A two-month course of therapy to prevent active tuberculosis (TB) is an effective alternative to the year-long regimen currently prescribed for persons co-infected with HIV and TB bacteria, a five-year international study has found.
The study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the Centers for Disease Control and Prevention (CDC), and the Pan American Health Organization (PAHO), holds promise for reducing HIV-related TB disease and death in the United States and throughout the world.
"This is an important finding that could have a very positive impact on the health of persons infected with both HIV and TB," says NIAID Director Anthony S. Fauci, M.D. "TB and HIV are synergistic infections -- HIV infection speeds the progression of TB disease and increases the rate of activation of latent TB infection. TB appears to increase HIV replication in HIV-infected individuals." The World Health Organization (WHO) estimates that more than 5 million people worldwide are co-infected with HIV and TB, and approximately one-third of all HIV-related deaths worldwide are caused by TB.
Study Chair Fred Gordin, M.D., of the Veterans Affairs Medical Center in Washington, D.C., presented preliminary results of the short-course prevention study last week at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago, Ill. He also will present the findings at a meeting of TB researchers scheduled for Feb. 18-20, 1998, at WHO headquarters in Geneva, Switzerland.
Nearly 1,600 HIV-infected people participated in the study, a randomized trial comparing two months of daily rifampin (RIF) and pyrazinamide (PZA) with 12 months of daily isoniazid (INH). More than 70 percent of the participants were from the United States, enrolled throughout the country at 53 different sites sponsored by NIAID's Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and Adult AIDS Clinical Trials Group (ACTG), and the CDC. Other participants were enrolled at CDC sites in Haiti and Brazil, and a site in Mexico sponsored by PAHO through an agreement with Mexico's Ministry of Health and National Institute of Public Health.
All participants had positive TB skin tests, indicating that they harbored inactive TB bacteria. Analysis of study data showed that after an average of 36 months of follow-up, the number of TB cases was the same in each treatment group. Fewer deaths occurred among patients in the two-drug arm than in the one-drug arm, but the difference was not statistically significant. Importantly, however, compliance with treatment was significantly better in the two-drug arm -- 80 percent of individuals in the RIF/PZA group completed their treatment, while less than half of the individuals in the INH group completed the year-long regimen.
"We know that 12 months of INH can prevent TB disease in people with HIV, but poor compliance limits the effectiveness of this regimen," explains Dr. Gordin, principal investigator at NIAID's CPCRA Unit in Washington, D.C. In most clinical settings, he says, compliance rates for patients receiving INH to prevent disease typically are lower than were seen in this study.
"In addition to improving treatment compliance, the short-course regimen could greatly reduce the cost of TB prevention programs," adds Dr. Gordin, who notes that personnel and administrative costs make running a 12-month, daily treatment program very expensive. Although RIF and PZA are more expensive than INH, Dr. Gordin says implementing the two-drug short-course regimen likely would be far less expensive and thus an attractive alternative to INH-based TB prevention programs. The prospect of less costly TB prophylaxis may also make such programs economically feasible in countries that cannot afford INH-based therapy.
"Certainly, the greatest impact of these findings will be in the United States and other countries where preventive therapy is widely recommended for individuals infected with TB and at risk for developing active disease," notes Helene Gayle, M.D., director of the CDC's National Center for HIV, STD and TB Prevention. "But as the role of preventive therapy continues to evolve in the developing world, this short-course regimen may help extend the reach of therapy in certain high-risk groups, including HIV-infected individuals and children living in households with people with infectious TB."
Dr. Gayle adds that although preventive therapy for infected individuals in these high-risk groups can play a role in TB control efforts in developing nations, the primary focus of efforts in areas with limited resources should remain the diagnosis and treatment of active cases of TB disease.
Although this study included only HIV-infected persons, Dr. Gordin notes that the short course RIF/PZA regimen also should be useful for preventing active TB in persons without HIV who have latent TB infection. The CDC currently recommends six to 12 months of daily INH prophylactic therapy for people with a positive TB skin test who are at increased risk for developing active TB. These include: people in close contact with a person who has active TB disease; people who became infected with TB bacteria in the last two years; babies and young children; people who inject drugs; people who have weakened immune systems; and elderly people. The results of this study will provide important information for new recommendations on tuberculosis preventive therapy to be issued by CDC later this year.
NIAID, part of the National Institutes of Health (NIH), supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, malaria, asthma and allergies. CDC is the nation's lead agency for the prevention and control of tuberculosis and other diseases. NIH and CDC are agencies of the U.S. Department of Health and Human Services.
PAHO is an international public health agency with more than 90 years of experience in working to improve health and living standards of the countries of the Americas. It serves as the specialized organization for health of the Inter-American System. It also serves as the Regional Office for the Americas of the World Health Organization and enjoys international recognition as part of the United Nations system.