CRCRA Researchers Present OI Studies at Vancouver

Date: September 1, 1996
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

The NIAID-supported Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), a consortium of 16 clinical sites in 15 cities, conducts clinical trials in communities where HIV-infected people receive primary care. CPCRA investigators presented recent findings from studies of treatments for people with AIDS-related opportunistic infections at the XIth International Conference on AIDS, held last July in Vancouver, B.C.

Fluconazole prevents yeast infections in women with HIV

Weekly doses of the drug fluconazole can safely prevent certain common yeast infections in HIV-infected women, according to results from the Women's Fungal Study, a multicenter CPCRA clinical trial. The study found that, on average, women who received 200 milligrams of fluconazole once a week had a risk for yeast infection of the mouth and vagina 44 percent lower than that of women who received placebo. The drug already is used to treat fungal infections in HIV-infected women.

The study proves that fluconazole has a useful role in the clinical management of HIV-infected women at risk for recurrent yeast infections," says study co-chair Paula Schuman, M.D., of the Detroit Medical Center at Wayne State University.

Vaginal yeast infections are common and easily treated in most women. They usually are caused by Candida albicans, a yeast that normally lives in the body. HIV-infected women, however, frequently develop yeast infections of the mouth, vagina and throat that are particularly persistent and difficult to treat, often increasing in severity as their immune systems weaken.

Dr. Schuman and her colleagues found that after a median follow-up period of 29 months, the weekly fluconazole regimen had reduced the risk of oral candidiasis by 50 percent and vaginal candidiasis by 38 percent, compared to placebo. Yeast infections of the throat and invasive fungal disease occurred too infrequently among the 323 women in the study for the researchers to determine with statistical certainty if fluconazole prevented these conditions. The fluconazole regimen produced no serious toxicities and did not lead to clinical signs of drug resistance.

Initial intermittent treatment is effective for HIV-related TB

In another multicenter clinical trial, CPCRA investigators have found that combination antibiotic therapy given intermittently (less than daily) is an effective initial treatment for persons with HIV-related tuberculosis (TB).

Patients with HIV-related TB received directly observed, multidrug antibiotic therapy during an eight-week induction, or treatment initiation, phase. Patients in each of two groups received four standard anti-TB drugs: isoniazid, rifampin, pyrazinamide and ethambutol. One group also received levofloxacin, an experimental anti-TB drug. The drugs were given daily for only the first two weeks, then three times a week for the six weeks remaining in the induction period. The four-drug and five-drug regimens were equally effective -- at the end of eight weeks, sputum specimens from more than 95 percent of patients in each group tested negative for the presence of TB bacteria.

"This is perhaps the first strong evidence that a largely intermittent induction schedule of directly observed, multidrug therapy is a very effective treatment for people with HIV-related TB, as measured by sputum culture response," says Wafaa El-Sadr, M.D., a CPCRA investigator at the Harlem Hospital Center in New York.

Although initial intermittent TB therapy is known to be effective in non-HIV-infected patients, its efficacy had not been proven in patients with HIV-related TB. Many clinicians, therefore, have continued to prescribe daily multidrug therapy for several months for these patients, before switching to intermittent therapy for the remainder of a typical nine-month course of treatment.

Dr. El-Sadr notes that a large part of the recent global increase in TB cases is due to the growing number of persons who are infected with both HIV and TB. HIV infection increases the chance that dormant TB infection will become activated. The progression of TB disease also is accelerated in persons with HIV infection. The greater convenience of intermittent TB therapy could have a major impact on the management of TB worldwide, she says.

"An effective intermittent regimen should increase rates of compliance with therapy, particularly for patients receiving directly observed therapy, because they will not have to come to the clinic as frequently to receive their medication," says Dr. El-Sadr.

Increased compliance with therapy would result in a better cure rate, less TB transmission and fewer opportunities for the TB organism to develop drug resistance.

High-dose clarithromycin ruled out for AIDS-related MAC

Preliminary results from an ongoing CPCRA study indicate that treatment regimens for people with Mycobacterium avium complex (MAC), a life-threatening infection common among people with late-stage AIDS, should include not more than a 500 milligram (mg), twice-daily dose of clarithromycin. A higher dose was associated with lower survival rates among study participants.

"All physicians who care for patients with HIV disease and AIDS should take note of this very important finding," says Jack Killen, M.D., director of NIAID's Division of AIDS. "Although the lower dose, given twice a day in combination with other drugs, is the standard of care in general practice, some studies had suggested that a higher dose might be more effective."

In the multicenter clinical trial comparing multidrug treatment regimens for people with MAC, researchers used regimens that included clarithromycin in twice-daily doses of either the standard dose of 500 mg or a higher dose of 1000 mg. Previous studies showed that higher doses kill MAC bacteria in AIDS patients' blood more quickly and thus might have greater clinical efficacy.

An interim analysis conducted several months after the study began indicated that 43 percent of the patients on the 1000 mg dose of the drug had died, compared with 22 percent of the patients receiving the 500 mg dose. The researchers immediately discontinued the clarithromycin dose comparison and began giving all patients in the study the 500 mg, twice-daily dose. NIAID also issued a note to physicians who treat patients with HIV, informing them of this finding. All patients also receive ethambutol, and either rifabutin or clofazamine.

"The data suggest that the higher dose is associated with higher mortality, but we can't explain why this happens," says CPCRA researcher David L. Cohn, M.D., of the Denver Public Health Department and the University of Colorado Health Sciences Center, also in Denver. "It is important to remember that clarithromycin remains the most potent drug for the treatment of people with disseminated MAC infection and that 500 mg, twice daily in combination with other antibiotics, is the standard of care," he adds. Treatment often results in improvement in symptoms and clearing of bacteria from the blood. However, relapse may occur several months after treatment.