Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.
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Meya David B, Cresswell Fiona V, Dai Biyue, Engen Nicole, Naidoo Kogieleum, Ganiem Ahmad Rizal, Imran Darma, Kabahubya Mable, Lessells Richard J, Yunivita Vycke, Estiasari Riwanti, Tugume Lillian, Hlabisa Bongeka, Kurniawati Media Yuni, Sagita Noveline, Kagimu Enock, Maharani Kartika, Gakuru Jane, Gaharu Maula N, Mugabi Timothy, Kimuda Sarah, Namombwe Suzan, Te Brake Lindsey, Aarnoutse Rob, Svensson Elin M, Bangdiwala Ananta S, Namanda Sylvia, Bahr Nathan C, Musubire Abdu K, Moosa Mahomed Yunus Suleman, Hamers Raph L, Marais Suzaan, Boulware David R, van Crevel Reinout, Ruslami Rovina, HARVEST Trial Team
Аннотация
METHODS: We performed a double-blind, randomized, placebo-controlled clinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda. We assigned persons with and those without human immunodeficiency virus (HIV) coinfection to receive standard daily isoniazid, rifampin (at a dose of 10 mg per kilogram of body weight), ethambutol, and pyrazinamide plus either additional rifampin (for a cumulative dose of 35 mg per kilogram; high-dose group) or matched placebo (standard-dose group) for 8 weeks; participants in both groups received standard therapy for the remainder of the 9-to-12-month treatment course. The primary outcome was 6-month mortality.
RESULTS: A total of 499 participants were included in the intention-to-treat population (249 randomly assigned to the high-dose group and 250 to the standard-dose group), of whom 304 (60.9%) were persons living with HIV and 428 (85.8%) had definite or probable tuberculous meningitis. During 6 months of follow-up, 109 participants (Kaplan-Meier estimate, 44.6%) in the high-dose group and 100 participants (Kaplan-Meier estimate, 40.7%) in the standard-dose group died (hazard ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P = 0.25). Among the participants who died within 6 months, the median time to death was 13 days (interquartile range, 4 to 39) in the high-dose group and 24 days (interquartile range, 6 to 56) in the standard-dose group. Drug-induced liver injury occurred in 8.0% of the participants in the high-dose group and in 4.4% of those in the standard-dose group, but no deaths from drug-induced liver injury occurred.
CONCLUSIONS: Among persons with tuberculous meningitis, no evidence of beneficial effect from high-dose rifampin was observed, and the potential for a harmful effect cannot be ruled out. (Funded by the U.K. Medical Research Council and others; ISRCTN Registry number, ISRCTN15668391.).