A clinical trial for uniform multidrug therapy for leprosy patients in Brazil : rationale and design

Leprosy will continue to be a public health problem for several decades. The World Health Organization (WHO) recommends that, for treatment purposes, leprosy cases be classified as either paucibacillary or multibacillary (MB). A uniform leprosy treatment regimen would simplify treatment and halve the treatment duration for MB patients. The clinical trial for uniform multidrug therapy (U-MDT) for leprosy patients (LPs) in Brazil is a randomised, open-label clinical trial to evaluate if the effectiveness of U-MDT for leprosy equals the regular regimen, to determine the acceptability of the U-MDT regimen and to identify the prognostic factors. This paper details the clinical trial methodology and patient enrolment data. The study enrolled 858 patients at two centres and 78.4% of participants were classified as MB according to the WHO criteria. The main difficulty in evaluating a new leprosy treatment regimen is that no reliable data are available for the current treatment regimen. Relapse, reaction and impaired nerve function rates have never been systematically determined, although reaction and impaired nerve function are the two major causes of nerve damage that lead to impairments and disabilities in LPs. Our study was designed to overcome the need for reliable data about the current treatment and to compare its efficacy with that of a uniform regimen

Diagnóstico por Teledermatologia em paciente do Alto Rio Solimões: um caso de escabiose crostosa

Teledermatology uses telecommunication technology and informatics on dermatologic practice without the presence of a specialist. This paper describes the diagnostic process of a Crusted Scabies (Norwegian Scabies) case in an elderly patient from the Alto Solimões River region using teledermatology resources. Moreover, the authors discuss the progress of these technologies, which allow healthcare assistance for those living in remote indigenous and riverine communities, particularly in isolated areas of the Legal Amazon where many diseases are neglected or underdiagnosed.La Teledermatología usa las tecnologías de las telecomunicaciones y de la informática para dar asistencia dermatológica sin la presencia de un especialista. Este artículo describe el proceso de diagnóstico de un caso de escabiosis costrosa (sarna norueguesa) en un paciente anciano de la región del Alto Rio Solimões, a través de recursos de la Teledermatología. Además, los autores discuten los avances de estas tecnologías que permiten llevar asistencia médica a las comunidades costeras e indígenas remotas, especialmente a aquellas de zonas aisladas del Legal Amazon, en las cuales numerosas enfermedades son negligenciadas y subdiagnosticadas.A Teledermatologia estuda o uso das tecnologias de telecomunicação e informática na assistência dermatológica sem a atuação presencial do especialista. Neste trabalho, é relatado o processo diagnóstico de um caso de escabiose crostosa (sarna norueguesa) em paciente idoso da região do Alto Rio Solimões, por meio de recursos de Teledermatologia. Além disso, os autores discutem os avanços dessa tecnologia que possibilita a assistência a distância para comunidades ribeirinhas e indígenas, sobretudo em áreas isoladas da Amazônia Legal, nas quais inúmeras doenças são negligenciadas e subdiagnosticadas

Brazilian clinical trial of uniform multidrug therapy for leprosy patients : the correlation between clinical disease types and adverse effects

This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.Faculdade de Medicina (FMD

Mycobacterium leprae-Specific Antibodies in Multibacillary Leprosy Patients Decrease During and After Treatment With Either the Regular 12 Doses Multidrug Therapy (MDT) or the Uniform 6 Doses MDT

Leprosy serology reflects the bacillary load of patients and multidrug therapy (MDT) reduces Mycobacterium leprae-specific antibody titers of multibacillary (MB) patients. The Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil (U-MDT/CT-BR) compared outcomes of regular 12 doses MDT/R-MDT and the uniform 6 doses MDT/U-MDT for MB leprosy, both of regimens including rifampicin, clofazimine, and dapsone. This study investigated the impact of R-MDT and U-MDT and the kinetic of antibody responses to M. leprae-specific antigens in MB patients from the U-MDT/CT-BR. We tested 3,400 serum samples from 263 MB patients (R-MDT:121; U-MDT:142) recruited at two Brazilian reference centers (Dona Libânia, Fortaleza, Ceará; Alfredo da Matta Foundation, Manaus, Amazonas). Enzyme-linked immunosorbent assays with three M. leprae antigens [NT-P-BSA: trisaccharide-phenyl of phenollic glycolipid-I antigen (PGL-I); LID-1: Leprosy Infectious Disease Research Institute Diagnostic 1 di-fusion recombinant protein; and ND-O-LID: fusion complex of disaccharide-octyl of PGL-I and LID-1] were performed using around 13 samples per patient. Samples were collected at baseline/M0, during MDT (R-MDT:M1–M12 months, U-MDT:M1–M6 months) and after MDT discontinuation (first, second year). Statistical significance was assessed by the Mann–Whitney U test for comparison between groups (p values < 0.05). Mixed effect multilevel regression analyses were used to investigate intraindividual serological changes overtime. In R-MDT and U-MDT groups, males predominated, median age was 41 and 40.5 years, most patients were borderline lepromatous and lepromatous leprosy (R-MDT:88%, U-MDT: 90%). The bacilloscopic index at diagnosis was similar (medians: 3.6 in the R-MDT and 3.8 in the U-MDT group). In R-MDT and U-MDT groups, a significant decline in anti-PGL-I positivity was observed from M0 to M5 (p = 0.035, p = 0.04, respectively), from M6 to M12 and at the first and second year posttreatment (p < 0.05). Anti-LID-1 antibodies declined from M0 to M6 (p = 0.024), M7 to M12 in the R-MDT; from M0 to M4 (p = 0.003), M5 to M12 in the U-MDT and posttreatment in both groups (p > 0.0001). Anti-ND-O-LID antibodies decreased during and after treatment in both groups, similarly to anti-PGL-I antibodies. Intraindividual serology results in R-MDT and U-MDT patients showed that the difference in serology decay to all three antigens was dependent upon time only. Our serology findings in MB leprosy show that regardless of the duration of the U-MDT and R-MDT, both of them reduce M. leprae-specific antibodies during and after treatment. In leprosy, antibody levels are considered a surrogate marker of the bacillary load; therefore, our serological results suggest that shorter U-MDT is also effective in reducing the patients’ bacillary burden similarly to R-MDT.Clinical Trial RegistrationClinicalTrials.gov, NCT00669643

Additional file 2: Table S1. of 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

Positivity to ML Flow test according to bacillary index (BI) and type of reaction. (DOC 43 kb

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.Faculdade de Medicina (FMD

Additional file 3: Figure S1. of 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

Receiver Operating Curves (ROC) for ML Flow test in leprosy patients who developed RR, ENL and reaction-free. (DOC 715 kb

Leprosy reactions: The predictive value of <i>Mycobacterium leprae</i>-specific serology evaluated in a Brazilian cohort of leprosy patients (U-MDT/CT-BR)

<div><p>Background</p><p>Leprosy reactions, reversal reactions/RR and erythema nodosum leprosum/ENL, can cause irreversible nerve damage, handicaps and deformities. The study of <i>Mycobacterium leprae</i>-specific serologic responses at diagnosis in the cohort of patients enrolled at the <i>Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil/U-MDT/CT-BR</i> is suitable to evaluate its prognostic value for the development of reactions.</p><p>Methodology</p><p>IgM and IgG antibody responses to PGL-I, LID-1, ND-O-LID were evaluated by ELISA in 452 reaction-free leprosy patients at diagnosis, enrolled and monitored for the development of leprosy reactions during a total person-time of 780,930 person-days, i.e. 2139.5 person-years, with a maximum of 6.66 years follow-up time.</p><p>Principal findings</p><p>Among these patients, 36% (160/452) developed reactions during follow-up: 26% (119/452) RR and 10% (41/452) had ENL. At baseline higher anti-PGL-I, anti-LID-1 and anti-ND-O-LID seropositivity rates were seen in patients who developed ENL and RR compared to reaction-free patients (p<0.0001). Seroreactivity in reactional and reaction-free patients was stratified by bacilloscopic index/BI categories. Among BI negative patients, higher anti-PGL-I levels were seen in RR compared to reaction-free patients (p = 0.014). In patients with 0</p><p>Conclusions</p><p>Overall, detection of anti-PGL-I, anti-LID-1 and anti-ND-O-LID antibodies at diagnosis, showed low sensitivity and specificity for RR prediction, indicating low applicability of serological tests for RR prognosis. On the other hand, anti-LID-1 serology at diagnosis has shown prognostic value for ENL development in BI positive patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00669643" target="_blank">NCT00669643</a></p></div

Group 3- Patients with BI≥3 (n = 161): Baseline antibody responses to different <i>M</i>. <i>leprae</i> antigens.

<p>Seropositivity to PGL-I (A), LID-1 (B) and ND-O-LID (C) antigens in patients that developed RR (n = 60), ENL (n = 41) and reaction-free (n = 60) patients. The box shows the interval between the first and the third quartiles, the middle line represents the median. The <i>p</i> value refers to differences in OD median. The traced horizontal line is the cut-off: PGL-I OD>0.25; LID-1: OD>0.3; ND-O-LID: OD>0.923. The numbers above each box represent the positivity rate and the points above each box are outliers results. OD = optical density; RR: reversal reaction; ENL: erythema nodosum leprosum.</p