© 2009 American Thoracic Society doi: 10.1164/rccm.200808-1333ED
Once-Weekly Treatment of Tuberculosis with the Diarylquinoline R207910A Real Possibility
Center for Tuberculosis Research
Department of Cellular and Molecular Medicine With the results of a landmark study (1) demonstrating that the chemotherapy of tuberculosis was equally efficacious whether administered to patients in sanatoria or in their own homes, domiciliary treatment became the preferred strategy. It was quickly evident that regular monitoring of medication intake would be necessary to ensure patient adherence. Because such supervision could be achieved most easily with intermittent drug administration, the efficacy of intermittent regimens was explored in British Medical Research Council trials, mainly in Madras (2). A twice-weekly regimen of streptomycin and isoniazid produced a favorable response in 94% of patients, but once-weekly regimens were less successful, particularly in rapid acetylators of isoniazid. Once-weekly regimens continued to be less efficacious among rapid acetylators even after the addition of rifampin to the regimen in a later trial. Renewed interest in once-weekly treatment came with the introduction of rifapentine, which has a half-life some five times longer than that of rifampin. However, a series of three clinical trials found that once-weekly continuation phase treatment with rifapentine (600–750 mg) and isoniazid was less effective than standard rifampin/isoniazid regimens (3–5). Furthermore, rifamycin mono-resistance developed in a small number of HIV-seropositive patients (6). Evidence from one of these trials suggested that failure was due to the inability of this rifapentine dosage to inhibit bacterial growth during the interval between doses, probably because of its 98% binding to plasma proteins (7). In another trial, failure was attributed to inadequate isoniazid exposure (8). It is relevant that the Rifaquin trial, which includes HIV-seropositive patients, has just begun with European Commission funding. This trial will address potential shortcomings of the previous regimens by examining the efficacy of a higher dosage (20 mg/kg) of rifapentine, given once weekly during the continuation phase together with moxifloxacin, a companion drug that may provide better protection against emergence of acquired rifamycin resistance. The diarylquinoline R207910 (also known as TMC207) is the first drug that kills mycobacteria by inhibiting ATP synthase and blocking energy production (9). Initial studies in murine models have indicated remarkable activity, especially in combinations containing pyrazinamide, which appear capable of rendering organs culture-negative after daily treatment for only 2 months. In this issue of the Journal (pp. 75–79), Veziris and colleagues report on the activity of once-weekly regimens containing R207910 in a murine model (10). In their first experiment, R207910 alone had similar activity when given at the same total dose either 5 days per week, twice weekly, or once weekly. In the second experiment R207910 was more active than rifapentine, both given once weekly, and its activity was not enhanced by the addition of rifapentine or moxifloxacin. In the third experiment, the addition of rifapentine to the once-weekly R207910 regimen again had little effect. However, the addition of pyrazinamide to the R207910/rifapentine combination yielded significantly greater bactericidal activity and culture-negative organs in 9 of the 10 mice after 2 months of treatment. These results suggest that R207910 and rifapentine kill much the same bacterial persister populations, while pyrazinamide is unique among antituberculosis drugs in showing greater bactericidal activity as metabolic activity decreases and therefore kills the most persistent residual mycobacteria. Such enhancement of activity against persisters has also recently been observed when pyrazinamide is combined with rifampin and the new nitroimidazo-oxazine, PA-824 (11). These new findings are promising for the development of effective once-weekly regimens that may also be capable of shortening the overall duration of treatment for tuberculosis. However, certain caveats must be considered. First, one should not assume that the ability to render mice culture-negative in 2 months indicates that human tuberculosis could be cured in the same time frame with these once-weekly regimens. Mice typically harbor viable, but uncultivable, bacteria at the time that cultures first become negative. These "persisters" will resume active growth and become detectable as a relapse within 3 months after treatment is discontinued. Therefore, the ability of once-weekly regimens containing R207910 to prevent relapse should be demonstrated in the murine model before drawing further conclusions about their efficacy. Second, it will be necessary to demonstrate in clinical trials that combinations including R207910 and rifapentine prevent the emergence of resistance to either drug. Pyrazinamide has a short half-life and cannot contribute appreciably to the prevention of resistance (11). R207910 has a very long half-life sufficient to act throughout the week between doses. Both R207910 and rifapentine are metabolized by the same hepatic enzymes, so considerable pharmacokinetic interactions, such as induction of R207910 metabolism, may be expected. However, they are unlikely to shorten the half-life of R207910 sufficiently to compromise its ability to exert bactericidal activity throughout the week between doses. When given alone, high doses of rifapentine also have a sufficiently long pulse, plus the period of its post-antibiotic effect, to prevent emergence of resistance to R207910 (12), though the effects of the interaction with R207910 will need exploration. Much will depend on the results of the Rifaquin trial and further trials in pulmonary tuberculosis. As promising as the results are for once-weekly drug administration, they may also herald the availability of twice- and thrice-weekly regimens that optimize the contributions of companion drugs such as rifapentine, and may shorten the treatment duration even more than what may be possible with once-weekly treatment. For treatment programs around the world, it is unlikely that "one size fits all," so one of R207910's finest attributes may be the ability to contribute potent activity no matter what the dosing schedule. FOOTNOTES Conflict of Interest Statement: E.N. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.A.M. has received a grant of £150,000 from Johnson & Johnson for research on the interaction between the diarylquinoline and pyrazinamide. REFERENCES
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