The project is a collaboration between the TRS/LCID/NIAID, Korean Ministry of Health & Welfare, Korea CDC, and Yonsei University College of Medicine in the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities, including a fully functional BSL3 laboratory facility. In addition, studies are being conducted in collaboration with Asan Medical Center, Samsung Medical Center, Pusan National University Hospital, and the National Medical Center, all located in Seoul. Specific protocol-driven investigations underway include: (1) NIAID 05-I-N069: A Natural History Study of MDR-TB Strains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR TB isolates and their contribution to human disease. A total of 776 subjects enrolled and this study is now closed to further enrollment. A substudy of this protocol has been investigating biomarkers of disease response in collaboration with Stellenbosch University and Rutgers New Jersey Medical School and analyses are ongoing. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Anti-TB Chemotherapy vs. Anti-TB Chemotherapy with Placebo in Subjects with Pulmonary MDR-TB. The importance of anaerobic activity in candidate TB drugs was investigated in this study. In 2009, the trial closed to enrollment after 35 subjects enrolled because of excessive peripheral neuropathies in the metronidazole arm. The study is now complete and the overall analysis has been published. Additional analyses have been done to determine whether or not PET/CT can serve as an early radiographic biomarker of treatment response. These results showed that changes on PET scans from baseline to 2 months of treatment and changes on CT scans from baseline to 6 months of treatment were both predictive of final treatment outcomes 6 months after the end of treatment, about 30 months after starting treatment. Both PET and CT changes were more predictive of final treatment outcomes than 2 month sputum culture conversion was, although statistical significance was limited by the small sample size. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Anti-TB Therapy in Subjects with Pulmonary XDR-TB. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). This trial opened in 12/2008 and enrolled 39 evaluable subjects with XDR TB and closed to enrollment in 7/2010. By four months, 15/19 (79%) subjects in the immediate-start arm and 7/20 (35%) subjects in the delayed-start arm achieved culture conversion (P=0.001). 34/39 (87%) subjects achieved culture negative sputum within six months of adding LZD to their failing drug regimens. Among the 38 subjects exposed to LZD, 31 (82%) experienced clinically significant adverse events (AEs) possibly or probably related to LZD that resulted in 3 subjects discontinuing therapy. Subjects who dose reduced to 300 mg/day after the second randomization had fewer adverse events than subjects who continued taking 600 mg/day. All subjects have now completed the study. Twenty-seven had negative results on sputum culture 1 year after the end of treatment, 3 were lost to follow-up, and 8 withdrew before the end of the study, including 4 patients in whom linezolid failed. Among the 27 patients who completed the study, 4 had a dose reduction from 600 mg to 300 mg of linezolid per day before the second randomization. Among the 13 patients who were assigned to continue receiving the 600 mg dose, 9 had a subsequent reduction in the dose to 300 mg. All the dose reductions were due to adverse events. Acquired linezolid resistance was observed only in 4 patients (11% of the 38 patients who received linezolid). This observed rate with monotherapy may be related to the infrequent emergence of resistance to this drug that has been observed in vitro. Thus, 27 of 38 patients (71%) with chronic XDR-TB were cured of the infection at 1 year after the termination of the study. LZD is highly effective at achieving culture conversion among subjects with treatment-refractory pulmonary XDR tuberculosis but adverse events must be monitored carefully. Due to these results, LZD is now an insurance reimbursable TB drug in Korea. Analyses of the PET/CT data collected during this study showed quantitative changes of a similar magnitude as those observed in macaques treated with oxazolidinones, demonstrating that the therapeutic effect of oxazolidinones in humans can be reproduced in the macaque model of experimental chemotherapy. (4) NIAID 09-I-N061; Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of TB chemotherapeutics into pulmonary TB lesions. The study opened in 2010 and completed at the end of 2014 after 15 subjects were enrolled. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up work we have conducted on lesion penetration in rabbits. Initial imaging mass spectrometry results show similar drug distribution results to those in the rabbit model, with concentration of moxifloxacin in the rim of lesions. A manuscript has been drafted and submitted for publication. (5) NIAID 12-I-N036; Risk Stratification in Latent Tuberculosis: PET/CT Findings in TB Contacts and the Effect of Preventive Treatment. The primary purpose of this study was to determine whether or not FDG uptake by PET scanning, as well as other biomarkers, can predict activation of latent TB infection in close contacts of active TB cases. This study has been closed due to poor enrollment but the study concept has been transferred to Robert Wilkinson at the University of Cape Town, where a very similar study is now underway in collaboration with TRS investigators. (6) In FY2014, a new study initiated, titled Feasibility and accuracy of a novel Xpert XDR cartridge for rapid molecular detection of drug resistant Mycobacterium tuberculosis in sputum (DMID Protocol Number 13-0029; DMID Funding Mechanism: Award Number N01AI90500C). This study is being conducted in conjunction with Susan Dorman at Johns Hopkins University under a grant from DMID. The primary objective of this prospective, cross-sectional study is to estimate the sensitivity and specificity of the investigational Xpert XDR cartridge for detection of M. tuberculosis resistance to isoniazid, fluoroquinolones, and aminoglycosides. With the first generation Xpert MTB/RIF cartridge only able to detect rifampin resistance, this second generation cartridge would provide a significant advancement in rapidly determining multidrug and extensively drug resistant tuberculosis. The study was conducted in Zhengzhou, Henan Province and Seoul, South Korea. The study began enrollment on June 5, 2014 and, as of June 15, 2015, the study completed with 192 subjects enrolled at in Korea. Data analyses are ongoing with preliminary analyses showing that the sensitivity/specificity of the new Xpert XDR cartridge is 99.7%/87.5% compared to the Xpert MTB/RIF cartridge. Resistance test results are still being analyzed and, in early analyses, appear to have good correlation with MGIT phenotypic resistance testing results.

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