Contribution of genetic variation to pharmacokinetic variability and toxicity in

描述（由申请人提供）：2010年，全球估计有880万例结核病病例，其中230万例报告发生在非洲，110万例艾滋病毒阴性结核病病例死亡，另有35万例艾滋病毒阳性患者死亡。结核病原、宿主和药物暴露在结核发病机制中的复杂关系尚不清楚。世卫组织目前为药物敏感结核病新发病例推荐的治疗方案非常有效，在艾滋病毒阴性患者中治愈率约为90%。然而，即使所有新发结核病病例都得到治疗并且患者坚持治疗，仍有10%的患者（即全世界88万患者，非洲23万患者）对治疗没有反应。即使坚持治疗，一部分利福平敏感结核病患者对药物反应缓慢或无反应。在感染艾滋病毒的患者中，这个问题更加复杂和严重，目前的治疗效果似乎较低。还有一些患者可以成功治疗，但会出现毒性，从而导致治疗中断。虽然认识到对药物治疗的不同反应的几个潜在决定因素（例如，性别、年龄、种族），但对抗结核反应的差异很大

DESCRIPTION (provided by applicant): In 2010 there were an estimated 8.8 million incident cases of tuberculosis (TB) globally, with 2.3 million of these reported in Africa, 1.1 million deats among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV-positive. The complex relationship between TB pathogen, host, and drug exposure in the pathogenesis of TB is poorly understood. The treatment regimen that is currently recommended by WHO for new cases of drug-susceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. However, even if all new TB cases were treated and patients were adherent to the treatment, there would still be 10% of patients (i.e. 880,000 patients worldwide, 230,000 patients in Africa) who fail to respond to treatment. Even if adherent to treatment, a proportion of patients, with rifampicin sensitive TB, are slow to respond to medication or are non-responders. The problem is even more complex and serious in HIV infected patients where the efficacy of the current treatments appears to be lower. Still other patients can be treated successfully, but will experience toxicity and thus treatment interruptions. While several potential determinants of the variable response to drug treatment are recognized (e.g. sex, age, ethnicity), much of the variability in response to anti-tuberculosis drugs remains unexplained. In recent years there has been a rapid development in the understanding of the genetics underlying inter- individual differences in drug metabolism and treatment efficacy. The field of pharmacogenetics encompasses the study of the heterogeneity in genes related to drug transporters, drug metabolizing enzymes and drug targets, in the context of efficacy of treatment and adverse drug reactions. Few studies have been conducted to explore this field for TB disease. Through this study we aim to explore and determine host genetic factors contributing to pharmacokinetic (i.e. drug concentration) and dynamic (i.e. treatment outcome) variability in TB patients. The "RAFAgene" study is a 4 year project which will be nested within two multi-country randomized phase III tuberculosis treatment trials, the OFLOTUB and RAFA trials (reg numbers NCT00216385 and PACTR 201105000291300) conducted in Sub-Saharan Africa. Patients enrolled in the pharmacokinetic studies within these 2 trials will be sampled for genetic analysis (genome-wide and targeted SNPs screening with in vitro confirmation of the biological plausibility of the association between pharmacokinetic and genetic characteristics). The proposed project is led by Dr. Dissou Affolabi at the National Hospital for TB and Pulmonary (NHTPD) with partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (SA), the Medical Research Council in Durban (South Africa), the University of Liverpool UK and the London School of Hygiene and Tropical Medicine UK. PUBLIC HEALTH RELEVANCE: While efficient, the current standard tuberculosis treatments fail in approximately 10% of patients, corresponding to almost 1 million individuals per year worldwide, despite good treatment adherence. Several potential determinants of the variable responses to some drug treatment are recognized, however, much of the variability to anti-tuberculosis drugs remains unexplained and could be partly due to host genetic variability. We aim with the proposed study to explore the role of host genetics and aim to build on the few pharmacogenetics studies which have been conducted in the context of tuberculosis treatment so far.