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International Consortium for Trials of Chemotherapeutic Agents in Tuberculosis (INTERTB)

SCIENTIFIC PROGRAMME

The scientific programme is aimed partly at improvement of current regimens, either by shortening durations of treatment or through the development of intermittent regimens, and partly at assessing new anti-tuberculosis drugs. For the moment, at least, the work will be confined to tuberculosis infections and not to infections with other mycobacteria.

Some of the methods used in assessing chemotherapeutic agents have been described by Mitchison (J Applied Bact 81 1996 & Frontiers in Bioscience 9  2004).

It is planned to study, through basic research and clinical trials, the speed of bactericidal activity of drugs during chemotherapy and the phenomenon of bacterial persistence.

2.1 Basic research on chemotherapy

Clinically, persistent bacteria, related to those in the latent state, are mainly responsible for the current lengthy duration of chemotherapy. It has been demonstrated (Hu et al. J. Bacteriology 2000; 182: 6358-6365) that these persistent bacilli are metabolically active. There are probably several distinct bacillary populations in lesions with different characteristics such as ability to grow in liquid or solid medium and tolerance to rifampicin. This implies that it may be possible to find new drugs which specifically target some or all of these persistent bacilli (Coates et al. Nature Reviews 2002; 1: 895-911). It also implies that it is possible to design in vitro tests that will distinguish between the efficacy of different drugs with respect to these populations of bacilli Hu et al. Antimicrob Agents Chemother 2003; 47: 653-657;  Mitchison DA, & Coates ARM Curr Pharm Design 2004. In press).

2.2. Surrogate markers of relapse

Studies of surrogate markers of relapse are required to obtain a preliminary indication of efficacy and of the sterilising activity of a drug. The advantage of such studies are that they require small groups of patients and results are available within a short space of time. These studies are also necessary because of the great difficulty of assessing a new drug or change of drug dosage in ethical phase III trials.

Surrogate markers would be one of the major areas of investigation by the consortium. The only marker that has been well validated so far is the culture result at two months following chemotherapy. These studies will include estimations of early bactericidal activity (EBA) and the several markers of sterilising activity.

2.3 Clinical trials

The major end-points in randomised clinical trials are failures during treatment and relapses after treatment while additional information is available from the proportion of patients with positive sputum cultures at 8 weeks. In most studies, there will be a bacteriological follow-up to detect relapse for 2 years after the end of chemotherapy.

2.3.1  See full document for details of the proposed trials.

2.3.2 Other clinical trials include:

There is some discussion about how best to treat cases of tuberculosis which are resistant to both isoniazid and rifampicin. These cases are defined as being multi-drug resistant (MDR) and their management poses problems in centres where susceptibility tests are not readily available. A major problem is that the activity of these drugs are not known and they have never been graded according to their activity.