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

该项目是LCID结核病研究科、NIAID、韩国卫生福利部国家马山结核病医院和大韩民国延世大学医学院合作开展的。这些合作者共同努力，于2005年建立了国际结核病研究中心（ITRC），负责管理实验室设施内的财务和科学活动。该医院因其耐药结核病患者的集中而在全球独一无二（每年超过1000名住院患者），相邻的中心配备了功能齐全的生物安全3级实验室设施。 具体研究包括根据方案NIAID 05-I-N 069（韩国肺结核患者中耐多药结核菌斑和宿主易感基因的自然史研究）对MDR和XDR结核分离株及其对人类疾病的贡献进行表征，目前招募了700多名受试者。NIAID 07-I-N 041正在研究候选结核病药物中厌氧活性的重要性（“一项随机、双盲、甲硝唑联合抗结核化疗与抗结核化疗联合安慰剂治疗耐多药肺结核患者的初步研究目前入组了27例患者，将在NIAID 06-I-N241中检测TB受试者是否存在厌氧环境（盐酸吡莫硝唑作为低氧标志物在接受选择性肺切除术治疗难治性肺结核受试者中的II期临床试验）。此外，将在08-N-I167（一项在广泛耐药（XDR）肺结核受试者中评价利奈唑胺联合抗结核治疗疗效的IIa期、随机化、2组、开放标签、临床试验）中研究一种已知对核糖体靶点具有静态活性（显然具有强效体内活性）的药物的活性。其他调查包括人类结核性肺组织切除后的大体物理和组织学结果与手术前相同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-N 069中，正在解决一些关于高度耐药和药物敏感结核病差异的基础生物学问题。这包括与诺华基金会基因组研究所的合作，对30多个XDR和药物敏感的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。目前正在对可能的新诊断工具进行几项调查，这些工具将评估在护理点测试中容易获得的人类样本（如尿液）中是否存在结核分枝杆菌片段。正在进行类似的努力，以检测痰样品中的Mtb耐药等位基因，以便在治疗开始时而不是药物治疗开始后3至4个月开出有效的治疗处方。其他研究正在寻求特定Mtb分子对发病机制，疾病严重程度和治疗结果的贡献。 利奈唑胺研究（08-N-I167）的主要目的是评价XDR TB患者的最后一种药物利奈唑胺（LZD，Zyvox，Pfizer）的疗效、安全性和耐受性。目前，LZD很少用于结核病患者，因为其高昂的成本和副作用，但XDR TB的出现引发了标签外，不受控制的使用在挽救治疗的少数患者可以负担得起它。LZD的剂量限制性副作用已被观察到经验性治疗XDR TB患者LZD，这限制了治疗的持续时间，因此，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.