The Peoples Republic of China has the second highest overall case burden of TB in the world (behind India). The WHO Global Tuberculosis Report 2011 estimated that, in 2010, China had 1,500,000 cases of TB, with a prevalence of 108/100,000 population and an incidence of 78/100,000 population. For MDR TB, China has the highest annual number of cases in the world. Among all new TB cases in 2010, an estimated 5.7% (49,000 people) were MDR-TB. Among retreated TB cases in 2010, an estimated 26% (14,000 people) were MDR. 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. In response the provincial government announced that they would construct a new provincial-level infectious diseases hospital to house the research facility and better accommodate the heavy burden of patients in Henan Province. A prospective, longitudinal natural history study entitled """"""""A Natural History Study of Tuberculosis in China: Correlates of a Successful Response in Treatment"""""""" (NIAID 10-I-N060) was approved by the NIAID IRB and enrollment commenced after lab renovation and installation of equipment in March 2010. This protocol enrolled 150 subjects with suspected TB at the Henan Provincial Chest Hospital. The subjects were divided into three cohorts according to their diagnosis: A) Acid-fast bacilli (AFB) smear positive pulmonary tuberculosis, B) AFB smear negative pulmonary tuberculosis, and C) extra pulmonary tuberculosis (EPTB) and these subjects will be followed during their initial response to antituberculous chemotherapy. 25 healthy controls (Cohort D) were also enrolled to determine baseline values for immunologic responses and laboratory values. This study will analyze changes in total volume of disease as assessed by quantitative CT scanning at baseline, 2, and 6 months. In addition, we will monitor chemotherapeutic regimens, changes in the host immune response, overall changes in clinical parameters, initial and acquired drug-resistance of the infecting isolates, and changes in bacterial and host markers in subject samples during chemotherapy. In each case, we will look for associations of these parameters with rates of disease resolution correlated with specific structural features determined by CT scanning the site of TB disease. This study will allow us to evaluate eligibility criteria for future clinical trials, establish TB diagnostic accuracy, understand standard of care initial regimen selection and subsequent modifications, evaluate mycobacterial strain characteristics, extent of disease, types of lesions and host immunologic response to chemotherapy, as well as identify surrogate markers for improving monitoring of the response to chemotherapy. As of August 1, 2012, all 150 subjects were fully enrolled into the study and completed six months of follow-up. Follow-up phone calls one year later (18 months after enrollment) to ascertain TB cure vs. relapse status are ongoing. Study personnel cultured bacteria from sputa and other samples, collected and froze plasma, performed gamma interferon stimulation assays, and completed case report forms on a regular basis. The Open Clinica database designed for the study is being used by the data entry personal, allowing us to monitor the progress of the study remotely. The study team is performing QuantiFERON (QFT) testing and two molecular tests for establishing drug resistance. The QFT test uses whole blood to detect interferon gamma production in response to mycobacterial antigens in serial samples collected prior to and during anti-tubercular treatment. We are also planning to assess the changes in cytokine and chemokine levels in the patient's sera during treatment in collaboration with Drs Kaplan and Dr Sher. In addition, bacterial DNA was isolated from cultured sputa and/or sputum sediment and was used to detect rifampicin and isoniazid resistance (Hain test) and speciate non-tuberculous mycobacteria (NTM) (reverse line blot assay). Among the subject specimens tested thus far, 12% were determined to be multidrug resistant by the Hain test, 2 had XDR-TB and 5% contained predominantly NTM based on the Reba results. Two of the 3 NTMs were identified as M. intracellulare and both were subjects that had had a history of TB treatment. While the rate of MDR-TB appears lower than might be expected in a tertiary hospital, 80% of subjects enrolled in the study have never been treated for TB. In addition, the hospital staff reported that most of their previously treated patients were not eligible for the study due to the limited time allowed on anti-tuberculosis medications prior to enrollment. Half of the confirmed MDR-TB cases have occurred in subjects who were treatment nave, suggesting on-going primary transmission of MDR-TB in this study population. The second protocol for this site is now in development and will build on the results of the metronidazole and linezolid studies from Korea. Titled Tomographic Radiomarkers to Evaluate Treatment shortening of Tuberculosis (TREAT TB), the primary objective is to determine whether or not the rate of quantitative pulmonary CT diseased lung volume change at 2 months of treatment can predict treatment outcomes (cure vs. relapse) in drug sensitive and MDR pulmonary TB subjects. There is currently no good biomarker to predict treatment outcomes early in therapy. For drug sensitive pulmonary TB, the biomarker with the most experience to predict non-relapsing cure is sputum culture conversion at 2 months. Even this biomarker, however, predicts poorly with one study noting 2-month culture positivity independently predicting relapse (HR 2.8, 95% CI 1.74.7) but with a positive predictive value of only 18% and sensitivity only 50%. The data for MDR-TB patients are even less certain. Thus, MDR-TB patients are left to take a long and complex treatment regimen with no clear early predictor of cure. If a sensitive marker to predict treatment success or failure could be identified early in treatment, this could potentially have a major impact on TB clinical trials by serving as an early surrogate endpoint for treatment outcomes in drug trials, significantly reducing the time to licensure. In addition, patients on routine treatment can be assessed early for treatment outcomes, allowing additional targeted interventions for those predicted to do poorly.
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