Understanding pharmacokinetic - pharmacodynamic determinants of outcome to inform dose optimisation for non-MDR TB re-treatment patients in Vietnam

结核病仍然是一个主要的全球公共卫生问题负担，2014年有960万新病例和120万人死亡。越南在22个结核病负担最高的国家中排名第12位。2014年，每10万人中报告了140例新病例。国家结核控制规划数据表明，对新发结核患者进行6个月一线治疗后，10%的病例不成功（一些患者在治疗结束时仍不舒服，另一些患者在明显治愈后复发）。只有20-30%的不成功治疗可归因于抗生素耐药性的重大问题，这需要专门管理。其余的继续接受标准的“第二类”治疗方案，这是国际上认可的，但尚未经过仔细研究。不幸的是，采用这种方案重新治疗的患者并不总是效果良好；在越南，第2类方案的治疗成功率只有60-75%。患者在两轮治疗中失败的原因尚不清楚。其中一个原因可能是一些患者体内的药物水平（一项被称为药代动力学的研究）太低，无法杀死感染。这一问题还可能因以下事实而恶化：杀死导致结核病的细菌（称为结核分枝杆菌）所需的药物水平在每个患者中并不相同，即一些患者感染的结核分枝杆菌菌株比其他患者能在更高浓度的药物中存活。在这个项目中，我们将重点关注再治疗患者群体，以确定是否可以通过测量个体患者的药物水平和仔细研究结核病药物杀死M结核的能力来解释临床结果。该项目将使用先进的分析技术来测量患者血液样本中的药物水平，并使用一些新的实验室技术来研究药物杀死每种结核分枝杆菌菌株的效果。然后，所有这些信息将使用数学模型进行组合和分析，以；(i)确定实验室/分析测量是否可以解释低治疗成功率，（ii）确定这些信息是否可以在未来通过早期预测不良结果和推荐更好的药物疗程来改善治疗。从这项研究中获得的数据将与世界各地从事结核病工作的其他研究人员共享，并将有助于通过设计更好的治疗方法来解决结核病的更广泛讨论。值得注意的是，该项目还旨在通过在上述所有方法学领域向我们的越南同事提供培训和指导，提高当地开展此类高级研究的能力。

TB remains a major global public health problem burden, with 9.6 million new cases and 1.2 million deaths in 2014. Vietnam is ranked 12th among the 22 highest TB burden countries (TB). 140 new cases were reported per 100,000 population in 2014. National TB Control Programme data indicates that 6 months of first-line month therapy for new TB patients is not successful in 10% of cases (some patients are still unwell at the end, and others relapse after apparent cure). Only 20-30% of unsuccessful treatments can be attributed to major problems with antibiotic resistance, which requires specialist management. The remainder go on to receive a standard "Category 2" treatment regimen, which is internationally approved but has not been carefully studied. Unfortunately, re-treatment patients on this regimen do not always do well; in Vietnam, the Category 2 regimen results in only 60-75% treatment success. The reason why patients may fail two rounds of treatment is not well understood. One reason could be that the levels of drug in the body (a study known as pharmacokinetics) of some patients is too low to kill the infection. This problem could also be worsened by the fact that the drug levels required to kill the bacteria causing TB (known as Mycobacterium tuberculosis) are not the same in every patient i.e. some patients are infected with a strain of the M. tuberculosis bacteria which can survive higher concentrations of drugs than others. In this project we will focus on the retreatment patient group to determine whether clinical outcome can be explained by measuring individual patient drug levels and carefully studying the ability of TB drugs to kill M tuberculosis. The project will use advanced analytical techniques to measure drug level in patient's blood samples and a number of new laboratory techniques to study how well the drugs kill each M. tuberculosis strain. All of this information will then be combined and analysed using mathematical models to; (i) determine whether the laboratory/analytical measurements can explain the low treatment success rates and (ii) determine whether this information can be used in the future to improve treatment by predicting bad outcomes at an early stage and recommending a better drug course. Data obtained from this study will be shared with other researchers working on TB around the world and will contribute to the wider discussion on tackling TB by designing better treatment. Significantly, this project aims to also increase the local capacity for advanced studies of this type by providing training and mentoring to our Vietnamese colleagues in all of the methodological areas described.