Rifapentine not suitable for HIV-positive patients
Rifapentine not suitable for HIV-positive patients
Manufacturer seeking new drug application
Whether the highly promising drug rifapentine will provide tuberculosis patients with a more manageable once-a-week treatment won’t be known until later this year. However, researchers already know that it is not suitable for HIV-positive patients after four of 36 HIV-positive patients in a large study relapsed with rifampin-resistant strains.
The results came earlier this year in Phase III of a U.S. Public Health Service Study 22, a randomized, open-label trial comparing once-weekly isoniazid plus rifapentine to twice-weekly rifampin during the 16-week continuation phase of TB therapy, says Rick O’Brien, MD, chief of the Centers for Disease Control and Prevention’s research and evaluation branch of the division of TB elimination. The arm treating HIV-positive patients was stopped after the high rate of relapse was seen in the co-infected patients. None of the HIV-positive patients in the rifampin arm developed resistance, and none of the relapsing HIV-negative patients in the rifapentine arm developed rifampin-resistant strains, O’Brien notes.
The study, which has nearly 900 patients from 15 medical centers and 14 VA hospitals in the United States and Canada, enrolled 36 HIV-positive patients. Five of those patients relapsed, of which four developed rifampin-resistant strains of TB. Of the 36 HIV-positive patients who were treated only with rifampin, only two relapsed, neither of which had rifampin resistance, according to an abstract presented at the October International Union Against Tuberculosis and Lung Disease’s international conference in Paris.
The results were unexpected and hard to explain, O’Brien says. "The most probable answer is that the number of organisms present at the time the continuation phase was initiated with rifapentine was much larger than anticipated, so there were naturally occurring rifampin-resistant mutants that weren’t being taken care of by once-weekly isoniazid, allowing for the emergence of rifampin-resistant strains," he explains.
Studies are under way to better determine the mechanism that led to rifampin resistance, as are animal and human studies to develop rifapentine-containing regimens suitable for HIV-positive patients.
Although Study 22 will continue to enroll patients through the fall, the drug’s manufacturer, Hoechst Marion Roussel of Kansas City, MO, has been conducting a similar Phase III study at sites in South Africa and the United States. Based on the results of that study, the company is submitting a new drug application to the FDA by late December or early January, says company spokeswoman Julie O’Dell.
The company will not be releasing results of the study prior to approval, O’Dell says. The CDC, however, has confidentially shared some of the current status results of the U.S. study sites and will update the FDA’s advisory committee in a closed session when it reviews the rifapentine submission most likely this spring, O’Brien adds.
Rifapentine, a derivative of rifampin, was first developed in the 1950s. Although it was shown to have a longer half-life than rifampin, it was never submitted for FDA approval. Recent research has shown that its long half-life may enable once-weekly treatment during the maintenance phase of treatment. By reducing the number of dosages, researchers hope that patients will be more compliant and treatment will be more successful.
In other related TB drug news, the FDA has approved two new quinoline antibiotics for treating adults with acute bacterial respiratory infections.
The drugs are levoflaxacin (Levaquin), manufactured by Ortho-McNeil Pharmaceuticals, and sparfloxacin (Zagam), manufactured by Rhone-Poulenc Rorer. Both drugs have significant activity against tuberculosis and are considered by some experts to be preferable to ciprofloxacin or ofloxacin as second-line drugs for treating multi-drug resistant TB.
Sparfloxacin is more active against TB but is more toxic than levoflaxin, says O’Brien. There is no consensus that one is routinely more favorable than the other, he notes, adding that treatment should be offered only by experts in TB as neither drugs are labeled for treating TB.
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