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Development and Implementation of Clinical Trials to improve Patient Management, Treatment Efficacy and Disease Prevention

The management of TB patients who fail, relapse or default from first-line treatment is becoming an increasingly complex and urgent problem. An estimated 1 million patients worldwide may be in need of 'retreatment' for TB. The development of currently recommended retreatment regimens pre-date the use of rifampicin-throughout regimens and there is clear consensus that they are no longer appropriate in the current environment of widespread six-month, rifampicin-throughout, first-line regimens. Moreover, their lack of effectiveness is likely accompanied by a substantial risk of amplification of drug-resistance and contribution to the global MDR-TB epidemic. While the state of research evidence and particularly clinical trial evidence for TB treatments in general is lacking, the necessary evidence to guide decision making for retreatment patients is almost non-existent. There is an urgent need for immediate guidance for global and national policy in this regard. This need is heightened by current efforts to revise global TB management guidelines by several international bodies. There is an equally urgent need for a comprehensive and efficient program of clinical research in this area to ensure a sufficient evidence base for future decision making in the field.

An estimated 490,000 new cases of multi-drug resistant tuberculosis (MDR-TB) emerged in 2006 according to the most recent available data. Less than 5% of these cases were officially reported on treatment with known regimens and outcomes. Others were likely treated using unproven or even dangerous treatment approaches. New treatments, as well as new approaches using existing drugs, are required in order to reach all patients with drug resistant TB. WHO recommends two basic models for the treatment of MDR-TB. Individualized Treatment (IT) relies on Drug Susceptibility Testing (DST) of the patients' strains to a full range of first- and second-line drugs. This strategy is both expensive and requires quality assured laboratories capable of undertaking DST, as well as the presence of specialist physicians to prescribe regimens. The Standardized Treatment (ST) model is an empiric alternative (WHO, 2006) based on a common DST profile of the prevalent MDR-TB strains in a given area, and is recommended in locations with homogeneous drug resistance patterns and limited use of second-line drugs. To date, there has been no controlled comparison of the relative merits of the two strategies. In situations where performance of DST is not optimal and/or IT monitoring is not possible, it is important to evaluate whether ST is safe and effective.