randomized trial of TB preventive therapy

世界卫生组织（世卫组织）已批准直接观察短程治疗（DOTS）作为全世界控制结核病的主要战略。然而，越来越多的证据表明，这一战略不足以降低结核病发病率。还有令人信服的证据表明，世卫组织目前未建议在发展中国家常规使用的异烟肼预防性治疗，可能在这些国家控制结核病方面极有价值。虽然INH预防性治疗非常有效且价格低廉，但其使用可能因依从性差而受到限制。最近完成的临床试验提供了证据，支持在发生活动性结核病的高风险患者中使用较短、间歇性的化学预防治疗方案预防结核病的有效性。这些研究比较了INH和联合利福平（Rif）吡嗪酰胺（PZA）。此外，直接观察预防性治疗（DOPT）已被证明可以提高不同环境下INH化学预防的完成率。利福喷丁（Rifapentine， RPT）是一种利福霉素- S衍生物，其抗菌活性与RIF相似，但半衰期较长。鉴于其治疗方案的有效性以及动物研究中的现有数据，RPT预防高风险人群结核病的有效性标记为短期间歇性DOPT试验。两组分别为RPT/INH，每周1次，持续12周；Rif/PZA，每周2次，持续8周。参与者将从项目1 DOTS+部门的结核病病例家庭接触者中招募。将在结核病索引病例水平上以10例为一组（每组5例）进行随机化，以确保将大致相同数量的病例接触者随机分配到每组。每个方案的疗效将通过比较每个组的结核病发病率与项目1 DOTS组中未接受预防治疗的结核病例接触者的发病率来确定。我们假设这两种方案都将提供针对活动性结核病的实质性临床保护，RPT/INH将与更高的治疗依从性和与Rif/PZA相当的毒性率相关。除了与项目1和项目3一起为全球结核病控制战略提供重要信息外，本研究还将提供关于RPT预防活动性结核病的安全性和有效性的数据，这种药物由于其药理学特征，可以每周使用一次，这是一个相当大的规划优势。

The World Health Organization (WHO) has endorsed directly observed therapy, short course (DOTS) as the principal strategy for controlling tuberculosis (TB) worldwide. Nevertheless, accumulating evidence suggests that this strategy will be insufficient to produce a reduction in TB incidence. There is also compelling evidence to suggest that isoniazid (INH) preventive therapy, which is not currently recommended by WHO for routine use in developing countries, may be extremely valuable in controlling TB in these countries. While INH preventive therapy is highly efficacious and inexpensive, its use may be limited by poor adherence. Recently completed clinical trials provide evidence supporting the efficacy of shorter, intermittent, chemoprophylactic regiments for preventing TB in patients at high risk for developing active TB. These studies have compared INH and the combination rifampin (Rif) pirazinamide (PZA). In addition, directly observed preventive therapy (DOPT) has been shown to improve completion rates of INH chemoprophylaxis in different settings. Rifapentine (RPT) is a rifamycin- S derivative with antimicrobial activity similar to RIF, but with a longer half-life. Given its efficacy for regimen and the and the available data in animal studies, the efficacy of RPT for the prevention of tuberculosis in people at high risk label trial of short-course, intermittent DOPT. The two arms will be RPT/INH given once weekly for 12 weeks, and Rif/PZA, given twice weekly for 8 weeks. Participants will be recruited from among household contacts of TB cases in the DOTS+arm of Project 1. Randomization will occur at the TB index case level in blocks of 10 (5 in each arm) to assure that an approximately equal number of case contacts are randomized to each arm. The efficacy of each regimen will be determined by comparing the incidence of TB in each arm to the incidence among TB case contacts who receive no prevention therapy in the DOTS arm of Project 1. We hypothesize that both regimens will offer substantial clinical protection against active TB, that RPT/INH will be associated with higher adherence to therapy and comparable rates of toxicity than Rif/PZA. Besides providing, in conjunction with projects 1 and 3, important information for TB control strategies worldwide, this study will provide data on the safety and efficacy of RPT for the prevention of active TB, a drug that, due to its pharmacologic profile, can be used once-weekly, a considerable programmatic advantage.