Leprosy is a chronic human disease caused by the yet-uncultured pathogenMycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtainM. lepraegenome sequences from DNA extracted directly from patients’ skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154 genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East. In addition to known MDT-resistance mutations, we detect other mutations associated with antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these (ribD,fadD9) are restricted to drug-resistant strains. Finally, nonsense mutations in thenthexcision repair gene are associated with greater sequence diversity and drug resistance.

In this review, the most relevant and current epidemiological data, the main clinical, laboratory and therapeutical aspects of leprosy are presented. Detailed discussion of the main drugs used for leprosy treatment, their most relevant adverse effects, evolution of the therapeutic regimen, from dapsone as a monotherapy to the proposed polychemotherapy by World Health Organization (WHO) can be found in this CME. We specifically highlight the drug acceptability, reduction in treatment duration and the most recent proposal of a single therapeutic regimen, with a fixed six months duration, for all clinical presentations, regardless of their classification.

Treatment default is a serious problem in tuberculosis control because it implies persistence of infection source, increased mortality, increased relapse rates and facilitates the development of resistant strains. This study analyzed tuberculosis treatment default determinants in the Amazonas State to contribute in planning appropriate control interventions. Observational study with a retrospective cohort using Brazilian Disease Notification System data from 2005 to 2010. A nested case control study design was used. Patients defaulting from treatment were considered as ‘cases’ and those completing treatment as ‘controls’. In the analysis, 11,312 tuberculosis patients were included, 1,584 cases and 9,728 controls. Treatment default was observed to be associated to previous default (aOR 3.20; p<0.001), HIV positivity (aOR 1.62; p<0.001), alcoholism (aOR 1.51; p<0.001), low education level (aOR 1.35; p<0.001) and other co-morbidities (aOR 1.31; p = 0.05). Older patients (aOR 0.98; p = 0.001) and DOT (aOR 0,72; p<0.01) were considered as protective factor for default. Associated factors should be considered in addressing care and policy actions to tuberculosis control. Information on disease and treatment should be intensified and appropriate to the level of education of the population, in order to promote adherence to treatment and counter the spread of multidrug resistance to anti-TB drugs.

Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. ClinicalTrials.gov: NCT00669643 Since the introduction of multidrug therapy for leprosy in the 80’s, different classification criteria for leprosy patients have been proposed and treatment has been progressively shortened. Currently, leprosy patients are classified into paucibacillary/PB and multibacillary/MB based on the number of skins lesions. MB patients (over 5 skin lesions) receive three drugs (rifampicin, dapsone, clofazimine) for 12 months, while PB patients (up to 5 skin lesions) receive two drugs (rifampicin, dapsone) for 6 months. We conducted a randomized clinical trial to evaluate the efficacy of a uniform treatment (U-MDT) for both PB and MB leprosy patients, regardless any classification criteria. The current study includes results from: laboratory tests (bacilloscopic index/BI, serology and histopathology), clinical evaluation during a long follow-up, and uses adequate epidemiological analysis that gives robust evidence on main parameters used to evaluate the efficacy of U-MDT. This study reports data among MB leprosy patients treated with regular/R-MDT and uniform/U-MDT regarding: (i) The frequency of leprosy reactions; (ii) BI decrease, (iii) Disability progression and (iv) Relapse. Overall, our results showed that there was no statistically significant difference in these outcomes for both treatment groups. In this sense, U-MDT can be considered as part of leprosy policy by control programs in endemic countries.

A sorologia utilizando o antígeno espécie-específico do Mycobacterium leprae, PGL-I, pode ser um marcador de carga bacteriana em pacientes com hanseníase. Estudos identificaram potencial de uso da sorologia na classificação de pacientes para fins de tratamento, monitoramento de terapia, risco de recidiva e na seleção dos contatos com maior risco de adoecer. Foi realizada uma revisão sistemática e 26 artigos foram incluídos na análise comparativa. Avaliamos os resultados do uso da sorologia PGL-I em diferentes situações, suas limitações e possíveis aplicações. Estudos mostraram eficácia da sorologia PGL-I na classificação de pacientes, monitoramento da terapia, e nas reações hansênicas como teste preditivo. Para diagnóstico precoce e seguimento de população de alto risco, as metodologias utilizadas ainda não demonstraram custo-benefício favorável, porém estudos indicam que a utilização do teste poderá influenciar positivamente nos programas de controle da hanseníase. Com técnicas simples e robustas, o uso da sorologia PGL-I é viável.

Since leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin. DNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico. In all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable. This is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission. Leprosy, one of the most ancient human infectious diseases, affects skin and nerves and is caused by Mycobacterium leprae infection. Despite the effective use of multidrug therapy/MDT since the 80´s, over 200,000 new cases are reported yearly, indicating active transmission, especially in India and Brazil. Although rare, recurrent clinical manifestations after MDT can occur due to leprosy reactions, relapse by drug resistance, insufficient treatment or reinfection. Relapse and reinfection cannot be differentiated clinically and molecular genotyping of a predefined set of loci have limited resolution due to exceptional M. leprae genome conservation and low sequence diversity between strains from the same geographical area. This is the first report that has compared whole-genome sequences of M. leprae strains from original and recurrent leprosy episodes. M. leprae genome differences were detected between the strains from the first and second episodes in the three patients. In one patient, there was clear evidence for reinfection with an unrelated strain whereas the other two were considered true relapses due to minor strain differences. No known drug resistance mutations were detected, excluding drug resistance as the recurrence cause. Next generation sequencing of M. leprae DNA discriminates relapse from reinfection representing a powerful tool for evaluating different disease outcomes and transmission.