The long-term impact of the Leprosy Post-Exposure Prophylaxis (LPEP) program on leprosy incidence: A modelling study.

BACKGROUND: The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of single dose rifampicin (SDR) to eligible contacts of newly diagnosed leprosy patients in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. As the impact of the programme is difficult to establish in the short term, we apply mathematical modelling to predict its long-term impact on the leprosy incidence. METHODOLOGY: The individual-based model SIMCOLEP was calibrated and validated to the historic leprosy incidence data in the study areas. For each area, we assessed two scenarios: 1) continuation of existing routine activities as in 2014; and 2) routine activities combined with LPEP starting in 2015. The number of contacts per index patient screened varied from 1 to 36 between areas. Projections were made until 2040. PRINCIPAL FINDINGS: In all areas, the LPEP program increased the number of detected cases in the first year(s) of the programme as compared to the routine programme, followed by a faster reduction afterwards with increasing benefit over time. LPEP could accelerate the reduction of the leprosy incidence by up to six years as compared to the routine programme. The impact of LPEP varied by area due to differences in the number of contacts per index patient included and differences in leprosy epidemiology and routine control programme. CONCLUSIONS: The LPEP program contributes significantly to the reduction of the leprosy incidence and could potentially accelerate the interruption of transmission. It would be advisable to include contact tracing/screening and SDR in routine leprosy programmes.

Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme.

BACKGROUND: Innovative approaches are required for leprosy control to reduce cases and curb transmission of Mycobacterium leprae. Early case detection, contact screening, and chemoprophylaxis are the most promising tools. We aimed to generate evidence on the feasibility of integrating contact tracing and administration of single-dose rifampicin (SDR) into routine leprosy control activities. METHODS: The leprosy post-exposure prophylaxis (LPEP) programme was an international, multicentre feasibility study implemented within the leprosy control programmes of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania. LPEP explored the feasibility of combining three key interventions: systematically tracing contacts of individuals newly diagnosed with leprosy; screening the traced contacts for leprosy; and administering SDR to eligible contacts. Outcomes were assessed in terms of number of contacts traced, screened, and SDR administration rates. FINDINGS: Between Jan 1, 2015, and Aug 1, 2019, LPEP enrolled 9170 index patients and listed 179 769 contacts, of whom 174 782 (97·2%) were successfully traced and screened. Of those screened, 22 854 (13·1%) were excluded from SDR mainly because of health reasons and age. Among those excluded, 810 were confirmed as new patients (46 per 10 000 contacts screened). Among the eligible screened contacts, 1182 (0·7%) refused prophylactic treatment with SDR. Overall, SDR was administered to 151 928 (86·9%) screened contacts. No serious adverse events were reported. INTERPRETATION: Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers. The programme has also invigorated local leprosy control through the availability of a prophylactic intervention; therefore, we recommend rolling out SDR in all settings where contact tracing and screening have been established. FUNDING: Novartis Foundation.

Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme

Background: Innovative approaches are required for leprosy control to reduce cases and curb transmission of Mycobacterium leprae. Early case detection, contact screening, and chemoprophylaxis are the most promising tools. We aimed to generate evidence on the feasibility of integrating contact tracing and administration of single-dose rifampicin (SDR) into routine leprosy control activities. Methods The leprosy post-exposure prophylaxis (LPEP) programme was an international, multicentre feasibility study implemented within the leprosy control programmes of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania. LPEP explored the feasibility of combining three key interventions: systematically tracing contacts of individuals newly diagnosed with leprosy; screening the traced contacts for leprosy; and administering SDR to eligible contacts. Outcomes were assessed in terms of number of contacts traced, screened, and SDR administration rates. Findings Between Jan 1, 2015, and Aug 1, 2019, LPEP enrolled 9170 index patients and listed 179 769 contacts, of whom 174782 (97·2%) were successfully traced and screened. Of those screened, 22 854 (13·1%) were excluded from SDR mainly because of health reasons and age. Among those excluded, 810 were confirmed as new patients (46 per 10 000 contacts screened). Among the eligible screened contacts, 1182 (0·7%) refused prophylactic treatment with SDR. Overall, SDR was administered to 151 928 (86·9%) screened contacts. No serious adverse events were reported. Interpretation Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers. The programme has also invigorated local leprosy control through the availability of a prophylactic intervention; therefore, we recommend rolling out SDR in all settings where contact tracing and screening have been established(AU).

The long-term impact of the leprosy post-exposure prophylaxis (LPEP) program on leprosy incidence: a modelling study

The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of SDR to eligible contacts of newly diagnosed leprosy patients in states or districts of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. This study investigated the long-term impact of the LPEP program on the leprosy new case detection rate (NCDR). Our results show that LPEP could reduce the NCDR beyond the impact of the routine leprosy control programme and that many new cases could be prevented. The benefit of LPEP increases gradually over time. LPEP could accelerate the time of reaching predicted NCDR levels of 2040 under routine program by up to six years. Furthermore, we highlighted how the impact varies between countries due to differences in the number of contacts per index patient screened and differences in leprosy epidemiology and national control programme. Generally, including both household contacts and neighbours (> 20 contacts per index patient) would yield the highest impact.

A comprehensive research agenda for zero leprosy.

BACKGROUND: Leprosy control achieved dramatic success in the 1980s-1990s with the implementation of short course multidrug therapy, which reduced the global prevalence of leprosy to less than 1 in 10 000 population. However, a period of relative stagnation in leprosy control followed this achievement, and only limited further declines in the global number of new cases reported have been achieved over the past decade. MAIN TEXT: In 2016, major stakeholders called for the development of an innovative and comprehensive leprosy strategy aimed at reducing the incidence of leprosy, lowering the burden of disability and discrimination, and interrupting transmission. This led to the establishment of the Global Partnership for Zero Leprosy (GPZL) in 2018, with partners aligned around a shared Action Framework committed to achieving the WHO targets by 2030 through national leprosy program capacity-building, resource mobilisation and an enabling research agenda. GPZL convened over 140 experts from more than 20 countries to develop a research agenda to achieve zero leprosy. The result is a detailed research agenda focusing on diagnostics, mapping, digital technology and innovation, disability, epidemiological modelling and investment case, implementation research, stigma, post exposure prophylaxis and transmission, and vaccines. This research agenda is aligned with the research priorities identified by other stakeholders. CONCLUSIONS: Developing and achieving consensus on the research agenda for zero leprosy is a significant step forward for the leprosy community. In a next step, research programmes must be developed, with individual components of the research agenda requiring distinct expertise, varying in resource needs, and operating over different timescales. Moving toward zero leprosy now requires partner alignment and new investments at all stages of the research process, from discovery to implementation.

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).

Corticosteroids for treating nerve damage in leprosy.

BACKGROUND: Leprosy causes nerve damage that can result in nerve function impairment and disability. Corticosteroids are commonly used for treating nerve damage, although their long-term effect is uncertain. This is an update of a review first published in 2007, and previously updated in 2009 and 2011. OBJECTIVES: To assess the effects of corticosteroids on nerve damage in leprosy. SEARCH METHODS: On 16 June 2015, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL Plus, and LILACS. We also checked clinical trials registers and contacted trial authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of corticosteroids for nerve damage in leprosy. The comparators were no treatment, placebo treatment, or a different corticosteroid regimen. DATA COLLECTION AND ANALYSIS: The primary outcome was improvement in nerve function after one year. Secondary outcomes were change in nerve pain, limitations in activities of daily living, limitations in participation, and adverse events. Two review authors independently extracted data and assessed trial quality. When data were lacking, we contacted trial authors for additional information. MAIN RESULTS: We included five RCTs involving 576 people. The trials were largely at low risk of bias, but we considered the quality of the evidence from these trials as moderate to low, largely due to imprecision from small sample sizes. Two out of the five trials reported on improvement in nerve function at one year. These two trials compared prednisolone with placebo. One trial, with 84 participants, treated mild sensory impairment of less than six months' duration, and the other, with 95 participants, treated nerve function impairment of 6 to 24 months' duration. There was no significant difference in nerve function improvement after 12 months between people treated with prednisolone and those treated with placebo. Adverse events were not reported significantly more often with corticosteroids than with placebo. The other three trials did not report on the primary outcome measure. One (334 participants) compared three corticosteroid regimens for severe type 1 reactions. No serious side effects of steroids were reported in any participant during the follow-up period. Another trial (21 participants) compared low-dose prednisone with high-dose prednisone for ulnar neuropathy. Two participants on the higher dose of prednisone reported adverse effects. The last (42 participants) compared intravenous methylprednisolone and oral prednisolone with intravenous normal saline and oral prednisolone. The trial found no significant differences between the groups in the occurrence of adverse events. AUTHORS' CONCLUSIONS: Corticosteroids are used for treating acute nerve damage in leprosy, but moderate-quality evidence from two RCTs treating either longstanding or mild nerve function impairment did not show corticosteroids to have a superior effect to placebo on nerve function improvement. A third trial showed significant benefit from a five-month steroid regimen over a three-month regimen in terms of response to treatment (need for additional corticosteroids). Further RCTs are needed to establish optimal corticosteroid regimens and to examine the efficacy and safety of adjuvant or new therapies for treating nerve damage in leprosy. Future trials should address non-clinical aspects, such as costs and impact on quality of life, which are highly relevant indicators for both policymakers and participants.

Role of contact tracing and prevention strategies in the interruption of leprosy transmission.

The global prevalence of leprosy has declined from 5.2 million in the 1980 s to 200,000 today. However, the new case detection rate remains high: over the last 8 years, around 220,000-250,000 people have been diagnosed with leprosy each year. In June 2013, an international meeting was organised by the Novartis Foundation for Sustainable Development in Geneva, Switzerland,2 with the objective of discussing the feasibility of interrupting the transmission of leprosy. The group of physicians, epidemiologists and public health professionals concluded that a successful programme would require early diagnosis and prompt multidrug therapy (MDT) for all patients, tracing and post-exposure prophylaxis (PEP) for contacts of patients newly diagnosed with leprosy, improvements in diagnostic tools, as well as strict epidemiological surveillance and response systems to monitor progress. As a follow-up, a second expert group meeting was convened by the Novartis Foundation in January 2014 in Zurich, Switzerland, with the objective of reviewing the evidence for chemoprophylaxis in contacts and high-risk communities. The meeting also considered the definitions of 'contacts' and 'contact tracing', discussed alternative prophylaxis regimens, preliminary findings of operational pilot projects on PEP in Indonesia, as well as the development of diagnostic tools, and identified the priority questions for operational research in leprosy transmission. The meeting outlined how contact tracing and chemoprophylaxis programmes can be implemented to interrupt leprosy transmission. The expert panel reached the following conclusions: Chemoprophylaxis with single-dose rifampicin (SDR) is efficacious in reducing the risk of developing leprosy, although the protective effect appears to be smaller in contacts closer to the index patient than in more distant contacts.3 SDR can be targeted to contacts or implemented as community mass prophylaxis in certain circumstances; the preferred approach depends on local factors, such as the case detection rate, the level of community stigma against leprosy, and the degree of access to healthcare for patients and contacts. Alternative prophylaxis regimens and the role of post-exposure immunoprophylaxis need to be further investigated. Contact tracing combined with PEP across very diverse settings offers protection rates similar to those reported in controlled trials. For high-incidence pockets ('hotspots') or remote or confined high-incidence populations ('hotpops'), blanket administration of PEP may be a better option. Implementation of contact-tracing programmes is feasible and cost-effective, particularly in high-risk groups, but it should be integrated into local healthcare services to ensure their long-term sustainability. Funding and support must be maintained after an initial pilot has finished. New programmes for contact tracing need effective surveillance systems to enable appropriate follow-up and outcome evaluation. The Novartis Foundation and Netherlands Leprosy Relief (NLR) are currently developing and implementing a large international programme to demonstrate the feasibility, acceptability, cost-effectiveness and real-world efficacy of PEP as a strategy to interrupt leprosy transmission, in six pilot projects in Asia, Africa and South America. These new pilot projects will be developed together with the local health authorities, healthcare workers, communities and patients, in order to create local ownership from the outset. The pilots should aim to be scalable and sustainable, and should therefore include an objective outcome assessment. Local ownership ensures that locally appropriate language and definitions of contacts are used in each of the pilots. A test to identify subclinical disease and distinguish M. leprae exposure from infection would facilitate early and appropriate therapy (with PEP or MDT). The identification and validation of new, sensitive biomarkers for M. leprae infection and exposure may allow better targeting of PEP to those contacts at highest risk of developing leprosy.

Comparing the clinical and histological diagnosis of leprosy and leprosy reactions in the INFIR cohort of Indian patients with multibacillary leprosy.

BACKGROUND: The ILEP Nerve Function Impairment in Reaction (INFIR) is a cohort study designed to identify predictors of reactions and nerve function impairment in leprosy. The aim was to study correlations between clinical and histological diagnosis of reactions. METHODOLOGY/PRINCIPAL FINDINGS: Three hundred and three newly diagnosed patients with World Health Organization multibacillary (MB) leprosy from two centres in India were enrolled in the study. Skin biopsies taken at enrolment were assessed using a standardised proforma to collect data on the histological diagnosis of leprosy, leprosy reactions and the certainty level of the diagnosis. The pathologist diagnosed definite or probable Type 1 Reactions (T1R) in 113 of 265 biopsies from patients at risk of developing reactions whereas clinicians diagnosed skin only reactions in 39 patients and 19 with skin and nerve involvement. Patients with Borderline Tuberculoid (BT) leprosy had a clinical diagnosis rate of reactions of 43% and a histological diagnosis rate of 61%; for patients with Borderline Lepromatous (BL) leprosy the clinical and histological diagnosis rates were 53.7% and 46.2% respectively. The sensitivity and specificity of clinical diagnosis for T1R was 53.1% and 61.9% for BT patients and 61.1% and 71.0% for BL patients. Erythema Nodosum Leprosum (ENL) was diagnosed clinically in two patients but histologically in 13 patients. The Ridley-Jopling classification of patients (n = 303) was 42.8% BT, 27.4% BL, 9.4% Lepromatous Leprosy (LL), 13.0% Indeterminate and 7.4% with non-specific inflammation. This data shows that MB classification is very heterogeneous and encompasses patients with no detectable bacteria and high immunological activity through to patients with high bacterial loads. CONCLUSIONS/SIGNIFICANCE: Leprosy reactions may be under-diagnosed by clinicians and increasing biopsy rates would help in the diagnosis of reactions. Future studies should look at sub-clinical T1R and ENL and whether they have impact on clinical outcomes.

Assessing and improving adherence with multidrug therapy.

INTRODUCTION: Adherence with multidrug therapy (MDT) in the treatment of leprosy is important to minimise the risk of relapse and avoid the emergence of drug resistance. Adherence is defined as the extent to which the patient's behaviour matches recommendations from the prescriber. This paper reviews the methods for assessing adherence with MDT in leprosy, and community approaches to improving adherence based on evidence from the treatment of tuberculosis (TB) and HIV, as well as leprosy. METHODS: To identify and summarise the available literature regarding the assessment of treatment regularity in leprosy, a literature search of MEDLINE was conducted using the following search terms: 'leprosy' AND ('adherence' OR 'compliance' OR 'concordance'). To identify evidence for interventions that have involved community members in HIV, TB or leprosy adherence support, a literature search was conducted using the key terms and medical subject headings 'treatment or adherence' 'community,' 'HIV, TB or Leprosy' and 'low and middle income countries' combined using Boolean operators. RESULTS: Leprosy programmes routinely use defaulting and treatment completion as proxy measures of adherence as recommended by the WHO global strategy. However, a number of other methods have been used to assess adherence including questionnaires, pill counts, as well as direct measures based on testing urine for the presence of dapsone. Direct methods were extensively used during the dapsone mono-therapy era but there is little evidence of their use in MDT. Use of multiple methods of assessing adherence improves the accuracy and reliability of the results. Community activities in TB and HIV such as variants of treatment observation, and/or wider programmes of counselling or direct support to the patient or their family or to increase community or social support were shown to improve treatment outcomes. Outcomes evaluated included treatment default and completion, clinical indicators, and adherence (pill-count, self report). CONCLUSIONS: Adherence is very important in leprosy and regular assessment of medication adherence together with constructive feedback and counselling of patients is likely to be beneficial. Leprosy programme can learn from adherence support interventions developed by both TB and HIV programmes.

Potential effect of the World Health Organization's 2011-2015 global leprosy strategy on the prevalence of grade 2 disability: a trend analysis.

OBJECTIVE: To assess different countries' chances of attaining the 2011-2015 global leprosy target set by the World Health Organization (WHO) and to assess the strategy's effect on the prevalence of grade 2 disability (G2D). METHODS: Trends in G2D rate were analysed for Brazil, China, India and Thailand and figures were compared with the WHO target: a 35% decrease by 2015 relative to the 2010 baseline. To estimate the prevalence of G2D in 2015 and 2035 for each country three assumptions were made: (i) maintenance of the current trend; (ii) attainment of the WHO target, and (iii) reduction of G2D by 50% every 5 years relative to 2010. FINDINGS: Since 1995, the G2D rate has decreased every 5 years in Brazil, China, India and Thailand by 12.7% (95% confidence interval, CI: 6.6-18.3), 7.7% (95% CI: 1.1-12.8), 53.7% (95% CI: 38.1-65.4) and 35.9% (95% CI: 23.4-46.3), respectively. New cases with G2D detected after 2010 will contribute 15% (Brazil), 3% (China), 2.5% (India) and 4% (Thailand) to the total prevalence of G2D in 2015. If no policies are changed, between 2015 and 2035, the prevalence of G2D will decrease by more than half in China, India and Thailand, and by 16% in Brazil. CONCLUSION: The implications of attaining the WHO target are different for each country and using indicators other than G2D prevalence will help monitor progress. The strategy will not immediately reduce the prevalence of G2D, but if it is applied consistently over the next 25 years, its long-term effect can be substantial.

Leprosy.

INTRODUCTION: The World Health Organization field leprosy classification is based on the number of skin lesions: paucibacillary leprosy (1-5 skin lesions), and multibacillary leprosy (more than 5 skin lesions). Worldwide, about 250,000 new cases of leprosy are reported each year, and about 2 million people have leprosy-related disabilities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent leprosy? What are the effects of treatments for leprosy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: chemoprophylaxis with single-dose rifampicin, Bacillus Calmette-Guerin (BCG) plus killed Mycobacterium leprae vaccine, BCG vaccine, ICRC vaccine, multidrug treatment, multiple-dose treatment, Mycobacterium w vaccine, and single-dose treatment.

Predicting neuropathy and reactions in leprosy at diagnosis and before incident events-results from the INFIR cohort study.

BACKGROUND: Leprosy is a disease of skin and peripheral nerves. The process of nerve injury occurs gradually through the course of the disease as well as acutely in association with reactions. The INFIR (ILEP Nerve Function Impairment and Reactions) Cohort was established to identify clinically relevant neurological and immunological predictors for nerve injury and reactions. METHODOLOGY/PRINCIPAL FINDINGS: The study, in two centres in India, recruited 188 new, previously untreated patients with multi-bacillary leprosy who had no recent nerve damage. These patients underwent a series of novel blood tests and nerve function testing including motor and sensory nerve conduction, warm and cold detection thresholds, vibrometry, dynamometry, monofilament sensory testing and voluntary muscle testing at diagnosis and at monthly follow up for the first year and every second month for the second year. During the 2 year follow up a total of 74 incident events were detected. Sub-clinical changes to nerve function at diagnosis and during follow-up predicted these new nerve events. Serological assays at baseline and immediately before an event were not predictive; however, change in TNF alpha before an event was a statistically significant predictor of that event. CONCLUSIONS/SIGNIFICANCE: These findings increase our understanding of the processes of nerve damage in leprosy showing that nerve function impairment is more widespread than previously appreciated. Any nerve involvement, including sub-clinical changes, is predictive of further nerve function impairment. These new factors could be used to identify patients at high risk of developing impairment and disability.

Cost-effectiveness of interventions to prevent disability in leprosy: a systematic review.

BACKGROUND: Prevention of disability (POD) is one of the key objectives of leprosy programmes. Recently, coverage and access have been identified as the priority issues in POD. Assessing the cost-effectiveness of POD interventions is highly relevant to understanding the barriers and opportunities to achieving universal coverage and access with limited resources. The purpose of this study was to systematically review the quality of existing cost-effectiveness evidence and discuss implications for future research and strategies to prevent disability in leprosy and other disabling conditions. METHODOLOGY/PRINCIPAL FINDINGS: We searched electronic databases (NHS EED, MEDLINE, EMBASE, and LILACS) and databases of ongoing trials (www.controlled-trials.com/mrct/, www.who.int/trialsearch). We checked reference lists and contacted experts for further relevant studies. We included studies that reported both cost and effectiveness outcomes of two or more alternative interventions to prevent disability in leprosy. We assessed the quality of the identified studies using a standard checklist for critical appraisal of economic evaluations of health care programmes. We found 66 citations to potentially relevant studies and three met our criteria. Two were randomised controlled trials (footwear, management of neuritis) and one was a generic model-based study (cost per DALY). Generally, the studies were small in size, reported inadequately all relevant costs, uncertainties in estimates, and issues of concern and were based on limited data sources. No cost-effectiveness data on self-care, which is a key strategy in POD, was found. CONCLUSION/SIGNIFICANCE: Evidence for cost-effectiveness of POD interventions for leprosy is scarce. High quality research is needed to identify POD interventions that offer value for money where resources are very scarce, and to develop strategies aimed at available, affordable and sustainable quality POD services for leprosy. The findings are relevant for other chronically disabling conditions, such as lymphatic filariasis, Buruli ulcer and diabetes in developing countries.