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

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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.