A benefit-risk trial of 1-month rifapentine and isoniazid to prevent tuberculosis and reduce morbidity in people with non-communicable multimorbidity

结核病导致的死亡人数比世界上任何其他传染病都多。生活在贫穷国家的人受到的影响最大；这给个人、他们的家庭和社区带来了巨大的个人和经济代价。疾病可以通过给感染了引起结核病的细菌的人服用结核病药物来预防，这被称为结核病预防治疗。世界卫生组织(WHO)目前建议对最有可能患上结核病的人进行结核病预防性治疗，比如与结核病患者同住一所房子的人，以及艾滋病毒携带者。对这些人来说，人们认识到结核病预防治疗的好处大于坏处。糖尿病患者罹患结核病和死于结核病的几率也增加。然而，世卫组织目前并不推荐结核病预防性治疗，因为尚不清楚治疗的益处是否会超过治疗的风险。没有足够的证据支持这一决定，特别是因为提供的唯一选择是标准的结核病预防治疗，每天服用6或9个月的异烟肼，可能会对肝脏造成损害。此外，由于为糖尿病提供良好的世卫组织标准护理可能已经降低了未来的结核病风险，因此好处可能会被低估。世卫组织糖尿病标准护理的目的是控制血糖水平，研究表明，通过这样做，患结核病的风险也将降低。此外，糖尿病的标准治疗包括一种名为二甲双胍的药物，最近的研究表明，与没有开这种药的人相比，开这种药的人患结核病的风险更低。新的短期治疗，包括一个月的结核病药物利福喷丁和异烟肼(1HP)，被证明可以预防艾滋病毒感染者的结核病。此外，1HP还有其他好处，因为更多的人完成了短期治疗，而且它引起的副作用更少。我们认为这种新的治疗方法可能会改变利与弊的平衡。这将导致世卫组织政策的改变，支持为糖尿病患者提供结核病预防治疗。这种治疗方法还没有在糖尿病患者或没有感染艾滋病毒的人身上进行研究。我们计划为未感染艾滋病毒并可能感染结核病的糖尿病患者找到预防结核病的最佳策略(如暴露于结核病的测试所示)。阳性检测将表明未来患结核病的风险增加。我们将进行一项研究，将人们随机分配到接受1HP糖尿病标准治疗的一组或只接受糖尿病治疗的一组，比如掷硬币。这种类型的研究被称为随机对照研究。在这项研究中，我们将评估每组中谁感染了结核病，谁因治疗而产生副作用。如果1HP减少了患结核病的机会，并且没有实质性的副作用，我们认为世卫组织的政策将迅速改变，建议在糖尿病患者中预防结核病。然而，如果在糖尿病标准治疗的基础上给予1HP治疗并不比单独给予标准治疗更好，那么当前的建议不会改变，从而避免结核病药物的不必要伤害。我们的试验将招募4130名年龄在15岁及以上的糖尿病患者，他们居住在菲律宾和南非。该项目将运行5年。

TB causes the most deaths than any other infectious disease worldwide. People who live in poor countries are mostaffected; this is at a large personal and financial cost to the individuals, their families and communities. Disease can beprevented by giving TB drugs to people who are infected with the bacteria that causes TB, this is called TB preventivetreatment.The World Health Organization (WHO) currently recommends TB preventive treatment for people who are most at risk ofdeveloping TB such as people who live in the same house as a person with TB, and also for people living with HIV. Forthese individuals, it is acknowledged that TB preventive treatment will achieve more benefit than harm. People withdiabetes also have an increased chance of developing TB disease and dying from TB. However, WHO does not currentlyrecommend TB preventive treatment since it is not clear if the benefit would outweigh the risks of treatment. There is notenough evidence to inform this decision especially since the only option on offer is the standard TB prevention treatmentwith 6 or 9 months of isoniazid which is taken daily and can cause harm especially to the liver. Moreover, benefit may belimited since providing good WHO standard care for diabetes could already reduce the risk of TB in the future. The aim ofWHO standard care for diabetes is to control blood sugar levels and by so doing, research suggests the risk of developingTB would also be reduced. In addition, standard care for diabetes includes a medicine called metformin which has beenrecently shown to reduce the risk of developing TB in people prescribed this medicine compared to those not prescribedthe medicine.The new short-duration treatment with one month of the TB drugs rifapentine and isoniazid (1HP) was shown to prevent TBdisease in people infected with HIV. Moreover, 1HP has other benefits since more people complete the short treatment,and it causes fewer side effects. We think this new treatment may alter the balance of benefit against the harms. Thiswould result in a change in WHO policy in favour of providing TB preventive treatment to people living with diabetes. Thetreatment has not not been studied in people with diabetes or people without HIV. We plan to find the best strategy for TBprevention for people with diabetes who are HIV-uninfected and likely infected with TB (as shown by a test of exposure toTB). A positive test would indicate an increased risk to develop TB in the future. We will carry out a study that will placepeople in a random manner, like tossing a coin, to a group that receives the standard care for diabetes with 1HP or a groupthat receives diabetes care alone. That type of study is called a randomised controlled study. In this study, we will assesswho gets TB disease and who develops side effects from the treatments in each group. If 1HP reduces the chance ofdeveloping TB and does so without substantial side-effects, we think WHO policy will change quickly to recommendprevention of TB in people with diabetes. However, if giving 1HP in addition to standard care for diabetes is not better thanstandard care alone, the current recommendation would not change thus avoid unnecessary harm from TB drugs. Our trialwill recruit 4,130 male and female individuals aged 15 years and older with diabetes, and who reside in Philippines andSouth Africa. The project will run for 5 years.