International Research in Korea: Clinical Studies of Drug-Resistant Tuberculosis

该项目是由日本国际开发署结核病研究科、韩国卫生福利部、国立Masan结核病医院和大韩民国延世大学医学院合作开展的。这些合作者于2005年合作建立了国际结核病研究中心，负责管理实验室设施内的财务和科学活动。该医院以其耐药结核病患者的集中(每年超过1000名住院患者)而在全球独一无二，邻近的中心配备了功能齐全的生物安全3级实验室设施。 具体研究包括根据NIAID 05-I-N069方案(韩国肺结核患者耐多药结核菌株和宿主易感基因的自然历史研究)对耐多药和广泛耐药结核分离株的特征及其对人类疾病的贡献，目前有700多名受试者。NIAID 07-I-N041正在研究候选结核病药物中厌氧菌活动的重要性(“一项关于在耐多药肺结核患者中使用甲硝唑联合抗结核化疗与使用安慰剂进行抗结核化疗的随机、双盲、安慰剂对照试验)，目前纳入了27名患者，且NIAID 06-I-N241将测试结核病患者中是否存在厌氧环境(盐酸匹莫硝唑作为选择性肺切除治疗难治性肺结核患者的缺氧标志物的第二阶段临床试验)。此外，08-N-I167将研究一种药物的活性，该药物以其针对明显具有体内有效活性的核糖体靶标的静态活性而闻名(A阶段2a，随机，2臂，开放标签，Linezolid联合抗结核治疗在广泛耐药(XDR)肺结核患者中的疗效临床试验)。其他研究包括人类切除的结核肺组织的大体物理和组织学结果与手术前同一组织的计算机断层扫描图像中的放射学结果之间的结构关系。 在05-I-N069号文件中，一些关于高度耐药结核病和药物敏感结核病的差异的基本生物学问题正在得到解决。这包括与诺华基金会基因组研究所合作对30多个XDR和药物敏感结核分枝杆菌分离株进行测序，以表征MDR和XDR分离株的变化，这些变化使它们在耐药等位基因突变之外具有独特性。对可能的新诊断工具的几项研究正在进行中，这些工具将评估在易于获取的人体样本中是否存在结核分枝杆菌片段，例如在护理点检测中的尿液。正在进行类似的努力，以检测痰样本中的结核分枝杆菌耐药等位基因，以便在开始治疗时而不是在药物治疗开始后3至4个月开出有效的治疗。其他研究正在探索特定的结核分枝杆菌分子对发病机制、疾病严重程度和治疗结果的贡献。 Linezolid研究(08-N-I167)的主要目的是评估治疗广泛耐药结核病患者的最后药物之一Linezolid(LZD、Zyvox、Pfizer)的有效性、安全性和耐受性。目前，LZD很少用于结核病患者，因为它的成本和副作用令人望而却步，但XDR TB的出现正在引发少数负担得起的患者在抢救治疗中不加控制地使用LZD。LZD在经验性使用LZD治疗的广泛耐药结核病患者中观察到了剂量限制性副作用，这限制了治疗持续时间，从而限制了治疗成功。

The project is conducted as a collaboration among the Tuberculosis Research Section of LCID, NIAID, the Korean Ministry of Health and Welfares National Masan Tuberculosis Hospital (NMTH), and Yonsei Universitys College of Medicine of the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) in 2005 that manages both financial and scientific activities within the laboratory facilities. The hospital is globally unique for its concentration of drug-resistant TB patients (over 1000 in-patients per year) and the adjacent center is equipped with a fully functional Biosafety Level 3 laboratory facility. Specific investigations include characterization of MDR and XDR tuberculosis isolates and their contribution to human disease under protocol NIAID 05-I-N069 (A Natural History Study of Multidrug-Resistant TB Stains and Host Susceptibility Genes in Korean Patients with Pulmonary TB) with over 700 subjects currently enrolled. The importance of anaerobic activity in candidate TB drugs is under investigation in NIAID 07-I-N041 ("A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Antituberculous Chemotherapy vs. Antituberculous Chemotherapy with Placebo in Subjects with Multi-drug Resistant Pulmonary Tuberculosis) with 27 patients currently enrolled and the existence of anaerobic environments in subjects with TB will be tested in NIAID 06-I-N241 (A Phase II Clinical Trial of Pimonidazole Hydrochloride as a Hypoxia Marker in Subjects Undergoing Elective Lung Resection for Treatment-Refractory Pulmonary Tuberculosis). Additionally the activity of a drug known for its static activity against a ribosomal target that apparently has potent in vivo activity will be investigated in 08-N-I167 (A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Antituberculous Therapy in Subjects with Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis). Other investigations include structural relationship between gross physical and histological findings in human resected tuberculous lung tissue and the radiological findings in computed tomographic images of the same tissue prior to surgery. Within 05-I-N069 a number of basic biology questions about the differences in highly drug resistant and drug sensitive tuberculosis are being addressed. This includes a collaborative effort with the Genomic Institute of the Novartis Foundation to sequence a panel of more than 30 XDR and drug sensitive Mtb isolates to characterize the changes in MDR and XDR isolates that make them unique beyond their mutations in the drug resistance alleles. Several investigations into possible new diagnostic tools are underway that will assess the presence of fragments of Mtb in easily accessible humans samples such as urine in point of care tests. Similar efforts are being made to detect Mtb drug resistance alleles in sputum samples so that effective therapy can be prescribed at the initiation of therapy rather than 3 to 4 months after drug treatment begins. Other studies are pursuing the contribution of specific Mtb molecules to pathogenesis, disease severity, and treatment outcome. The major aim of the linezolid study (08-N-I167) is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). For the moment LZD is infrequently used in TB patients because of its prohibitive cost and side-effects but the emergence of XDR TB is sparking off-label, uncontrolled use in salvage therapy for the few patients that can afford it. Dose-limiting side-effects of LZD have been observed in XDR TB patients treated empirically with LZD which has limited the duration of treatment, and hence, limited the therapeutic success.