Short-course preventive therapy works for HIV-positive patients, study shows
Short-course preventive therapy works for HIV-positive patients, study shows
Regimen could cut costs while increasing compliance
A five-year international study has concluded that two months of therapy for preventing tuberculosis in HIV-positive patients is an effective alternative to the year-long regimen that has been recommended. However, until the Centers for Disease Control and Prevention makes that assessment, clinicians could be stepping out on a limb if they switch to the new regimen, says a leading TB expert.
The study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers for Disease Control and Prevention (CDC), holds strong promise for reducing HIV-related TB disease and death, particularly in the United States where use of preventative therapy is widespread, say CDC officials.
"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 active disease," says Helene Gayle, MD, MPH, 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."
The finding, reported at the 5th Conference on Retroviruses and Opportunistic Infections, is significant because TB and HIV are synergistic infections, says Anthony Fauci, MD, director of NIAID. "HIV infection speeds the progression of TB disease and increases the activation of latent TB infection. TB appears to increase HIV replication in HIV-infected individuals."
The mechanics of that synergy were illustrated in another study presented at the conference showing that HIV viral load increases six- to seven-fold during the course of TB treatment.1
Compliance better with short-course
The short-course study followed nearly 1,600 HIV-infected patients randomized to take either two months of daily rifampin and pyrazinamide or 12 months of daily isoniazid. After 36 months of follow-up, the number of TB cases was the same in both treatment arms. Fewer deaths were found in the two-drug arm, but the difference was not statistically significant, the researchers noted.
Moreover, researchers found a significantly greater number of patients complied with the two-drug regimen. While 80% of patients in the two-drug group completed their treatment, less than half completed the year-long regimen, says Fred Gordin, MD, NIAID's principal investigator for the study.
Compliance with TB regimens is a serious problem in patients, particularly in those who are HIV-positive. A study of co-infected patients attending New York City HIV clinics showed a substantial number were lost to follow-up. Of patients who received all or part of their preventive therapy after their first visit at the clinic, only 46% completed at least 12 months of therapy, and 43% were lost to follow up.2
In addition to improving treatment compliance, short-course regimens could greatly reduce the cost of TB prevention programs, Gordin notes, adding that the lower cost could make the regimen more available in developing countries.
Indeed, other short-course regimens are proving to be as effective as the standard 12-month duration. A study of three short-course preventive therapy regimens in 2,736 HIV-infected Ugandans found similar mortality rates, after adjusting for anergy, in three treatment groups. This included patients treated for six months with isoniazid, patients treated with isoniazid and rifampin for three months, and patients treated with isoniazid, rifampin, and pyrazinamide for three months. Overall, the short-term risk of TB was reduced in the three groups by more than 60% with minimal side effects, the authors note.3
While the NIAID short-course included only HIV-positive patients, Gordon points out that the short course two-drug regimen (rifampin and pyrazinamide) could be successful for preventing active disease in patients who don't have HIV but have latent TB infection. The CDC currently recommends six to 12 months of daily isoniazid therapy for skin-test positive patents at high risk for TB disease.
Switching regimens may be premature
While the two-month, two-drug preventive regimen appears to be an effective alternative to existing recommendations for preventing TB in HIV-positive patients, the study has not been published in a peer review journal, and a committee of TB experts is not expected to meet until later this year to consider changing recommendations for tuberculosis preventive therapy.
And that leaves clinicians who want to provide state-of-the-art therapy in a bind.
"This finding has the potential to change practice more than most things we do," says Lee Reichman, MD, MPH, director of the National Tuberculosis Center in Newark, NJ. "But without a CDC written recommendation, if I give that prophylaxis and my patient has toxicity or he gets TB, I may have some liability."
Indeed, a study of adverse reactions in HIV-positive patients taking standard TB therapy underscores the difficulties in treating co-infections. Researchers from Brazil, where TB is the second most common opportunistic infection in HIV-positive patients, reported recently that a group of 64 HIV-positive patients treated with rifampin, pyrazinamide, and isoniazid were 6.7 times more likely to report toxic hepatitis compared with a group of 77 HIV-negative patients.4
Although Reichman predicts that the CDC will recommend that short-course regimen is an effective option to 12-month, single-drug prophylaxis, he says clinicians want to be absolutely sure of the results, especially when entering new territory. "There is no precedent for this. It is like using an out-of-label recommendation for a drug," he says, adding that his center will be meeting in the next month to decide whether to change practices now or wait.
The CDC plans to evaluate the new data and to review existing preventive therapy guidelines in a meeting later this year that will be co-hosted with the American Thoracic Society and possibly the Infectious Diseases Society of America, says Kenneth Castro, MD, director of the CDC's division of TB elimination. Until then, the CDC cannot make recommendations about use of the two-drug, two-month regimen, he tells TB Monitor.
"Because these trials have not shown superior efficacy to what is available, I think we will be at a minimum obligated to offer it as an alternative option," he says. "However, we first need to look at toxicity data with the multidrug regimen to make sure we are not increasing the potential for toxicity before the recommendation is issued. I would suspect that after the discussion, debate, and looking at the data, the outcome is likely to be that this is an alternative that may be very reasonable."
Short-course would make DOPT easier
The possibility of a preventive therapy regimen that is only two months instead of six or 12 months would make it easier to ask HIV-positive patients to delay or temporarily discontinue taking protease inhibitors, which have strong interactions with rifampin, Reichman notes. Although some clinicians are replacing rifampin with rifabutin because of studies showing less severe interaction with protease inhibitors, there are no prospective studies showing that the switch is an effective option, he adds.
A two-drug, two-month regimen also makes it more feasible to provide directly observed preventive therapy for HIV-positive patients, says Joan Otten, RN, director of the tuberculosis control program at Jackson Memorial Hospital in Miami. "If you do two-months twice weekly therapy, you could do directly observed therapy, and that would be ideal," she says, adding that the state of Florida is considering providing directly observed preventive therapy for HIV-infected patients.
A far-reaching issue the study raises is whether the results translate to HIV-negative patients - an assumption that would seem to hold true, Reichman points out. However, there have been no definitive studies in HIV-negative patients, he says.
References
1. Ellner J. Interaction between HIV and TB. Presented at the 5th Conference on Retroviruses and Opportunistic Infection, Chicago, 1998.
2. Sackoff J, Torian L, Vavagiakis P, et al. TB preventive therapy in HIV-infected patients. Presented at the 5th Conference on Retroviruses and Opportunistic Infection, Chicago, 1998.
3. Whalen C, Okwera A, Johnson J, et al. Preventive therapy for tuberculosis in HIV-infected Ugandans. Presented at the 5th Conference on Retroviruses and Opportunistic Infection, Chicago, 1998.
4. Pedral-Sampaio D, Netto E, Alcantar A, et al. Increased frequency of adverse reactions with standard therapy in HIV patients. Presented at the 5th Conference on Retroviruses and Opportunistic Infection, Chicago, 1998.
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