THELEP, The Scientific Working Group on the Chemotherapy of Leprosy

(a brief history, and a summary of its activities)

In the course of a workshop on the chemotherapy of leprosy (Gelber RH, Int J Lepr 44 (1976) 369-373), sponsored by the U.S. Leprosy Panel of the U.S.-Japan Cooperative Medical Science Program, and held at the National Institutes of Health in Bethesda in the summer of 1975, the need to develop combined drug regimens for the treatment of multibacillary (MB) leprosy was discussed. It was clear that drug-resistance could be prevented only by the employment of combinations of bactericidal agents, each agent acting by a different mechanism. And it was hoped that the Mycobacterium leprae persisting after treatment by a single drug would be killed by the other drugs comprising the combination.

A practical problem was the limited sensitivity of the mouse foot pad system employing immunologically intact mice: M. leprae fail to multiply in these mice if the inoculum were much larger than 104 organisms per foot pad, and it is difficult to distinguish persistence of the inoculated organism in the foot pad from true multiplication. The M. leprae that persisted during treatment with rifampicin, which had been demonstrated by Rees and his colleagues (Rees RJW, et al., Int J Lepr 44 (1976) 156-169), comprised too small a proportion of the bacterial population to be detected by so small an inoculum. It was clear that, because of its great efficacy, one of the components of any combined regimen would be rifampicin; yet, rifampicin alone was so rapidly bactericidal that no additional effect of the other components of a combined regimen could be demonstrated by inoculating intact mice with a small number of M. leprae. The workshop concluded that it would be necessary to carry out clinical trials of combined drug regimens among previously untreated patients with MB leprosy, employing immunosuppressed mice inoculated with 105 M. leprae per foot pad. Such trials became the first order of business of the Scientific Working Group (SWG) on Chemotherapy of Leprosy, THELEP.

THELEP controlled clinical trials

THELEP began in April 1976 with the meeting of the THELEP Planning Committee (1), which commissioned the preparation of a Standard Protocol for Controlled Clinical Trials of Combined Chemotherapy (2) among previously untreated MB patients. The primary focus of the trials was to be the detection of persisting M. leprae by the inoculation of thymectomized-irradiated mice with approximately 105 organisms per hind foot pad. At the first meeting of the THELEP SWG, in April 1977, a draft Standard Protocol was reviewed and adopted, experimental combined-drug regimens were designed, and applications were approved from the Institut Marchoux, Bamako, Mali and the Central Leprosy Teaching and Research Institute, Chingleput, South India, to conduct trials of the regimens, and from the National Institute for Medical Research (NIMR), London, to inoculate mice with the M. leprae recovered from biopsy specimens to be obtained at intervals from the patients recruited into the trials in Bamako and Chingleput. In addition, the pre-treatment susceptibility to dapsone of the patients' organisms was to be measured by inoculation of intact mice at St. George's Hospital Medical School, London.

In Bamako and Chingleput, 215 patients were recruited into the two trials, and 769 biopsy specimens were shipped to London for inoculation of mice. Five regimens were selected for study, not because they might be applied in leprosy control, but rather to test various hypotheses with respect to the nature of persisting M. leprae. Two were "maximal" regimens, consisting of daily doses of rifampicin, dapsone and either clofazimine or protionamide; two were intermediate regimens, consisting of either daily dapsone supplemented by an initial single dose of rifampicin and clofazimine administered daily for only the first three months, or daily dapsone supplemented by daily doses of protionamide and weekly 900-mg doses of rifampicin for the first three months; the fifth regimen, the "minimal" regimen, consisted of daily dapsone supplemented only by a single initial dose of rifampicin. The regimens were to be administered for two years. The results of these trials, which were reported in a series of publications (3-11), may be summarized as follows:

· persisting M. leprae were detected in approximately 9 per cent of all biopsy specimens; and

· more than one-third of the patients recruited into the trials in Bamako and Chingleput were found to harbor M. leprae resistant to dapsone in the biopsy specimens obtained before treatment by the experimental regimens was begun.

Detection of the persisters appeared to be a random event: the frequency with which persisting organisms were detected in more than a single specimen from the same patient was no greater than that predicted by chance; and persisters were detected with approximately the same frequency in specimens obtained after 3, 12 and 24 months, without regard to regimen.

Studies of dapsone-resistance

Studies of resistance to dapsone were also an important priority for THELEP. Approximately 37 percent of the patients recruited into the THELEP trials of combined chemotherapy in Bamako and Chingleput were found to harbor primarily dapsone-resistant M. leprae (4, 6). In addition, THELEP prepared the protocols for and supported surveys of primary resistance to dapsone in Addis Ababa (12), which yielded a prevalence of 67 per 100 patients at risk, and Cebu (13), which yielded a prevalence of only 3 - 6 per 100. The high prevalence of primary dapsone-resistance in Addis Ababa, Bamako and Chingleput suggested that patients who relapsed during dapsone monotherapy infected their contacts with dapsone-resistant M. leprae.

Other studies

In addition to the conduct of controlled clinical trials of combined chemotherapy of MB leprosy, and work to measure the extent of dapsone-resistance, THELEP conducted important activities and promoted research in other areas including:

· screening of drugs, both old and novel, for antimicrobial activity against M. leprae, and studies of the mechanisms of action these compounds (drug-development);

· "field" trials of practical MDT regimens, administered for no longer than a few years, among large numbers of both paucibacillary (PB) and MB patients; and

· short-term trials of new agents and combinations of agents among patients with MB leprosy.

Drug-development and screening

With support from THELEP, a number of workers screened for activity against M. leprae a large number of compounds representing many classes of compounds, including analogs of cycloserine, dapsone and rifampicin, as well as series of thiosemicarbazones, thioamides, cephalosporins, macrolides and inhibitors of dihydrofolate reductase, employing both M. leprae and batteries of cultivable mycobacterial species. This work was reviewed in (14).

More recently, in work supported by THELEP, a number of new compounds demonstrating bactericidal activity against M. leprae were identified in the mouse foot pad system, including the fluoroquinolones pefloxacin (15), ofloxacin (16, 17), sparfloxacin (18, 19), moxifloxacin (20), the macrolide clarithromycin (21, 22), the tetracycline minocycline (22, 23), and the rifamycin rifapentine (20, 24-27). These studies revealed that clarithromycin, minocycline, ofloxacin and sparfloxacin exert a similar degree of bactericidal activity against M. leprae, and that, although they are less potent than rifampicin, they are significantly more active than either dapsone or clofazimine alone. Moxifloxacin is the first and, thus far, the only non-rifamycin that displays a degree of activity virtually identical to that of rifampicin in mice, and is far more bactericidal than is ofloxacin, clarithromycin or minocycline. Rifapentine is more powerfully bactericidal against M. leprae than rifampicin or the combination rifampicin-ofloxacin-minocycline (ROM). These results demonstrated that screening of existing compounds is the most cost-effective approach for drug development in leprosy, and indicated that the most productive approach is to screen compounds that display powerful activity against either a wide spectrum of gram-positive microorganisms in general, or cultivable mycobacteria in particular, or that exhibit pharmacokinetic properties more favorable than those exhibited by the member of the class presently employed for treatment of leprosy (20).

Field trials

At its first meeting, in April 1977, the THELEP SWG decided that it could not ethically discontinue treatment once patients had completed two years of therapy by the experimental combined-drug regimens; it was feared that a significant proportion of the patients would relapse once treatment was withdrawn. However, at its second meeting, two years later, the THELEP SWG became aware of the results of work in Sungei Buloh (Waters MFR, et al., Lepr Rev 57 (1986) 101-109) and Malta (Jopling WH, et al., Lepr Rev 55 (1984) 247-253), which suggested that the risk of relapse after withdrawal of treatment among well-treated patients was very small. These results encouraged the SWG to conduct "field trials" in Polambakkam and Gudyattham Taluk, both in South India, in which large numbers (approximately 400 per regimen) of previously treated (by monotherapy with dapsone) and bacteriologically negative MB patients were to be administered a combined-drug regimen for two years after achievement of skin-negativity, after which treatment was to be withdrawn and the patients observed for evidence of relapse.

The regimen, which consisted of rifampicin and clofazimine, each administered in a monthly dosage of 600 mg daily on two consecutive days, accompanied by bimonthly injections of 225 mg acedapsone and daily self-administered dapsone, served as a model for the MDT regimen for MB leprosy recommended by the WHO Study Group on the Chemotherapy of Leprosy for Control Programmes (WHO Tech Rep Series 675, 1982). Immediately following the meeting in 1981 of the WHO Study Group, THELEP added a second regimen - that recommended by the Study Group for treatment of MB leprosy, the WHO/MDT regimen - to the "THELEP regimen" already described. Newly recruited patients in Polambakkam and Gudyattham Taluk were randomly assigned to treatment by either the THELEP or the WHO/MDT regimen. No relapses were encountered among the more than 2,200 patients treated by either regimen (28-31).

Recognizing the importance of PB leprosy, both as an important cause of impairments, and as a precursor of MB leprosy, THELEP sponsored two field trials of chemotherapy among patients with PB leprosy -- one in Indonesia, and the other in Malawi. Although no publications resulted from the trial in Indonesia, the results of the trial in Malawi were published (32, 33).

In 1991 and 1992, THELEP (now known as "THEMYC") launched a large multicenter field trial of ofloxacin-containing combined regimens in a randomized, double-blind, controlled clinical trial among both MB and PB leprosy patients (34). One of the regimens in the trial is a combination of rifampicin plus ofloxacin daily for 4 weeks for both MB and PB leprosy. The other two regimens, both for MB leprosy, are the WHO-recommended MDT for 1 year, with or without supplementation by daily ofloxacin during the first 4 weeks. The control regimen is the standard WHO-recommended MDT regimen for 24 months. Fifteen centers from eight endemic countries are participating in this trial. The intake of nearly 4000 patients was completed in June 1994, treatment was completed in December 1996, and follow-up will continue until December 2003.

Short-term trials

Short-term trials require the recruitment of only 6 - 10 untreated MB patients per regimen. Treatment is administered as a single dose or for no longer than a few months, skin lesions are biopsied at intervals during treatment, and the M. leprae recovered from the biopsy specimens are inoculated into mice. After treatment by the experimental drug or regimen has been completed, the patient is placed under treatment by MDT as if he had not previously been treated.

Immediately after the active new drugs had been identified by screening in M. leprae-infected mice, short-term clinical trials of pefloxacin (35), ofloxacin (35-37), clarithromycin (38, 39), minocycline (38, 40), and sparfloxacin (41) were launched, in most of which the therapeutic effects of the treatment were monitored by mouse foot pad inoculation. Treatment by any of these compounds alone demonstrated considerable bactericidal activity against M. leprae. For example, 99.99% of viable M. leprae were killed by 22 daily doses of pefloxacin 800 mg or ofloxacin 400 mg (35), and > 99% killing was observed after 28 days of daily administration of 100 mg minocycline, 500 mg clarithromycin (38) or 200 mg sparfloxacin (41). Single doses of the combinations clarithromycin-minocycline (39) or ofloxacin-minocycline (36) displayed bactericidal activity against M. leprae equivalent to that of four weeks of daily treatment by the combination dapsone-clofazimine; however, the gastrointestinal side-effects associated with large doses of clarithromycin were not well tolerated by patients.

Encouraged by these results, the combination rifampicin-ofloxacin-minocycline (ROM) was tested in clinical trial; a single dose of this combination displayed great bactericidal activity against M. leprae (36). More recently, following the discovery that moxifloxacin exerts a very powerful bactericidal effect on M. leprae, virtually identical to that of rifampicin, that rifapentine is far more bactericidal than is rifampicin, and that a single dose of the combination rifapentine-moxifloxacin-minocycline (PMM) killed 99.9% of viable M. leprae, it appeared likely that PMM may be more efficient than ROM as a fully supervised, monthly-administered multidrug regimen for leprosy (20). A clinical trial is being conducted to compare, in terms of both therapeutic effects and side-effects, PMM with ROM and the combination moxifloxacin-minocycline with the combination ofloxacin-minocycline.

Literature cited

Entry updated February 2016