Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.

Standard-dose rifampin has limited central nervous system penetration.

标准剂量的利福平对中枢神经系统的渗透有限。

Whether high-dose rifampin could improve survival outcomes is unknown.

高剂量利福平是否能改善生存结果尚不明确。

Methods

We performed a double-blind, randomized, placebo-controlledclinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda.

我们在印度尼西亚、南非和乌干达进行了一项双盲、随机、安慰剂对照的临床试验，涉及患有结核性脑膜炎的成年人。

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.

我们安排了有和没有人类免疫缺陷病毒（HIV）共感染的人员接受标准的每日异烟肼、利福平（剂量为每公斤体重10毫克）、乙胺丁醇和吡嗪酰胺治疗，另外给予额外的利福平（累积剂量为每公斤体重35毫克；高剂量组）或匹配的安慰剂（标准剂量组）治疗8周；两组的参与者在剩余的9至12个月治疗期间均接受标准治疗。

The primary outcome was 6-month mortality.

主要结果是6个月的死亡率。

Results

A total of 499 participants were included in the intention-to-treatpopulation (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.

共有499名参与者被纳入意向治疗人群（249人随机分配至高剂量组，250人分配至标准剂量组），其中304人（60.9%）为HIV感染者，428人（85.8%）被确诊为肯定或可能的结核性脑膜炎。

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).

在6个月的随访期间，高剂量组有109名参与者（Kaplan-Meier估计值，44.6%）和标准剂量组有100名参与者（Kaplan-Meier估计值，40.7%）死亡（风险比，1.17；95%置信区间，0.89至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.

在6个月内死亡的参与者中，高剂量组的中位死亡时间为13天（四分位数间距，4至39天），标准剂量组为24天（四分位数间距，6至56天）。

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.

高剂量组中有8.0%的参与者发生了药物性肝损伤，而标准剂量组为4.4%，但两组均未出现因药物性肝损伤导致的死亡。

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.

在结核性脑膜炎患者中，未观察到高剂量利福平的有益效果，且不能排除有害效果的可能性。

(Funded by the U.K.

(由英国资助)

Medical Research Council and others; ISRCTN Registry number, ISRCTN15668391.).

医学研究委员会等; ISRCTN注册号, ISRCTN15668391。