Evaluation of time to detection of mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials.

Abstract

Development of new treatments for tuberculosis is hampered by the lack of an accurate surrogate end point and the high degree of efficacy of current 6-month regimens. Sputum culture status after 2 months of therapy, a binary test, is widely used for phase IIB trials but has only moderate accuracy for predicting failure/relapse (12) and requires large sample sizes (4, 8). Changes in the number of colonies found in dilutions of sputum applied to solid medium is an end point that has been used to assess activities of single drugs and doses in phase IIA (early-bactericidal-activity) studies (10) and has also been suggested as an end point for phase IIB trials (15). Though promising, quantitative culture on solid medium involves prolonged sputum collections and intensive laboratory techniques and has been difficult to standardize at multiple sites. Time to detection in broth culture (TTD) is a potential end point that has a good correlation with quantitative culture on solid medium (11, 13). An initial small study had suggested a correlation between a shorter time to detection (an indication of higher numbers of viable bacilli) and poor treatment outcomes (9). In this study, TTD was evaluated as a marker of regimen potency. Preliminary results have been reported elsewhere (16).