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 2015 estimated that, in 2014, China had 1,200,000 cases of TB, with a prevalence of 89/100,000 population and an incidence of 68/100,000 population. For MDR TB, China has the 2nd highest annual number of cases in the world. Among all new TB cases in 2014, an estimated 5.7% (43,000 people) were MDR-TB. Among retreated TB cases in 2014, an estimated 26% (8,200 people) were MDR. (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 the 13th 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 in Zhengzhou, the capital of Henan Province, the Tuberculosis Research Section is developing the sites capacity to conduct high-quality clinical research. In 2009, NIAID Deputy Director Hugh Auchincloss signed an Implementing Arrangement with the Henan Provincial Bureau of Health to establish a collaborative research center. 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, began enrollment in 2010 with all subjects completing the study 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, one patient from this cohort was noted to have dramatically increased sputum AFB bacillary load 6 weeks after starting treatment, after which bacterial counts slowly decreased. This patient had multiple anatomically discrete sites of pulmonary disease that responded different to treatment, suggesting that heterogeneous Mtb populations existed. Deep whole genome sequencing of serial sputum isolates confirmed three dominant subclones at week 6, two of which were not observed at baseline. The three subclones had different drug resistance patterns, which may explain the heterogeneous response to treatment. This result suggests that branched evolution of Mtb in vivo can lead to divergent Mtb subclones and heterogeneous responses to treatment within a single individual. (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 began in FY2014 and was conducted in conjunction with the Clinical Diagnostics Research Consortium (PI: Susan Dorman, Johns Hopkins University). 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. From June 2014 to June 2015, the study enrolled 286 subjects in the Korean sites. Data analyses show 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, 2016, had screened 46 subjects and enrolled 40 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 1st quarter 2016 across 5 sites: Brazil, Kenya, Uganda, South Africa and China (HPCH). China completed its enrollment quota in August 2016 with 286 total participants and the last follow up visit is expected in October 2016. Data analysis for the study is currently ongoing in collaboration with Cepheid and FIND.
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