Safety and Tolerability of Ultra-short Course Rifapentine and Isoniazid (1HP) for Prevention of Tuberculosis in HIV-Uninfected Individuals

项目摘要 结核病（TB）是全球因单一病原体导致死亡的主要传染性原因，联合国已 制定了到2030年减少结核病负担的宏伟目标。结核病预防性治疗（TPT）是一项关键的 预防结核病干预措施和模型研究一致表明，扩大TPT覆盖率 是实现联合国目标的关键。在高危人群中实施TPT仍然是极端困难的。 然而，新的治疗方案比几十年前的异烟肼标准更短，更安全， 迫切需要预防性治疗。在过去的几十年里，我们率先开发了 短程利福霉素TPT我们证明了每周服用利福喷丁3个月的疗效， 异烟肼（3 HP）在有和没有艾滋病毒感染的人，并显示它是不劣于较长的疗程， 异烟肼，具有更好的粘附性和更低的毒性。目前推荐将此方案作为一线治疗方案 疾病预防控制中心和世界卫生组织对潜伏性结核病感染的研究， 作为结束结核病战略的一部分，增加了TPT的使用。最近，在NIAID的支持下，我们证明了 每日利福喷丁和异烟肼（1HP）1个月不劣于异烟肼9个月， 艾滋病毒感染，完成率较高，毒性较小。两个创新的，新的短- TPT方案为全球结核病控制提供了变革性机会。一个月的潜力 在高危人群中催化TPT摄取的方案是巨大的，但关于其安全性和耐受性的数据， 需要没有艾滋病毒感染的人。 这项由制药商发起的临床试验申请的目标是进行一项随机试验， 1HP和3 HP TPT方案在无HIV感染的高危患者中的治疗成功率和安全性。 虽然3 HP已被证明是安全和有效的艾滋病毒阳性和阴性的人， 对HIV阳性者安全有效。1HP在非HIV人群中的疗效可能 根据既往经验推断，TPT方案在各风险组之间具有可比性，但 毒性和耐受性尚不清楚。我们将1）比较治疗成功与良好的依从性，记录 通过自我报告、药丸计数和药理学监测，与未感染HIV的成人中的3 HP相比， 和青少年结核病风险增加和2）比较1HP与3 HP在该人群中的安全性。我们 假设1HP成功治疗上级3 HP，且 1HP将上级3 HP。我们还将使用社会调查比较1HP和3 HP的成本效益。 方法，模拟1HP与3 HP、6 H和无治疗的增量成本效益。我们假设 1HP将比3 HP节省成本，比6 H的建模成本和无TPT节省成本。这次审判的结果将是 对于建立全球和美国HIV阴性人群使用1HP的指南非常有价值。

Project Summary Tuberculosis (TB) is the leading infectious cause of death due to a single pathogen globally and the UN has set ambitious targets for reducing the burden of TB by 2030. TB preventive therapy (TPT) is a critical intervention for preventing TB disease and modeling studies consistently indicate that expanded TPT coverage is essential for reaching UN targets. Implementation of TPT among the populations at risk remains extremely poor, however, and new regimens that are shorter and safer than the decades-old standard of isoniazid preventive therapy are urgently needed. Over the past several decades, we have pioneered the development of short-course, rifamycin-based TPT. We demonstrated the efficacy of 3 months of weekly rifapentine and isoniazid (3HP) in people with and without HIV infection and showed that it is non-inferior to longer courses of isoniazid, with better adherence and less toxicity. This regimen is now recommended as a first-line treatment for latent TB infection by the CDC and the World Health Organization, offering the potential of substantially increased uptake of TPT as part of the END TB Strategy. More recently, supported by NIAID, we have shown that one month of daily rifapentine and isoniazid (1HP) is non-inferior to nine months of isoniazid in people with HIV infection, with higher completion rates and less toxicity. The availability of two innovative, new short- course TPT regimens offers a transformative opportunity to global TB control. The potential of a one-month regimen to catalyze uptake of TPT in high-risk populations is enormous, but data on its safety and tolerability in people without HIV infection are needed. The goal of this investigator-initiated, clinical trial application is to conduct a randomized trial comparing treatment success rates and safety of 1HP and 3HP TPT regimens in high-risk patients without HIV infection. While 3HP has been proved safe and effective in HIV-positive and –negative people, 1HP has only been shown to be safe and efficacious in HIV-positive people. Efficacy of 1HP in non-HIV populations may be inferred based on previous experience that shows comparability of TPT regimens across risk groups, but toxicity and tolerability is not known. We will 1) compare treatment success with good adherence, documented by self-report, pill count, and pharmacologic monitoring, of 1HP compared with 3HP in HIV-uninfected adults and adolescents at increased risk of TB and 2) compare the safety of 1HP vs 3HP in this population. We hypothesize that successful treatment with 1HP will be superior to 3HP, and that the safety and tolerability of 1HP will be superior to 3HP. We will also compare the cost-effectiveness of 1HP and 3HP using a societal approach, modeling the incremental cost-effectiveness of 1HP vs 3HP, 6H, and no treatment. We hypothesize that 1HP will be cost saving vs 3HP, vs modelled costs of 6H and v no TPT. The results of this trial will be extremely valuable for establishing global and US guidelines for use of 1HP in HIV-negative people.