The Peoples Republic of China has the third highest overall case burden of TB in the world (behind India and Indonesia). The WHO Global Tuberculosis Report 2016 estimated that, in 2015, China had 918,000 cases of TB, with an incidence of 67/100,000 population. This included an estimated 57,000 people with pulmonary MDR-TB, including 6.6% of new TB cases and 30% of previously treated cases. (1) NIAID 10-I-N060: A Natural History Study of Tuberculosis in China: Correlates of a Successful Response in Treatment. Henan Province is Chinas third largest province by population, with about 94 million people. By global population rankings, that would make it roughly the 15th largest country in the world. About ten percent of all new pulmonary TB cases in China each year occur in Henan Province and reported MDR TB rates in Henan are among the highest across the country. In partnership with provincial health authorities, the Tuberculosis Research Section is developing site research capacity to conduct high-quality clinical research. Our first study, a prospective, longitudinal natural history study titled A Natural History Study of Tuberculosis in China: Correlates of a Successful Response in Treatment, completed in 2014. Data analyses are ongoing, including interferon-gamma release assay responses in TB subjects on treatment and quantitative changes on CT scans of patients on treatment over time. An automated CT reading algorithm is being developed which can quantitate the amount of diseased lung by lung segment and compare changes over time in a very reproducible manner. In another analysis, very deep whole genome sequencing on sequential sputum sampling of pulmonary TB patients on treatment identified transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. Sufficient drug pressure leads to apparent genetic stability whereas less drug pressure allows acquisition of additional drug resistance. Monitoring bacterial population dynamics could therefore provide an informative metric for assisting the efficacy of novel drug combinations. (2) DMID Protocol Number 13-0029, DMID Funding Mechanism: Award Number N01AI90500C: Feasibility and accuracy of a novel Xpert cartridge for rapid molecular detection of drug resistant Mycobacterium tuberculosis in sputum. This prospective, cross-sectional study was conducted in conjunction with the Clinical Diagnostics Research Consortium (PI: Susan Dorman, Johns Hopkins University) and is now complete. The primary objective was to estimate the sensitivity and specificity of the investigational Xpert XDR cartridge to detect M. tuberculosis resistant to isoniazid, fluoroquinolones, and second-line injectable drugs. This highly multiplexed second generation cartridge may provide significant advancement in determining multidrug and extensively drug resistant tuberculosis within 2 hours and with minimal technical expertise. The study was conducted in Zhengzhou, Henan Province and Seoul, South Korea. Data analyses showed that, compared with DNA sequencing, overall sensitivities and specificities of the investigational assay for detection of resistance, by drug, were 98.1% and 100% for isoniazid, 95.8% and 100% for fluoroquinolones, 92.7% and 99.6% for kanamycin, and 96.8% and 100% for amikacin. (3) NIAID 15-I-0187: Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance. This study began in FY2015 with the hypothesis that sputum drug levels are predictive of drug concentrations in plasma and/or in specific lung lesion compartments such as caseum of open cavities. The primary objective of this prospective study is to determine concentrations of TB drugs in plasma and sputum over time. Subjects already on treatment for TB or NTM infection and who are still symptomatic and producing copious amounts of sputa will provide at least 3 sputa over 2 or more days and blood at baseline, then 2, 4, and 6 hours after taking their anti-TB or anti-NTM medications on 2 separate days. Sputa drug concentrations will then be compared to plasma drug concentrations, as well as to historically collected lung lesion drug concentrations. If sputa drug concentrations correlate as well as or better than plasma drug concentrations with lung lesion concentrations, therapeutic drug monitoring may be able to be done more easily and more accurately with sputa than with plasma. This study is being conducted at the NIH Clinical Center and the Henan Chest Hospital, Zhengzhou, Henan Province, China. The study initiated on 9/23/2015 and, as of August 2, 2017, had screened 156 subjects and enrolled 123 subjects. (4) DMID Protocol Number 15-0029; DMID Funding Mechanism: Award Number N01AI90500C: Multicenter Study of the Accuracy and Feasibility of the Xpert Ultra Test. This is another NIH-CDRC collaborative study that began in FY2016 evaluating the clinical diagnostic accuracy of another novel GeneXpert cartridge for detection of M.tb and rifampin resistance. Like its predecessor Xpert MTB/Rif, Xpert MTB/Rif Ultra is an integrated cartridge-based nucleic acid amplification test that incorporates additional amplification targets and technical upgrades to achieve an estimated 10 fold increased sensitivity for tuberculosis detection within 1.5-2 hours, compared to that of conventional Xpert MTB/Rif. The primary objective of this non-inferiority study is to compare the sensitivity of the Xpert MTB/RIF Ultra test vs. standard Xpert MTB/RIF to detect culture-positive pulmonary TB in new TB suspects, with a special interest in TB suspects whose sputum smears are negative. Enrollment began in 2016 across 5 sites: Brazil, Kenya, Uganda, South Africa and China (HPCH) and the study is now complete. Data analysis for the study is currently ongoing in collaboration with Cepheid and FIND. (5) NIAID 16-I-N133: Using Biomarkers to Predict TB Treatment Duration. This study hypothesizes that a combination of radiographic characteristics at baseline, the rate of change of these features at one month, and markers of residual bacterial load at the end of treatment will identify patients with tuberculosis who are cured with 4 months (16 weeks) of standard treatment. The primary objective is to demonstrate that the 18-month treatment success rate of standard treatment stopped early at week 16 (Arm C) is not inferior to standard treatment stopped at week 24 (Arm B), in participants classified as low risk for disease failure and relapse by radiographic and bacterial load markers. This is a collaborative study with funding from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, the National Natural Science Foundation of China, the China Ministry of Science and Technology, and the NIH. Study enrollment began on 6/22/2017 across 5 sites in South Africa and, as of August 1, 2017, had screened 10 and enrolled 7. The 4 sites in Henan Province, China are awaiting final regulatory approvals and are expected to be activated soon. The study will enroll 620 participants total and is expected to complete in FY 2022.
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