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: 10018455
• 负责人: Richard E. Chaisson
• 金额: $ 91.63万
• 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/10018455
• 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; 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.

项目摘要 结核病（TB）是全球单一病原体引起的主要传染病，联合国 设定雄心勃勃的目标，可在2030年之前减少结核病的燃烧。TB预防疗法（TPT）是关键 防止结核病疾病和建模研究的干预措施始终表明扩大TPT覆盖范围 对于达到联合国目标至关重要。在处于危险中的人群中实施TPT仍然极为 然而，较差的新方案比数十年历史的Isoniazid标准更短，更安全 迫切需要预防治疗。在过去的几十年中，我们开创了发展 短期，基于利福反霉素的TPT。我们证明了每周三个月的利福丁仪的效率和 患有和没有艾滋病毒感染的人的异oni偶（3HP），表明它与更长的课程不属于 异念珠菌，具有更好的依从性和较小的毒性。现在建议该方案作为一线治疗 疾病预防控制中心和世界卫生组织的潜在结核病感染 作为结核病策略的一部分，TPT的吸收增加了。最近，在Niaid的支持下，我们已经显示 那个月的利法生和异oni偶（1HP）的一个月不到9个月的异oni偶 艾滋病毒感染，完成率较高，毒性较小。两个创新的新短暂的可用性 课程TPT方案为全球结核病控制提供了变革的机会。一个月的潜力 催化高危人群中TPT吸收的方案是巨大的，但有关其安全性和耐受性的数据 需要没有艾滋病毒感染的人。 该研究者发动的，临床试验应用的目的是进行随机试验，以比较 在没有HIV感染的高危患者中，1HP和3HP TPT方案的治疗成功率和安全性。 尽管3HP在HIV阳性和负人中被证明是安全有效的，但1HP才是 在艾滋病毒阳性的人中表现出安全有效的效率。 1HP在非HIV人群中的功效可能是 根据以前的经验推断出，该经验显示了风险群体中TPT方案的兼容性，但 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 通过自我报告，药丸计数和药学监测，为1HP，而HIV未感染的成年人则为3HP 和有TB风险增加的青少年和2）比较该人群中1HP与3HP的安全性。我们 假设通过1HP成功治疗将优于3HP，并且安全性和耐受性 1HP优于3HP。我们还将使用社会比较1HP和3HP的成本效益 方法，建模1HP与3HP，6H的增量成本效益和无治疗方法。我们假设 1HP将节省成本，而3HP，与6H的建模成本和V n tpt。该试验的结果将是 对于在HIV阴性人群中使用1HP的全球和美国准则非常有价值。