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)是全球由单一病原体引起的主要传染病死亡原因，联合国 制定雄心勃勃的目标，到2030年减轻结核病负担。结核病预防治疗(TPT)是一个关键 预防结核病的干预措施和模拟研究一致表明，扩大TPT覆盖面 是实现联合国目标的关键。在高危人群中实施TPT的情况仍然非常严重 然而，糟糕的是，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 以利福霉素为基础的短程TPT。我们证明了每周服用3个月的利福喷丁和 在感染和不感染艾滋病毒的人中使用异烟肼(3HP)，并表明它不逊于较长疗程的 异烟肼，依从性好，毒性小。这种疗法现在被推荐作为一线治疗方案。 美国疾病控制与预防中心和世界卫生组织为潜在的结核病感染提供了大量潜在的 作为结束结核病战略的一部分，增加对TPT的吸收。最近，在NIAID的支持下，我们展示了 每日服用利福喷丁和异烟肼(1HP)1个月不低于服用9个月异烟肼的患者 HIV感染，完成率较高，毒性较小。推出两款创新的新短片- 疗程TPT方案为全球结核病控制提供了一个变革性的机会。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在 需要没有感染艾滋病毒的人。 这项由研究人员发起的临床试验应用程序的目标是进行随机试验比较 1HP和3HP 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3HP已被证明在HIV阳性和阴性的人中是安全有效的，但1HP只在 对艾滋病毒阳性者证明是安全和有效的。1HP在非HIV人群中的疗效可能是 根据以前的经验推断，表明TPT方案在不同风险组之间具有可比性，但 毒性和耐受性尚不清楚。我们会将治疗成功与良好的依从性进行比较，并记录在案 通过自我报告、药片计数和药物监测，未感染HIV的成年人1HP与3HP的比较 以及2)在这一人群中比较1HP和3HP的安全性。我们 假设用1HP成功治疗将优于3HP，并且 1马力将优于3马力。我们还将比较1HP和3HP的成本效益 方法，模拟1 HP与3 HP、6H和不治疗的增量成本效益。我们假设 与3HP相比，1HP将节省成本，与6H和v无TPT的建模成本相比。这场审判的结果将是 对于建立全球和美国对艾滋病毒阴性者使用1HP的指导方针非常有价值。

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.