Manifesto of medical associations and societies against the implementation of the 6 dose Uniform Multidrug Therapy (U-MDT) for leprosy patient treatment in Brazil

It is essential to look to U-MDT (Uniform Multidrug Therapy) through the patients’ eyes. The question should be, is there strong scientific evidence to justify shortening the almost 40 year old standard antibiotic treatment regimen period for leprosy?

In a meeting on April 18^th, 2018, at the Ministry of Health headquarters, the Brazilian Technical Advisory Board (CTA) of leprosy was informed that U-MDT would be implemented in Brazil with the same antibiotics used for almost 40 years, but with half of the minimal time used now for treating multibacillary (MB) patients, and with the same antibiotics for all patients, meaning that even paucibacillary (PB) patients, currently in Brazil around 30% of all patients, would have to use rifampicin, dapsone and clofazimine, which are usually only used for MB patients.

The reasons for this change are based on a single work published in PLoS Neglected Tropical Diseases, that would support the change for the treatment regimen. Before this meeting that was held on April, 18^th, and already with the knowledge that the theme of the meeting would be U-MDT, The Brazilian Leprosy Society (SBH) published a public letter to CTA and to the Brazilian society in general, specifically to the doctors who treat thousands of cases every year in Brazil.

Despite this open letter against U-MDT, together with the opposition of 4 out of the 6 national leprosy reference centers that were represented at the meeting, there is no signal at all from the Ministry of Health to suspend the implementation of U-MDT for even a minimal discussion with stakeholders, neither patients nor the different entities that represent health professionals and scientists of this country.

Therefore, the different societies and associations signing this document, based on the following points, request to the Ministry of Health to suspend any proposal of implementation of U-MDT at this moment, and to make available resources to 1) intensify leprosy training to health professionals working at family health strategies all over Brazil; 2) support active surveillance of new cases of leprosy; 3) increase the quantity and quality of contact examination in Brazil; 4) determine the true percentage of cases with antibiotic resistance and; 5) make available new drugs for alternative drug regimens for patients with drug resistant strains or those that who do not respond well to the regular MDT used for the present treatment of leprosy. Stamp out the present troubling situation of drug resistance in the percentage of M. leprae strains on the planet (1).

The following are reasons why we believe it is irresponsible to implement U-MDT at this time:

1. An internet search for “U-MDT” on medline (US National Library of Medicine, National Institutes of Health) results in 17 citations (2–18). However, examination of the body of  these works show that 10 (58.8%) of them are from the same Brazilian group, with the same study subjects, therefore, the same sample divided between different papers, with different approaches (4–6,8–10,15–18). Among those 10, only one paper shows the results of the clinical tests per se. In addition, there are 3 works from the same Chinese/Indian group, one with the design of the study (12) and other 2 with the results (7,14), including another Indian study with clinical results of U-MDT. Therefore, altogether, there are only 3 works published with clinical results of U-MDT on leprosy patients.
2. Among all of them, published in PLoS Neglected Tropical Diseases, the Indian Journal of Medical Research, and Leprosy Review, the biggest problem is with the short follow up time of the patients, being no more than 5 years.  Important leprosy researchers, like Ji Bahong and Jacques Grosset, have always emphasized a minimum of 5 to 7 years of follow up for the evaluation of any novel leprosy regimen that makes use of rifampicin. In addition, many other leprosy clinicians and researchers, including Brazilians, are already in agreement that leprosy relapses begin to appear after 6 years of the preset therapeutic regimen, with a mean time of 10 years following treatment. Therefore, for therapeutic studies with the regular MDT scheme, the minimal period of 10 years of follow up must be obeyed. If not, as in this case, the relapse rate may not reflect the real size of the problem, with serious consequences for the patients and resulting in the continued chain of transmission of bacilli within the community.
3. Regarding the Brazilian paper used as the basis for the Ministry of Health to implement U-MDT, published in PLoS Neglected Tropical Diseases in 2017, the following shortcomings were observed:
   1. Of the 613 patients included in the study, 439 were included in the follow up study. There is no information at all about what happened to the missing 194 (31.6%) patients that were not followed until the end of the study. It is well documented that there are large numbers of drug resistance and relapses among patients who discontinue therapy.
   2. After 5 years follow up, among 439 patients, 7 relapses were observed on the U-MDT scheme, while only one relapse occurred on the regular MDT scheme. Among the 7 relapses, 4 were diagnosed during the observation period, while 3 others were seen during the passive period of follow up. It is quite obvious that when those numbers are analyzed in the totality of 439 patients, the difference between 7 relapses versus 1 may not seem to be significant, but this is not the point that should be raised. Other questions should be asked: What would be the relapse rate after 10 or 15 years of observation? Would it be higher or lower than the one observed by the authors? They estimate 4.4% of relapses in 10 years, that they refer to be “acceptable for use (of U-MDT)”. The patients in the study were evaluated in two reference centers, but in an eventual implementation of U-MDT, the patients will be treated within the family health strategy, that we already know have serious problems to correctly diagnose leprosy. What would happen with those patients if they were attended in our present care network? What is the potential of transmission of the bacilli harbored by patients to other people, who wrongly think that patients are cured by the shortened treatment period, on the community?
   3. The comparison of the relapse time of leprosy with the rapid relapse time of 4 months for tuberculosis is not reasonable. The doubling time of M. leprae (14 days) and of M. tuberculosis (1 day) is completely different. It is important to remember that the largest study of single dose rifampicin for contacts of leprosy patients was only found to be significant during the first 2 years of the study, but was insignificant from the third year of observation, with similar rates of disease in both groups, indicating that rifampicin just “delayed” the diagnosis of cases.
   4. It should be mentioned the total absence of histopathology, serology and molecular data in this study, associated with the use of the WHO operational classification, that uses only lesion counting to define the cases as PB or MB, although Ridley and Jopling has been the most used classification for leprosy research for more than 50 years.
   5. Additionally, the authors state that U-MDT adoption would prevent excessive treatment of PB patients wrongly classified as MB. However, those same patients will receive daily clofazimine for 6 months, that leads to a brownish discoloration and dry skin caused by the drug. In addition, information about PB/MB diagnosis errors is scarce.
   6. Finally, the authors state that “one potential drawback of our study may be the relatively short follow up, which does not allow the detection of late relapse cases.” Thus, even the authors admit, considering the long course of leprosy, that this short evaluation period is a drawback to their own study design, that would not permit the detection of late relapses.
4. The other 2 available papers are of short follow up, less than 5 years.
   1. The Indian/Chinese work, published in 2016 in the Indian Journal of Medical Research, shows a very low relapse rate in 5 years of follow up, but the authors state it is a rate much lower than that observed in India, and, of course, it is  less than 5 years after treatment. In addition, they state that a “key limitation (of the study) was that of inability to meet the sample size requirements for MB”. There are no data on bacilloscopy, histopatology, serology or molecular biology. The authors state that the work was done mainly for programmatic implementation.
   2. In contrast to the very low relapse rate presented above, the third work, by Rao et al. cited in 2009 in Leprosy Review, had a short follow up and only a small number of patients. It affirmed that “the study group (U-MDT) did not have a single good response at 12 and 18 months with the poor responses being 50%, 67% and 75% at 12, 18 and 24 months.” It concluded that “U-MDT of 6 months duration was well tolerated and effective in patients with PB leprosy but was too short a regimen adequately to treat patients with MB leprosy.”
5. It is important to highlight one more significant finding about the use of U-MDT in PB patients. One of the studies by the same group demonstrated that PB patients that received clofazimine had much higher rates of anemia (65% without clofazimine and 95% with the drug) in comparison to those who received regular PB MDT. There was a statistical significance when comparing PB on regular MDT to PB on U-MDT, indicating that at least 30% of the PB patients would be at significantly higher risk of anemia, unnecessarily, on this U-MDT regimen (17).
6. Finally, during the CTA meeting in Brasília, on April 18^th, 2018, four out of 6 national reference centers for leprosy, FIOCRUZ in Rio de Janeiro, Instituto Lauro de Souza Lima and the National Center in Ribeirão Preto, both in São Paulo, and the National Reference Center in Uberlândia in Minas Gerais, expressed opinions by their representatives against U-MDT implementation, and some presented data demonstrating higher relapse rates among patients that received 12 doses of regular MDT, the present scheme used in Brazil.

We believe, in addition, that it is important to cite a recent document released by WHO where it is possible to interpret that “Evidence on the potential benefits and harms of a shorter (6-month) 3-drug regimen was limited and inconclusive, with a potential increase in the risk of relapse. Therefore, the GDG determined that there was not enough evidence of equivalent outcomes to support a recommendation to shorten the treatment duration for MB leprosy”, a obviously clear position against U-MDT implementation.

It is clear to us that the present data is insufficient and, thus, there are many reasons against implementing this U-MDT regimen.

Therefore, the Brazilian Leprosy Society (SBH) and all the entities signed below, the Brazilian Society of Infection (SBI), the Brazilian Medical Association (AMB), and the representatives of the Brazilian Association of Collective Health (ABRASCO), the National Counselor of Municipal Health Secretaries (CONASEMS), the National Reference Center at Uberlândia, Minas Gerais (CREDESH), and the National Reference Center at Ribeirão Preto, São Paulo, state publicly in this manifesto that there are insufficient data to support the implementation for the short regimen proposed of 6 doses of MDT, named U-MDT.  We also want to emphasize the compelling need for increased training of basic health network personnel, aiming to increase the detection of hidden leprosy cases present today in our communities, that are suffering with the lack of diagnosis either due to the low coverage by the health network, by the absence of contact examination or by the difficulties found by the health professionals to give the correct diagnosis of leprosy (19–21). The different entities believe that is imperative to have more robust data to support major decisions like this one, that would have a significant impact on the life of the leprosy community in the present and in the future.

Date of publishing Portuguese version: May 10^th, 2018

Date of publishing English version: June 10^th, 2018

1. Benjak A, Avanzi C, Singh P, Loiseau C, Girma S, Busso P, et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nat Commun. 2018;9(1).

2. Ji B, Saunderson P. Uniform MDT (U-MDT) regimen for all leprosy patients--another example of wishful thinking. Lepr Rev[Internet]. 2003 Mar [cited 2018 Apr 29];74(1):2–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12669926

3. John AS. Incidence of neuritis among paucibacillary leprosy patients during treatment and surveillance. Indian J Lepr [Internet]. 2004 [cited 2018 Apr 29];76(3):215–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15835606

4. Penna MLF, Bűhrer-Sékula S, Pontes MA de A, Cruz R, Gonçalves H de S, Penna GO. Results from the clinical trial of uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): decrease in bacteriological index. Lepr Rev [Internet]. 2014 Dec [cited 2018 Apr 29];85(4):262–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25675650

5. Moura RS, Penna GO, Cardoso LPV, de Andrade Pontes MA, Cruz R, de Sá Gonçalves H, et al. Description of leprosy classification at baseline among patients enrolled at the uniform multidrug therapy clinical trial for leprosy patients in Brazil. Am J Trop Med Hyg [Internet]. 2015 Jun 3 [cited 2018 Apr 29];92(6):1280–4. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.14-0049

6. Hungria EM, Oliveira RM, Penna GO, Aderaldo LC, Pontes MA de A, Cruz R, et al. Can baseline ML Flow test results predict leprosy reactions? An investigation in a cohort of patients enrolled in the uniform multidrug therapy clinical trial for leprosy patients in Brazil. Infect Dis poverty [Internet]. 2016 Dec 6 [cited 2018 Apr 29];5(1):110. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27919284

7. Manickam P, Mehendale SM, Nagaraju B, Katoch K, Jamesh A, Kutaiyan R, et al. International open trial of uniform multidrug therapy regimen for leprosy patients: Findings & implications for national leprosy programmes. Indian J Med Res [Internet]. 2016 Oct [cited 2018 Apr 29];144(4):525–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28256460

8. Hungria EM, Bührer-Sékula S, de Oliveira RM, Aderaldo LC, Pontes A de A, Cruz R, et al. Leprosy reactions: The predictive value of Mycobacterium leprae-specific serology evaluated in a Brazilian cohort of leprosy patients (U-MDT/CT-BR). Johnson C, editor. PLoS Negl Trop Dis [Internet]. 2017 Feb 21 [cited 2018 Apr 29];11(2):e0005396. Available from: http://dx.plos.org/10.1371/journal.pntd.0005396

9. Stefani MMA, Avanzi C, Bührer-Sékula S, Benjak A, Loiseau C, Singh P, et al. Whole genome sequencing distinguishes between relapse and reinfection in recurrent leprosy cases. Small PLC, editor. PLoS Negl Trop Dis [Internet]. 2017 Jun 15 [cited 2018 Apr 29];11(6):e0005598. Available from: http://dx.plos.org/10.1371/journal.pntd.0005598

10. Penna GO, Bührer-Sékula S, Kerr LRS, Stefani MM de A, Rodrigues LC, de Araújo MG, et al. Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients. Azman AS, editor. PLoS Negl Trop Dis [Internet]. 2017 Jul 13 [cited 2018 Apr 29];11(7):e0005725. Available from: http://dx.plos.org/10.1371/journal.pntd.0005725

11. Prasad PVS, Babu A, Kaviarasan PK, Viswanathan P, Tippoo R. MDT-MB therapy in paucibacillary leprosy: a clinicopathological assessment. Indian J Dermatol Venereol Leprol [Internet]. 2005 [cited 2018 Apr 29];71(4):242–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16394431

12. Kroger A, Pannikar V, Htoon MT, Jamesh A, Katoch K, Krishnamurthy P, et al. International open trial of uniform multi-drug therapy regimen for 6 months for all types of leprosy patients: rationale, design and preliminary results. Trop Med Int Health [Internet]. 2008 May 13 [cited 2018 Apr 29];13(5):594–602. Available from: http://doi.wiley.com/10.1111/j.1365-3156.2008.02045.x

13. Rao PN, Suneetha S, Pratap DVS. Comparative study of uniform-MDT and WHO MDT in Pauci and Multi bacillary leprosy patients over 24 months of observation. Lepr Rev [Internet]. 2009 Jun [cited 2018 Apr 29];80(2):143–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19743618

14. Shen J, Bathyala N, Kroeger A, Arana B, Pannikar V, Mou H, et al. Bacteriological results and leprosy reactions among MB leprosy patients treated with uniform multidrug therapy in China. Lepr Rev [Internet]. 2012 Jun [cited 2018 Apr 29];83(2):164–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22997692

15. Penna MLF, Buhrer-Sékula S, Pontes MADA, Cruz R, Gonçalves HDS, Penna GO. Primary results of clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): reactions frequency in multibacillary patients. Lepr Rev [Internet]. 2012 Sep [cited 2018 Apr 29];83(3):308–19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23356032

16. Penna GO, Pontes MA de A, Cruz R, Gonçalves H de S, Penna MLF, Bührer-Sékula S. A clinical trial for uniform multidrug therapy for leprosy patients in Brazil: rationale and design. Mem Inst Oswaldo Cruz [Internet]. 2012 Dec [cited 2018 Apr 29];107 Suppl 1:22–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23283449

17. Gonçalves H de S, Pontes MA de A, Bührer-Sékula S, Cruz R, Almeida PC, Moraes MEA de, et al. Brazilian clinical trial of uniform multidrug therapy for leprosy patients: the correlation between clinical disease types and adverse effects. Mem Inst Oswaldo Cruz [Internet]. 2012 Dec [cited 2018 Apr 29];107 Suppl 1:74–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23283457

18. Ferreira IPS, Buhrer-Sékula S, De Oliveira MRF, Gonçalves H de S, Pontes MA de A, Penna MLF, et al. Patient profile and treatment satisfaction of Brazilian leprosy patients in a clinical trial of uniform six-month multidrug therapy (U-MDT/CT-BR). Lepr Rev [Internet]. 2014 Dec [cited 2018 Apr 29];85(4):267–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25675651

19. Smith WC, van Brakel W, Gillis T, Saunderson P, Richardus JH. The Missing Millions: A Threat to the Elimination of Leprosy. PLoS Negl Trop Dis. 2015;9(4).20. 21.

20. Salgado CG, Barreto JG, da Silva MB, Frade MAC, Spencer JS. What do we actually know about leprosy worldwide? Lancet Infect Dis [Internet]. 2016 Jul 1 [cited 2016 Jul 22];16(7):778. Available from: http://www.thelancet.com/article/S1473309916300901/fulltext

21. Salgado CG, Barreto JG, Silva MB da, Goulart IMB, Barreto JA, Junior NF de M, et al. Are leprosy case numbers reliable? Lancet Infect Dis [Internet]. 2018 Feb 1 [cited 2018 Jan 26];18(2):135–7. Available from: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30012-4/fulltext#.

Claudio Guedes Salgado - President of the Brazilian Leprosy Society

Sérgio Cimerman - President of the Brazilian Society of Infectious Diseases

Paulo Velho - Representative of the Brazilian Association of Collective Health

Lincoln Lopes Ferreira - President of the Brazilian Medical Society

Marco Andrey Cipriani Frade – Coordinator of the leprosy National Reference Center at Ribeirão Preto, São Paulo

Isabela Goulart – Coordinator of the leprosy National Reference Center at Uberlândia, Minas Gerais

Nesio Fernandes – Representative of the National Counselor of Municipal Health Secretaries

Claudio Guedes Salgado
Presidente da Sociedade Brasileira de Hansenologia (SBH)