Leprosy Mailing List – February 18, 2015
Ref.: (LML) How Efficacious is MDT
From: Robert Gelber, University of California, San Francisco, USA
Dear Pieter,
I have been following with great interest and firm applause the several contributions to these compelling dialogues. I too wish to weigh in here:
The preponderance of evidence suggests that MB relapse is a significant problem resulting in double digit relapse rates in a number of locales, particularly occurring in patients with a high BI, and results from the failure of chemotherapy to reduce the number of viable M leprae in the patients' tissue below a critical level, thereby enabling re-multiplication of M leprae. In fact this is not surprising as many years ago in Malaysia we found following a far more robust and bactericidal treatment than MB MDT, consisting of 5 years of daily rifampin, that M leprae grew in mice in 1 or more tissue samples (skin, peripheral nerves, dartos muscle and skeletal muscle) in 20 of 32 patients, these persisters being most likely the source of relapsed leprosy in MB patients.
Dr. Warren rightly makes the case for carefully following patients after completion of MDT. Unfortunately, the WHO has never recommended follow-up of patients after completion of MDT and conversely view that once therapy is complete the leprosy burden would be eliminated, those patients no longer considered a “case". Surely with the current reduction of leprosy and its resources follow- up after completion of MDT is rare. Importantly, we found in the Philippines that MB relapses were detected 3 times more frequently when conducted by seasoned leprologists rather than by the general health services. Certainly relapse detection cannot be expected to be robust in the integration era and when leprosy skills are on the wane.
Prior to the initiation of MDT for leprosy, painstaking short course chemotherapy trials for pulmonary tuberculosis, which ultimately resulted in the sequential and successful reduction of therapy from 2 years to 6 months, rejected regimens with relapse rates greater than 5%. Yet for leprosy policy makers appear unconcerned with relapse frequencies which are considerably higher. In fact success in leprosy treatment is measured by the number of patients completing MDT, and treatment recommendations have progressively reduced the duration of therapy and operational requirements to promote the elimination goal, while ignoring the considerable problem of MB relapse and in fact the reliable cure and well-being of leprosy patients, that relapse being a source of the spread of infection to others. Surely there are studies that have found MB relapse after MDT to be low but these are flawed owing to the follow- up duration being too short and the studies conducted in locales with but a few MB patients with a high BI.
Definition of MB relapse has varied considerably and included one or more of 3 features- new skin lesions, a rise in BI (generally of 2 + or more) and growth of M leprae from relapse sites in the mouse foot pad. In Cebu, Philippines where I was Scientific Director all 3 requirements were met in 22 patients. I wish to share a few more observations from that best documented relapse series:
1. The earliest relapse occurred 6 years after the completion of MB MDT and 2/3 of relapses 10 or more years thereafter.
2. All relapses occurred in BL (10) or LL (12) patients.
3. All but 1 of the relapses occurred in MB patients with an average BI (6 sites) of greater than or equal to 2.7.
As a consequence of claims of leprosy elimination the very tools to recognize MB relapse have been largely lost - skilled leprologists are rapidly disappearing, while more and more the general health services, largely untrained and inexperienced with leprosy are the primary providers of leprosy care, skin smears and biopsies are no longer required and rarely practiced, and mouse footpad facilities are close to non-existent.
My own experience with treating 125 BL and LL patients in San Francisco for 19 years found that the regimen used, daily dapsone and rifampin for an average of 5 years followed by daily dapsone alone indefinitely resulted in no relapses after an average follow up of 10 years which included annual clinical examination and skin smears. Perhaps for a subset of MB patients, particularly those with a high initial BI lifelong therapy could be the treatment of choice. In fact, if I had such leprosy that is what I would do. Though largely forgotten it should be remembered that the WHO regimens were first designated for Control Programmes and never considered to be the optimal therapy for leprosy. Of course lifetime therapy for a subset of MB patients surely will not promote elimination targets but may reliably cure patients which it is of course our goal. Many medical conditions require lifetime treatment, including diabetes, hypertension, gout, hypercholesterolemia and etc. Once we did this for certain forms of leprosy with great success. Why not again for some?
MB relapse following MDT with its potential to result in neuropathy and deformity as was reported by Dr. Shetty is not the only reason to advocate for alternative regimens. Patient intolerance and side effects to the 3 components of MDT is not uncommon, and yet alternative antimicrobials, when these occur, have not been addressed by policy makers. The current high MB relapse rate is surely a compelling cause to seek improved MDT. I believe a new generation of more bactericidal MDT composed of 2 other agents which have proved more active and bactericidal both in M leprae infected mice and in MB patients and superior to 2 of the 3 individual components of MDT, namely dapsone and clofazimine both of which are bacteriostatic. To replace dapsone and clofazimine candidate agents include the fluoroquinolones, particularly moxifloxicin which has been established in mice and MB patients to be the only agent to date which is similarly bactericidal as is rifampin, minocycline and clarithromicin. This prospect holds promise for the subset of leprosy patients prone to fail MDT as the short course of chemotherapy of tuberculosis was found to require 2 or more bactericidal agents, while current MDT for leprosy has but 1, rifampin.
The most recent WHO amendments to MDT, A-MDT and U-MDT, surely promote the elimination goal. A-MDT permits the distribution of the full complement of medication at the time of diagnosis, making a new patient no longer a considered "case", while U-MDT reduces the duration of leprosy treatment for MB patients from 1 year to 6 months. A-MDT compromises effective treatment by eliminating DOT which contains the most robust MDT component, rifampin, DOT being considered necessary and critical to successful treatment of active pulmonary tuberculosis. Furthermore, the reduction of treatment duration of MB leprosy provided by U-MDT is occurring in the context where 1 year MDT has not yet been shown to result in a reliable and convincing cure rate and adds clofazimine with its troublesome discoloration to the treatment of PB patients where cure rates without it are already exemplary.
In conclusion, those at risk for relapse after completion of MDT are a substantial percentage of the leprosy population, those previously classified as LL and BL. While the WHO advocates follow-up for relapse in patients completing treatment of active pulmonary tuberculosis, 90% of relapses occurring within the first year after completion of MDT, while no active follow up after completion of leprosy MDT has been advocated. Surely for not looking for relapse and in a systematic annual fashion it has been under reported. Also, the fact that MB relapse occurs very late and only in a subset of MB patients, it has not been universally evident. Nonetheless, it should no longer be ignored.
Selective references:
1. Baihong J, Does there exist a subgroup of BM patients at greater risk of relapse after MDT? Leprosy Review, 2001, 72, 3-7.
2. Gelber R H, Balagon VF, Cellona RV, The relapse of MB leprosy patients treated with 2 years WHO-MDT is not low Int, J, Lepr, 2004, 72, 493-500
3. Gelber R H, Grosset, J, The chemotherapy of leprosy: An interpretive history, Leprosy Review, 2012, 83, 221-240.
Robert Gelber
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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