Leprosy Mailing List – July 26, 2018
Ref.: (LML) Manifest Against the Implementation of U-MDT
From: Robert Gelber, San Francisco, USA
Dear Pieter,
In Cebu (1,2) I participated in the most thorough and well-documented evaluation of MB relapse following 2 year MDT. Because the results are most pertinent to the current discussion I wish to review some of these and their implications with your readers.
All patients (500) had skin lesions of leprosy, a BI at 1 or more skin sites of 2 plus or greater, and had a skin biopsy for histopathology performed by a pathologist experienced with the method of Ridley and Jopling. After the completion of therapy annual clinical follow-up and skin smears were conducted for up to 16 years. The majority of patients (316) were followed up by experienced leprologists, while the minority (184) by the general health services. Relapse (23 patients) was confirmed by both new skin lesions consistent with leprosy and an increase of BI of 2 or more at any single slit/skin site. Additionally upon relapse, skin biopsy for histopathology and in the mouse footpad M leprae viability and drug sensitivity to dapsone, clofazimine and rifampin was conducted.
Some important relevant findings of this study:
1. Most relapses occurred very late, more than 10 years after the completion of therapy, and long after the 5 to 7 years follow-up advocated by the WHO and the duration of almost all published relapse experience. In Cebu no relapses were detected in less than 5 years after the end of treatment; 8 relapsed patients were recognized 6 to 9 years thereafter, while importantly 15 patients who relapsed were only identified 10 years or more after MDT treatment had concluded. There has been precedence for vary late relapse in MB patients when as in the Cebu study rifampin is part of the regimen. Grosset (3) found in MB patients receiving a variety of rifampin containing regimens 39 relapses, all first observed a minimum 6 years after completion of therapy, on an average of 8 years and as long as 12 years after therapy had been discontinued. Pattyn (4) reported in MB patients after completing an intensive 6 week regimen of daily rifampin, dapsone, minocycline and ofloxacin that relapses began to appear 6 years after treatment and most at the completion of followup at 8-9 years. From the Cebu and these experiences, although operationally difficult, we recommend, if most relapses are to be recognized and the true incidence of relapse obtained, that follow-up for MB relapse be conducted for fully 15 years after MDT.
2. All but one of the 23 patients that relapsed had an average initial BI (6 sites) of 2.7 or more. All relapse patients prior to MDT were classified histologically to be BL or LL and at relapse BL or LL. Importantly no relapse was detected in patients with an initial biopsy of TT, BT and BB, nor in any but the one relapse with an initial average BI of 2.7 or less. Therefore, in Cebu not only do skin smears and biopsies identify those MB patients who are at risk for relapse, but, also, those who would be most unlikely to relapse. We agree then, like several others who participated in this current dialogue, that particularly skin smears but, also, skin biopsies be evaluated prior to leprosy chemotherapy. Such information is invaluable to direct reliable chemotherapy and predict the risk of relapse.
3. In Cebu relapse was found significantly higher when performed by experienced leprologists (16%) then the general health services (3%). In those with the initial BI of 2.7 or greater followed-up by experienced leprologists relapse was detected at a rate of 21%, while those by the general health services it was but 3%. These findings of a significant and profound difference in identifying relapses by well trained leprologists and the general health services demonstrate that the knowledge base,, experience and possibly procedures employed in follow-up evaluation are quite important if relapses are to be identified. In the current climate where access to trained leprosy workers has largely disappeared, training in leprosy of all physicians and health workers charged with identifying MB relapse deserves the utmost attention.
4. Skin biopsy from all 23 relapse patients grew M leprae in mice, confirming that viable bacilli were present at the time of relapse. M leprae from all 23 relapse patients were found sensitive to rifampin and clofazimine and but one dapsone resistant, demonstrating in Cebu that relapse is not associated with a significant problem of drug resistance.
There are several reports that MB relapse is both rare and common, the latter often associated with a high BI. That discrepancy may, at least in part, be a function of the frequency of the varying faces of leprosy disease and relapse presentation in disparate locales and of the different forms of the disease encountered from place to place. There are reasons why MB relapse may be missed and in studies underestimated. Some of these we touched on earlier: not a sufficiently large MB proportion who are BL/LL and with a high BI, follow-up not of sufficient duration to capture the majority of relapses and the absence of knowledgeable, thorough and sequential evaluation for relapse. On the other hand, it is hard to dismiss a relapse diagnosis when confirmed, especially with a rising BI. Though this current dialogue evolved from plans to reduce the recommendation of MB therapy from 1 year to 6 months, in Cebu and a number of other sites even 2 years MDT resulted in unacceptably high rates of relapse. MB relapse is not merely an epidemiological observation that requires further therapy, but the cause of potential pain and suffering associated with the very relapse diagnosis itself, its morbidity and the potential for side effects and toxicities of further treatment.
Now that leprosy elimination by MDT has been reliably disproved, I am sure it is sad to hear that reliable cure of MB patients is, also, in doubt. Surely then improved regimens should be developed with great urgency and implemented. Superior bactericidal activity in mice and clinical trial in leprosy to the components I most favor to marry with rifampin, moxifloxicin and minocyline, have been well-documented.
References
- Cellona RV, Balagon MF, dela Cruz EC, Gelber RH et al. Long term efficacy of 2 year WHO multiple drug therapy (MDT) in multibacillary (MB) leprosy patients. Int J Lepr Other Mycobact Dis, 2003; 71: 308-319.
- Gelber RH, Balagon MF, Cellona RV. The relapse rate in MB leprosy patients treated with 2 - years of WHO-MDT is not low. Int J Lepr Other Mycobact Dis, 2004; 2004; 72: 493-500.
- Grosset JH, Guelpa-Lauras CC, Bobin P. Study of 39 documented relapses of multibacillary leprosy after treatment with rifampin. Int J Lepr Other Mycobact Dis, 1989; 57: 607-614
- Pattyn S, Grillone S. Relapse rates and a 10 year follow-up of a 6 week quadruple drug regimen for multibacillary leprosy, Lepr Rev, 2002; 73: 245-247
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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