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

超短疗程利福喷丁和异烟肼 (1HP) 用于预防未感染 HIV 个体结核病的安全性和耐受性

• 批准号: 10413161
• 负责人: Richard E. Chaisson
• 金额: $ 95.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413161
• 关键词: Adherence; Adolescent; Adult; Adverse event; Biological; Cause of Death; Centers for Disease Control and Prevention (U.S.); Child; Clinical Trials; Consumption; Cost Analysis; Cost Savings; Data; Development; Disease model; Dose; Epidemic; Event; Exanthema; Fever; Goals; Guidelines; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; Hepatotoxicity; Hypersensitivity; Immunosuppression; Incidence; Individual; Intervention; Meta-Analysis; Modeling; Monitor; National Institute of Allergy and Infectious Disease; Nausea and Vomiting; Patient Self-Report; Patients; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Pharmacology; Population; Populations at Risk; Prevention; Preventive therapy; Pyrazinamide; Randomized; Regimen; Research; Research Personnel; Rifampin; Rifamycins; Risk; Safety; Study models; Syndrome; Therapy trial; Time; Toxic effect; Tuberculosis; United States National Institutes of Health; Work; World Health Organization; base; clinical practice; comparative cost effectiveness; cost; cost effectiveness; discontinuation study; efficacy study; experience; high risk; high risk population; incremental cost-effectiveness; innovation; isoniazid; mortality risk; mouse model; novel; pathogen; patient population; pill; prevent; randomized trial; rifapentine; side effect; success; treatment comparison; trial comparing; uptake

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.

项目概要 结核病 (TB) 是全球范围内由单一病原体引起的导致死亡的主要传染病，联合国已 制定到 2030 年减轻结核病负担的雄心勃勃的目标。结核病预防治疗 (TPT) 是关键 预防结核病的干预措施和模型研究一致表明，扩大 TPT 覆盖范围 对于实现联合国目标至关重要。在高危人群中实施 TPT 仍然极为困难 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。几十年来，我们率先开发 短期的基于利福霉素的 TPT。我们证明了每周一次利福喷汀 3 个月的疗效 异烟肼 (3HP) 在感染和未感染 HIV 的人群中进行治疗，结果表明它不劣于较长疗程的治疗 异烟肼，依从性较好，毒性较小。该方案现在被推荐作为一线治疗 疾病控制和预防中心 (CDC) 和世界卫生组织 (WHO) 针对潜伏性结核感染提供了巨大潜力 作为终止结核病战略的一部分，提高 TPT 的采用率。最近，在 NIAID 的支持下，我们展示了 对于患有以下疾病的患者，每日服用利福喷丁和异烟肼 (1HP) 一个月不劣于九个月异烟肼 HIV感染，完成率较高，毒性较小。两种创新的新短期的可用性 当然，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，但其安全性和耐受性的数据 需要没有感染艾滋病毒的人。 这项由研究者发起的临床试验申请的目标是进行一项随机试验，比较 1HP 和 3HP TPT 方案在未感染 HIV 的高危患者中的治疗成功率和安全性。 虽然 3HP 已被证明对 HIV 阳性和阴性人群安全有效，但 1HP 仅被证明是安全有效的。 已被证明对艾滋病病毒感染者安全有效。 1HP 在非 HIV 人群中的功效可能是 根据先前的经验推断，显示 TPT 方案在不同风险组之间具有可比性，但是 毒性和耐受性尚不清楚。我们将 1) 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、药丸计数和药理学监测，对未感染 HIV 的成人中 1HP 与 3HP 进行比较 以及结核病风险增加的青少年和 2) 比较 1HP 与 3HP 在该人群中的安全性。我们 假设 1HP 的成功治疗将优于 3HP，并且 1HP 的安全性和耐受性 1HP会优于3HP。我们还将使用社会指标来比较 1HP 和 3HP 的成本效益 方法，对 1HP 与 3HP、6H 和不治疗的增量成本效益进行建模。我们假设 与 3HP、6H 的建模成本以及无 TPT 相比，1HP 将节省成本。此次试验的结果将是 对于制定全球和美国在 HIV 阴性人群中使用 1HP 的指南非常有价值。