Leprosy Mailing List – January 8, 2014
Ref: (LML) Duration of MDT MB, relapses and reinfection; (LML) higher risk of relapses in BL/LL with BI 4 or more after MDT-U and MDT 12 doses
From: Robert Gelber, University of California, San Francisco, USA
Dear Dr. Schreuder,
The critical issue in this ongoing important dialogue is whether leprosy relapse after MDT in BL/LL patients with a high BI is of considerable frequency or rare. In fact Ji Baohong (1) and I (2) separately concluded that such relapse is indeed frequent and an important problem long-needing to be addressed. Indeed, there are a number of published series confirming that conclusion from India [17% ( 3)], South America [20% ( 4)], Southeast Asia [17% ( 5)], and Africa [40% ( 6)], as well as several others, which found unacceptably high relapse rates in MB patients with a heavy bacterial burden, that to date remain unpublished.
At the skin clinic of the Leonard Wood Memorial, I and my colleagues reported relapse in a high percentage of MB patients treated with 2 years of WHO MDT (2,5). All relapse cases were BL or LL, all with an average BI of 2.7 or greater in 6 sites, and on prolonged annual follow-up comprised the largest well-documented MB relapse cohort, a total of 23 cases. In all these relapses M leprae grew in the mouse footpad and was consistently found sensitive to rifampin and clofazimine, while one isolate was dapsone resistant. In that cohort relapse was in all instances associated with new leprosy skin lesions and an increase in the BI of 2 or more. In the Philippines it was noteworthy that the earliest relapse was detected 6 years after the completion of MDT. There we found that the risk of relapse was nearly twice as much 10 years after MDT was completed, than prior to that time. A similar experience of late relapse in MB patients was reported by Pattyn after a 6 week intensive quadruple regimen (rifampin, ofloxacin, dapsone, and minocycline), where relapses were first detected 6 years after the completion of therapy and with a doubling of relapse rate in years 8 and 9 thereafter. Also, in the Philippines (5) the detection of relapse was found to be substantially and significantly lower (3%) when patient follow up was conducted by well-trained and experienced leprosy health workers rather than the seasoned physician staff of the skin clinic.
There is certainly contradictory data demonstrating that relapse rates following 2 year MDT for MB leprosy is low. However these studies are wanting on several grounds, including in all instances 2 or more of the following: data was either based on questionnaires, a short duration of follow up, a low percentage of patients with a high bacterial burden, follow up not conducted by experienced leprologist, and follow up not conducted annually. In a recent editorial I and Grosset (8) reviewed the evidence that relapse in MB patients with a high BI is in fact frequent and proposed alternative regimens for such patients.
Unfortunately, evidence that MB relapse in patients with a high BI has not been generally recognized because the same powerful forces in the leprosy oligarchy that have long promoted that MDT can promote leprosy elimination are, also, of a mind that the WHO regimens themselves are reliably curative in treating all patients. We believe this is not true for MB patients with a high bacterial index, there is substantial data to support that conclusion, and that a new generation of MDT should be evaluated in that cohort.
Since 1982 when MDT was first adopted, particularly minocycline (9) and moxifloxacin (10) have been convincingly demonstrated in clinical trial in MB leprosy to be far more rapid in both clinical improvement and the killing of M leprae than dapsone and clofazamine, the killing of M leprae by moxifloxocin only equaled by rifampin.
At the recent international congress in Brussels, there were presentations confirming that in MB patients the combination of rifampin, minocycline and moxifloxacin, resulted in both a faster clinical response and a lower relapse rate than did WHO MDT. Large scale trials with prolonged follow up comparing that regimen with MDT are certainly in order. I believe we can do better, but will progress be supported or thwarted by lobbies unwilling to acknowledge that current MDT can, despite the available data, be unreliable for a subset of MB leprosy patients.
Best regards,
Robert Gelber
References:
1. Baohong, J. Does there exist a subgroup of MB patients at greater risk of relapse after MDT? Lepr Rev, 2001; 72: 3-7.
2. Gelber RH, Balagon MVF, Cellona RV. The relapse rate in MB leprosy patients treated with 2-years of WHO-MDT is not low. Int J Lepr, 2004; 72: 493-500.
3. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. Lepr Rev, 2000; 71: 144-153.
4. Guerrero - Guerrero MI, Muvdi- Arenas SM, Leon - Franco CI. Relapses in multibacillary leprosy patients: A retrospective cohort of 11 years in Colombia. Lepr Rev, 2012; 83: 247-259.
5. Cellona RV, Balagon MVF, dela Cruz EC et al. Long-term efficacy of 2 year WHO multiple drug therapy (MDT) in multibacillary (MB) leprosy patients. Int J Lepr, 2003; 71: 308-319.
6. Jamet P, Baohong J. Relapse after long - term follow up of multibacillary patients treated by WHO multi drug regimen. Marchoux Chemotherapy Study Group. Int J Lepr, 1995; 63: 195-201.
7. 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.
8. Gelber RH, Grosset J. The chemotherapy of leprosy: An interpretive history. Lepr Rev, 2012; 83: 221-240.
9. Gelber RH, Fukuda K, Byrd S et al. A clinical trial of minocycline in lepromatous leprosy. BMJ, 1992; 304: 91-92.
10. Pardillo FE, Burgos J, Farjardo TT et al. Powerful bactericidal activity of moxifloxacin in human leprosy. Antimicrob Agents Chemother, 2008; 52: 3113-3117.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
