Multi-Drug Resistant Tuberculosis in Korea

This natural history study seeks to determine some of the mycobacterial and host factors involved in the failure of antituberculous chemotherapy, disease recurrence, and the development of multidrug resistance by M. tuberculosis. Despite optimal treatment with directly-observed short-course therapy (DOTS), about 5-10% of compliant patients with "cured" tuberculosis relapse, usually within a year after completion of therapy. In Korea, where DOTS is not practiced, the relapse rate has been reported to be 15 to 20 %. In individual patients, failure to eradicate disease contributes directly to the development of drug-resistance and to low overall cure rates. While factors such as patient drug compliance and HIV status have been extensively studied in relation to rates of relapse; host genetic factors and the specific relevance of the infecting mycobacterial strain have not yet been investigated in detail. Identification of patient characteristics and specific strains of M. tuberculosis that are associated with relapse and the evolution of drug resistance would greatly facilitate the development of treatment protocols that might avoid these complications.

Our study population will consist of subjects with pulmonary tuberculosis receiving treatment at our study sites. Healthy volunteers will be selected as the genotypic control population. All subjects with tuberculosis enrolled in the study will be followed by periodic chart review and data extraction during their treatment and follow-up at participating study sites. For 2.5 years after completing drug treatment, tuberculosis recurrence among study subjects will be identified using periodic chart abstraction and follow-up phone calls every 6 months to determine the 2 year recurrence rate for tuberculosis (TB). M. tuberculosis isolates may be collected from subjects with recurrent TB and analyzed to distinguish between relapse and re-infection.

Study subjects will be asked to provide 10 mL of blood and 5 to 30 mL of sputum for acid-fast bacilli (AFB) smear and culture at entry. Sputum will be cultured for M. tuberculosis and isolates will be tested for drug resistance (DR). The research staff may use molecular DR tests to confirm the agar-growth DR results. In addition, subjects will be asked a series of medical history questions including history of prior tuberculosis, antituberculous treatment, disease contacts, and risk factors associated with tuberculosis; and will be asked to give consent to allow clinical research staff to abstract treatment regimens and results from their inpatient and outpatient medical charts for the duration of their participation in the study (treatment and follow-up).

• INCLUSION CRITERIA:

For the new cases disease group (Cohort A):

• Age greater than or equal to 20 years old;
• Primary treatment (new TB subject by WHO definition) for tuberculosis without treatment interruption (greater than or equal to 60 days) and with at least 4 months of treatment remaining;
• Clinical signs or symptoms suggestive of tuberculosis;
• Sputum AFB smear-positivity or confirmed MTB using any molecular test

For previously treated disease group (Cohort B):

• Age greater than or equal to 20 years old;
• Treated for tuberculosis previously with more than 30 days of drug treatment and either:

• a treatment interruption of greater than or equal to 60 days (includes relapse and treatment after interruption), or
• who have experienced treatment failure or have chronic TB.
• Clinical signs or symptoms suggestive of tuberculosis;
• Sputum AFB smear-positivity or confirmed MTB using any molecular test

For healthy controls (Cohort C):

• Age greater than or equal to 20 years old;
• No previous diagnosis of TB as reported by the subject;

Exclusion criteria

For TB Subjects

• Women who report themselves to be pregnant or possibly pregnant during the protocol introduction and consent process (pregnant women are not normally treated at NMTH).

For Healthy Volunteers:

• Women who report themselves to be pregnant or those found to be pregnant by a urine Beta-HCG test during the protocol introduction and consent process.
• Those having a chest X-ray suggestive of active tuberculosis.