The PEP++ study protocol: a cluster-randomised controlled trial on the effectiveness of an enhanced regimen of post-exposure prophylaxis for close contacts of persons affected by leprosy to prevent disease transmission.

BACKGROUND: Leprosy is an infectious disease with a slow decline in global annual caseload in the past two decades. Active case finding and post-exposure prophylaxis (PEP) with a single dose of rifampicin (SDR) are recommended by the World Health Organization as measures for leprosy elimination. However, more potent PEP regimens are needed to increase the effect in groups highest at risk (i.e., household members and blood relatives, especially of multibacillary patients). The PEP++ trial will assess the effectiveness of an enhanced preventive regimen against leprosy in high-endemic districts in India, Brazil, Bangladesh, and Nepal compared with SDR-PEP. METHODS: The PEP++ study is a cluster-randomised controlled trial in selected districts of India, Brazil, Bangladesh, and Nepal. Sub-districts will be allocated randomly to the intervention and control arms. Leprosy patients detected from 2015 - 22 living in the districts will be approached to list their close contacts for enrolment in the study. All consenting participants will be screened for signs and symptoms of leprosy and tuberculosis (TB). In the intervention arm, eligible contacts receive the enhanced PEP++ regimen with three doses of rifampicin (150 - 600 mg) and clarithromycin (150 - 500 mg) administered at four-weekly intervals, whereas those in the control arm receive SDR-PEP. Follow-up screening for leprosy will be done for each individual two years after the final dose is administered. Cox' proportion hazards analysis and Poisson regression will be used to compare the incidence rate ratios between the intervention and control areas as the primary study outcome. DISCUSSION: Past studies have shown that the level of SDR-PEP effectiveness is not uniform across contexts or in relation to leprosy patients. To address this, a number of recent trials are seeking to strengthen PEP regimens either through the use of new medications or by increasing the dosage of the existing ones. However, few studies focus on the impact of multiple doses of chemoprophylaxis using a combination of antibiotics. The PEP++ trial will investigate effectiveness of both an enhanced regimen and use geospatial analysis for PEP administration in the study communities. TRIAL REGISTRATION: NL7022 on the Dutch Trial Register on April 12, 2018. Protocol version 9.0 updated on 18 August 2022 https://www.onderzoekmetmensen.nl/en/trial/23060.

The Leprosy Post-Exposure Prophylaxis (LPEP) programme: update and interim analysis.

Innovative approaches are required to further enhance leprosy control, reduce the number of people developing leprosy, and curb transmission. Early case detection, contact screening, and chemoprophylaxis currently is the most promising approach to achieve this goal. The Leprosy Post-Exposure Prophylaxis (LPEP) programme generates evidence on the feasibility of integrating contact tracing and single-dose rifampicin (SDR) administration into routine leprosy control activities in different settings. The LPEP programme is implemented within the leprosy control programmes of Brazil, Cambodia, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. Focus is on three key interventions: tracing the contacts of newly diagnosed leprosy patients; screening the contacts for leprosy; and administering SDR to eligible contacts. Country-specific protocol adaptations refer to contact definition, minimal age for SDR, and staff involved. Central coordination, detailed documentation and rigorous supervision ensure quality evidence. Around 2 years of field work had been completed in seven countries by July 2017. The 5,941 enrolled index patients (89·4% of the registered) identified a total of 123,311 contacts, of which 99·1% were traced and screened. Among them, 406 new leprosy patients were identified (329/100,000), and 10,883 (8·9%) were excluded from SDR for various reasons. Also, 785 contacts (0·7%) refused the prophylactic treatment with SDR. Overall, SDR was administered to 89·0% of the listed contacts. Post-exposure prophylaxis with SDR is safe; can be integrated into the routines of different leprosy control programmes; and is generally well accepted by index patients, their contacts and the health workforce. The programme has also invigorated local leprosy control.

Cross-cultural validation of two scales to assess mental wellbeing in persons affected by leprosy in Province 1 and 7, Nepal.

To assess mental wellbeing among persons affected by leprosy, this study aimed to validate the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) and the Patient Health Questionnaire (PHQ-9, depression tool) in Province 1 and 7, Nepal. Using purposive and convenience sampling, cross-cultural equivalences were assessed through semi-structured interviews with persons affected by leprosy (>18 years). Data were transcribed, translated, analysed and discussed with experts before revising the tools. Psychometric properties of the scales were assessed using an interviewer-administered questionnaire with cases affected by leprosy and controls not affected by leprosy (>18 years). Statistical analysis included internal consistency, construct validity, floor and ceiling effects, and interpretability. The qualitative study included 20 respondents of whom eleven were female. The statements in the original tools were rephrased to questions as participants had difficulties understanding the statements. Six additional changes were made to ensure items were understood well. The quantitative study included 90 cases (46% female) and 50 controls (54% female). The WEMWBS and PHQ-9 had adequate psychometric properties. Cronbach's alphas were 0.85 and 0.76, respectively, indicating good internal consistency, 75% of hypotheses for construct validity were confirmed, no floor and ceiling effects were found, and data to help users interpret results are presented. Our study provides evidence that the adapted versions of the WEMWBS and PHQ-9 have good cultural validity to measure mental wellbeing and depression among persons affected by leprosy in Province 1 and 7, Nepal.

Implementation approaches for leprosy prevention with single-dose rifampicin: A support tool for decision making.

BACKGROUND: In the past 15 years, the decline in annually detected leprosy patients has stagnated. To reduce the transmission of Mycobacterium leprae, the World Health Organization recommends single-dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients. Various approaches to administer SDR-PEP have been piloted. However, requirements and criteria to select the most suitable approach were missing. The aims of this study were to develop an evidence-informed decision tool to support leprosy programme managers in selecting an SDR-PEP implementation approach, and to assess its user-friendliness among stakeholders without SDR-PEP experience. METHODOLOGY: The development process comprised two phases. First, a draft tool was developed based on a literature review and semi-structured interviews with experts from various countries, organisations and institutes. This led to: an overview of existing SDR-PEP approaches and their characteristics; understanding the requirements and best circumstances for these approaches; and, identification of relevant criteria to select an approach. In the second phase the tool's usability and applicability was assessed, through interviews and a focus group discussion with intended, inexperienced users; leprosy programme managers and non-governmental organization (NGO) staff. PRINCIPAL FINDINGS: Five SDR-PEP implementation approaches were identified. The levels of endemicity and stigma, and the accessibility of an area were identified as most relevant criteria to select an approach. There was an information gap on cost-effectiveness, while successful implementation depends on availability of resources. Five basic requirements, irrespective of the approach, were identified: stakeholder support; availability of medication; compliant health system; trained health staff; and health education. Two added benefits of the tool were identified: its potential value for advocacy and for training. CONCLUSION: An evidence-informed SDR-PEP decision tool to support the selection of implementation approaches for leprosy prevention was developed. While the tool was evaluated by potential users, more research is needed to further improve the tool, especially health-economic studies, to ensure efficient and cost-effective implementation of SDR-PEP.

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.