An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP+.

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP++

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

Drug-resistant M leprae.

Dapsone was used as a single drug to treat leprosy, and secondary resistance soon developed, greatly reducing its effectiveness. Multidrug therapy has been used successfully since 1982, and until now, only a few sporadic cases of rifampicin resistance have been reported. Surveillance is needed to make sure that chemotherapy for leprosy remains effective for the foreseeable future. This review is based on reports from the annual drug resistance surveillance meetings convened by the World Health Organization and related literature. Very few cases of rifampicin resistance are currently known globally, except for a small group of cases in a former leprosy colony in Brazil. A low level of ofloxacin resistance has been found, especially in India. A larger number of patient samples should be tested each year. The results give grounds for cautious optimism, although the number of samples tested should be significantly increased. Possible foci of rifampicin resistance near former leprosy colonies in Brazil should be further investigated.

Drug-resistant M. leprae

Dapsone was used as a single drug to treat leprosy, and secondary resistance soon developed, greatly reducing its effectiveness. Multidrug therapy has been used successfully since 1982, and until now, only a few sporadic cases of rifampicin resistance have been reported. Surveillance is needed to make sure that chemotherapy for leprosy remains effective for the foreseeable future. This review is based on reports from the annual drug resistance surveillance meetings convened by the World Health Organization and related literature. Very few cases of rifampicin resistance are currently known globally, except for a small group of cases in a former leprosy colony in Brazil. A low level of ofloxacin resistance has been found, especially in India. A larger number of patient samples should be tested each year. The results give grounds for cautious optimism, although the number of samples tested should be significantly increased. Possible foci of rifampicin resistance near former leprosy colonies in Brazil should be further investigated.

A retrospective study of the epidemiology of leprosy in Cebu: an eleven-year profile.

BACKGROUND: Cebu has been one of the most leprosy endemic areas in the Philippines. Despite the high coverage rates of multiple drug therapy (MDT) and high BCG-vaccine coverage in children, leprosy control authorities believe that leprosy transmission and incidence (as evidence by continuing new case detection in both adults and children) have not declined as expected, once leprosy had been eliminated. In response to the concerns communicated by the authorities regarding ongoing leprosy transmission in Cebu, this study aims to examine the evidence for the hypothesized ongoing transmission, both in children and adults. Furthermore, it will be assessed which groups and areas are experiencing a continuing risk of leprosy infection; this can form a starting point for more targeted approaches to leprosy control. METHODOLOGY & PRINCIPAL FINDINGS: Case records from 2000-2010 were retrospectively collected from the Leonard Wood Memorial Clinic archives, and all other clinics on the island where leprosy was treated. Between 2000 and 2010, 3288 leprosy cases were detected. The overall five year case notification rate (CNR) dropped significantly from 47.35 (2001-2005) to 29.21 cases (2006-2010) per 100.000 population. Smaller CNRs were reported for children; however the decline in child-CNR over the same period was minimal. Furthermore, no increase in median age of notification in children or adults was found between 2000 and 2010. Population-adjusted clustering of leprosy cases was mainly detected in urban and peri-urban areas. CONCLUSIONS & SIGNIFICANCE: Although the overall CNR declined significantly, CNR seems to be rather static in lower risk populations and areas. Cases are mainly found in urban areas, however CNRs in these areas decline at a much faster rate than in the lower endemic rural areas. A similar situation was found when comparing adults and children: CNRs observed in children were lower than in adults, but further decline (and elimination) of these childhood CNRs was found to be difficult. Moreover, the median age of notification in children has remained stable, suggesting transmission is still on-going. It is unclear why many years of good MDT-coverage and a gradual decline in CNR have not been accompanied by evidence of reduced transmission, especially beyond a certain threshold level of case notification. We believe that a new approach to leprosy control is required to tackle transmission more directly. The most promising approach may involve chemoprophylaxis and/or immunoprophylaxis interventions, targeted at high risk (urban) areas and groups such as household contacts, followed by a different approach once decline in CNR starts to level off. Identified clusters and trends can form the starting point for implementing this approach.

Limited susceptibility of cynomolgus monkeys (Macaca fascicularis) to leprosy after experimental administration of Mycobacterium leprae.

Cynomolgus monkeys are a useful model for human tuberculosis, but susceptibility to M. leprae is unknown. A cynomolgus model of leprosy could increase understanding of pathogenesis-importantly, neuritis and nerve-damaging reactions. We administered viable Mycobacterium leprae to 24 cynomolgus monkeys by three routes, with a median follow-up period of 6 years (range = 1-19 years) involving biopsies, nasal smears, antiphenolic glycolipid-1 (PGL-1) antibody serology, and lepromin skin testing. Most developed evanescent papules at intradermal M. leprae inoculation sites that, on biopsy, showed a robust cellular immune response akin to a lepromin skin test reaction; many produced PGL-1 antibodies. At necropsy, four monkeys, without cutaneous or gross neurological signs of leprosy but with elevated PGL-1 antibodies, including three with nasal smears (+) for acid fast bacilli (AFB), showed histological features, including AFB, suggestive of leprosy at several sites. Overall, however, cynomolgus monkeys seem minimally susceptible to leprosy after experimental M. leprae administration.

Nerve damage in leprosy: a continuing challenge to scientists, clinicians and service providers.

This review focuses on nerve damage in leprosy. We present evidence to support the argument that leprosy is best seen as a chronic neurological condition rather than a simple skin disease. Nerve damage affects small dermal nerves and peripheral nerve trunks. Perineural inflammation is a characteristic and hallmark of early leprosy. T cell-mediated inflammation is the main pathological process in leprosy nerve damage. The level of nerve damage in leprosy is high with up to 60% of multibacillary patients having clinically apparent nerve damage at the time of diagnosis; 30% of patents may develop further nerve damage during treatment and 10% may develop new nerve damage after drug treatment. Since the nerve damage is immune mediated, the antibiotics used to treat Mycobacterium leprae infection have little effect on the accompanying nerve damage. This requires treatment with immunosuppressants to stop the inflammation. Treatment of nerve damage with steroids can be effective but about 50% of patients relapse and require a further course of steroids. Research is needed to refine steroid regimens to be used and define appropriate alternatives. Neuropathic pain is now being recognised as another late complication for leprosy patients. There are also service challenges relating to how best to identify patients who need steroid treatment and how to manage patients with established neuropathy who may require health services for many years.

Does clofazimine prevent erythema nodosum leprosum (ENL) in leprosy? A retrospective study, comparing the experience of multibacillary patients receiving either 12 or 24 months WHO-MDT.

OBJECTIVE: To compare the occurrence, duration and severity of ENL in leprosy patients treated with either 12 or 24 months of standard multi-drug therapy (MDT). STUDY POPULATION: 296 patients treated with MDT for 2 years, between 1985 and 1992 and followed up as part of a relapse study; and 293 patients, treated between 1998 and 2004, with MDT for 1 year and also followed up as part of a relapse study. The Chi squared test and multiple logistic regression analysis were used to test for statistical significance. RESULTS: ENL was not significantly more common, but it was longer-lasting and more severe in patients receiving only 12 months of MDT, as compared with those receiving 24 months treatment. A high BI at the start of treatment significantly increased the risk of severe ENL by a factor of between 6 and 12, while treatment with 12 instead of 24 months of MDT significantly increased the risk by a factor of between 3 and 10. CONCLUSIONS: This study provides further evidence that a high initial BI is the key risk factor for ENL. It also suggests that the difference between these two cohorts in their experience of ENL as demonstrated in this study, may be related to the different amounts of clofazimine which the two cohorts were given in the early years of their treatment. Further studies are needed to determine whether clofazimine could be used more specifically to reduce the severity of ENL in the small group of patients at high risk for the condition.

Informe de la sexta reunión del consorcio (iniciativa para técnicas diagnósticas y epidemiológicas para la lepra) ideal celebrada en Beijing, China, del 23-25 agosto de 2010 / No disponible

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The efficacy of a four-week, ofloxacin-containing regimen compared with standard WHO-MDT in PB leprosy.

OBJECTIVES: To compare the efficacy of a 4-week ofloxacin-containing regimen and the standard WHO-MDT regimen for PB leprosy, in terms of the rate and timing of relapse after treatment completion. DESIGN: 124 PB patients were enrolled in a randomised, double-blind trial. Of these, 66 received the standard 6-month WHO-MDT regimen, whereas 58 received 28 daily supervised doses of rifampicin 600mg + ofloxacin 400 mg, plus 5 months of placebo. Patients were regularly monitored for clinical response and for signs of relapse after treatment completion. RESULTS: Patients enrolled in the ofloxacin group had a mean follow-up of 10.8 years (628 patient-years) with 1 early relapse at 3 years after treatment completion. On relapse, this patient remained smear negative but was reclassified by current WHO criteria (> or =6 skin lesions) as multibacillary (MB). Patients on the WHO-MDT regimen had a mean follow-up of 11.3 years (749 patient-years) with two late relapses at 8 and 12 years, both still classified as PB on relapse. CONCLUSION: In conclusion, both regimens appeared generally efficacious, and, in particular, resulted in few relapses.

Rational design and evaluation of a multiepitope chimeric fusion protein with the potential for leprosy diagnosis.

Despite the reduction in the number of leprosy cases registered worldwide as a result of the widespread use of multidrug therapy, the number of new cases detected each year remains stable in many countries. This indicates that Mycobacterium leprae, the causative agent of leprosy, is still being transmitted and that, without an earlier diagnosis, transmission will continue and infection will remain a health problem. The current means of diagnosis of leprosy is based on the appearance of clinical symptoms, which in many cases occur after significant and irreversible nerve damage has occurred. Our recent work identified several recombinant antigens that are specifically recognized by leprosy patients. The goal of the present study was to produce and validate the reactivity of a chimeric fusion protein that possesses the antibody binding properties of several of these proteins. The availability of such a chimeric fusion protein will simplify future test development and reduce production costs. We first identified the antibody binding regions within our top five antigen candidates by performing enzyme-linked immunosorbent assays with overlapping peptides representing the amino acid sequences of each protein. Having identified these regions, we generated a fusion construct of these components (protein advances diagnostic of leprosy [PADL]) and demonstrated that the PADL protein retains the antibody reactivity of the component antigens. PADL was able to complement a protein that we previously produced (the leprosy IDRI [Infectious Disease Research Institute] diagnostic 1 [LID-1] protein) to permit the improved diagnosis of multibacillary leprosy and that had a good ability to discriminate patients with multibacillary leprosy from control individuals. A serological diagnostic test consisting of these antigens could be applied within leprosy control programs to reduce transmission and to limit the appearance of leprosy-associated disabilities and stigmatizing deformities by directing treatment.

Long-term relapse risk of multibacillary leprosy after completion of 2 years of multiple drug therapy (WHO-MDT) in Cebu, Philippines.

From 1987 to 1994, we enrolled 500 subjects completing 2-year WHO multiple drug therapy (MDT) for multibacillary leprosy in a prospective relapse study. Relapse was defined as new skin lesions and an increase in the bacterial index (BI) > or = 2+ (> or = 100x) at any single slit-skin smear site. At the study end in 2006, follow-up was 6,401 subject-years, a mean of 12.8 years/subject. We observed 23 relapses, 6-16 years after MDT (mean, 10.5 years; 95% confidence interval [CI], 9.2-11.8), peaking in Years 11-12 (> 1%/year). The cumulative risk was 6.6% (95% CI, 5.0-8.2%). In a subset of 181 subjects with pre-MDT average BI > or = 4+, 11 relapses occurred (cumulative risk, 10.1%). In mouse footpad assays, Mycobacterium leprae from relapsed subjects were rifampin and clofazimine sensitive. Taken together, the data suggest relapses are related to activation of dormant organisms (persisters) not killed by MDT rather than new infection.

Capacitación para integrar

La capacitación o formación es considerada frecuentemente como la solución para las carencias del sistema sanitario general y existen pocas dudas de que sin él la calidad del servicio se resentiría y resultaría difícil introducir nuevas técnicas y terminologías y en todo caso se trata de un componente fundamental en la búsqueda de la calidad del servicio. Sin embrago, es estos tiempos de coste/efectividad y reducción de gastos, motivos en parte del proceso de integración, resulta sorprendente que la capacitación frecuentemente no se planifica y pocas veces resulta evaluada de manera racional. Este trabajo revisa diversos planteamientos recientes de ILEP sobre la capacitación y el uso de materiales para la formación en lepra en el contexto que la mayoría de los programas están siendo integrados en los servicios de salud generales. Se propone el desarrollo de un Plan Nacional para la Formación en Lepra con objetivos claros y concisos para así optimizar los recursos disponibles.

Training for integration.

Training is often suggested as the solution to the inadequacies of the health care system, and there is little doubt that without it, service quality would suffer and new techniques and technologies would be difficult to introduce; clearly it is an important component in any drive to achieve quality of care. However, in this era of cost-effectiveness and cost cutting, which is part of the reason for integration, it is surprising that training is often not well planned and is rarely evaluated in a rational manner. This paper relies on recent discussions within ILEP about training and the use of training materials for leprosy in the present environment--one in which most programmes are being integrated into the general health services. The development of a National Training Plan for Leprosy is proposed, with clear objectives, in order to best utilize the resources available.

Monitoring steroid use in a field program; possible process indicators

Two new indicators are proposed in order to make the task of monitoring certain prevention of disability (POD) activities more straightforward. The indicators are very similar to the case detection rates and the cohort analyses already used in both leprosy and tuberculosis (TB) control; this makes them very simple to put into practice. Despite their simplicity, it is argued that these indicators can give important information about the implementation of POD activities in a routine field program and could, therefore, help in improving the quality of those services to patients. The indicators are the steroid start rate (SSR) and the steroid completion rate (SCR). A number of possible confounding factors have been looked at and they are not negligible. However, the case detection rates for new cases of leprosy and treatment completion rates for multidrug therapy (MDT) are subject to similar biases, which are well recognized and which have not detracted from the usefulness of these indicators in evaluating leprosy control activities. The POD indicators, if used with an awareness of the possible biases involved, can help to improve the quality of certain POD activities.