infectious diseases, including an extensive AIDS clinical research program at the Clinical Center, a 500-bed hospital on the NIH campus. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.
The ACTG, established in 1987, is a nationwide clinical trials network that conducts studies to evaluate the safety of new drugs, drug combinations and vaccines in adults and children at various stages of HIV disease.
For information on AIDS clinical trials open to accrual, call 1-800-TRIALS-A, Monday through Friday, 9 a.m. to 7 p.m., EDT. For press inquiries only, call Greg Folkers at (301) 402-1663.