Leprosy Mailing List – November 25, 2015
Ref.: (LML) Draft WHO Leprosy Strategy 2016-2020
From: Isabela Goulart, Uberlândia, Brazil
Dear Pieter,
Follow below my contribution to the LML debate about the Draft WHO Leprosy Strategy 2016-2020.
- Why do we need to use and discover new antimicrobials and regimens to treat leprosy?
To replace current drugs when unacceptable side effects / toxicities occur; to obtain a more “reliable” cure and to shorten the duration of treatment.
Currently it is generally recommended the same 2 or 3 drugs regimen to treat every patient with leprosy. Adverse effects of each pharmaceutical limit their utilization in a significant number of patients; leprosy is no exception; however, alternative agents and regimens have not been recommended.
The key component of the current WHO MDT treatment for the most severe cases of leprosy includes only rifampin as bactericidal agent, and the regimen with monthly administration is generally successful. The potential for intermittency with rifampin monthly doses for the treatment of leprosy may be due to the long generation time demonstrated for M. leprae, 2 weeks in vivo.
Relapse and treatment failure in MB patients, especially those with a high BI, are unacceptably high. In the National Reference Centre for Sanitary Dermatology and Leprosy, Clinics Hospital, Federal University of Uberlandia/MG-Brazil, the relapse has progressively increased from 2010. According to WHO, all MB relapse cases included in the surveillance should immediately be put on treatment with standard MB-MDT, without waiting for the results from the reference laboratory on the status for drug resistance. If the result comes back as susceptible to rifampin, MB-MDT treatment is to be continued. For patients with resistance reported only to dapsone, standard MB-MDT can be continued. In case of a patient harbouring rifampin resistant M. leprae, the following treatment should be given: administration of 50 mg of clofazimine, together with 400 mg of ofloxacin and 100 mg of minocycline, daily for six months; and 50 mg of clofazimine, together with 100 mg of minocycline or 400 mg of ofloxacin daily for an additional 18 months. This above mentioned treatment regimen is also to be used for patients reported as harbouring both rifampin and dapsone resistant M. leprae.
Can ofloxacin or minociclin replace rifampin? No. Why? Because the relative potency of active agents against LL leprosy is best judged by the time taken to clear viable M. leprae: ofloxacin and minociclin take 1-2months and rifampin takes a few days; and whether single dose regularly kill M. leprae: ofloxacin and minociclin = no; rifampin = yes. An urgent review of the recommended scheme is necessary in the light of current knowledge.
About U-MDT: paper of reference from Dr. Robert Gelber - Leonard Wood Memorial, Cebu, Philippines (Gelber et al., 2009)
The successful short-course treatment for tuberculosis requires two or more bactericidal agents (rifampin and pyrazinamide). Only rifampin is bactericidal for M. leprae and not dapsone and clofazimine.
Again, it is important to emphasize that the relative potency of active agents against LL leprosy is given by the time taken to clear viable M. leprae: rifampin takes few days; dapsone and clofazimine take 3-6 months; and also whether single dose regularly kill M. leprae: rifampin = yes; dapsone and clofazimine = no.
Considering this scientific evidence and the experience with short-course treatment for tuberculosis, how can we accept, as competent researchers, to prescribe U-MDT during 6 months for every leprosy patients, with a single bactericidal drug (rifampin) and two bacteriostatic drugs (dapsone and clofazimine), that take up to 6 months to eliminate skin bacilli in LL patients? This question has to be raised in this crucial moment.
Ideal antimicrobials to treat leprosy : 1- Bactericidal in patients (single dose kill and clear detectable viable M. leprae in days to few weeks); 2- Effective against dormant M. tuberculosis; 3- Active against M. leprae when administered intermittently.
The recent demonstration that in leprosy patients’ moxifloxacin is as bactericidal for M. leprae as is rifampin, brings into leprosy chemotherapy, for the first time, the possibility for combination of two truly bactericidal drugs (Pardillo et al., 2008). It is urgent to add moxifloxacin to leprosy therapeutic arsenal.
From the earlier results of Ji et al., 2006 and from the study of Gelber et al., 2009 with murine leprosy, the authors have demonstrated that bedaquiline (dyarilquinoline/ R207910) is bactericidal against M. leprae, not only when given once weekly, but also once monthly. All treatments were found to be bactericidal, suggesting that both low dosage and intermittent treatment with R207910 holds promise for leprosy patients . Furthermore, in 2012, The U.S. FDA, based on efficacy and safety, has approved bedaquiline for the treatment of MDR-TB. Based on these results, bedaquiline is a promising candidate for trials with leprosy patients.
I think that Dr. Gelber's team is already developing a protocol with this new drug, as was shown at the International Leprosy Congress in Brussels- Belgium in 2013. He said in his presentation that if bedaquiline proves similar bactericidal activity for M. leprae in patients and safety for long-term administration, a three drug regimen with rifamicin (rifampin) and moxifloxacin holds the best potential for leprosy treatment with an intermittent, perhaps monthly, supervised regimen, with a shorter duration than the currently required one year.
There should be an innovative approach to the leprosy treatment of the twenty-first century.
MDT, as is currently recommended by WHO, is a worn out strategy.
Furthermore, I am absolutely convinced by the scientific evidences, that U-MDT will be a mistaken strategy for the control of leprosy disease.
Best regards,
Isabela Goulart
Dr. Isabela Maria Bernardes Goulart, MD, PhD
Associate Professor – School of Medicine
Universidade Federal de Uberlândia - UFU
Coordinator and Head of the National Reference Center for Sanitary Dermatology and Leprosy - Clinics Hospital – UFU, Uberlândia - MG, Brazil
www.credesh.hc.ufu.br; credsh@hc.ufu.br; imbgoulart@gmail.com
Phone/Fax: +55 34 3216 7872; 
(34) 3210-3545
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
