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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

Abstract

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.

Keywords: Blanket campaigns; Clarithromycin; High-endemic areas; Leprosy; Post-exposure prophylaxis; Rifampicin.

Effectiveness of ongoing single-dose rifampicin post-exposure prophylaxis (SDR-PEP) implementation under routine programme conditions—An observational study in Nepal

Banstola NL*1; Hasker E2, Mieras L3, Gurung D4, Baral B4, Mehata S5, Prasai S6, Ghimire Y7, Kumar Das B8, Napit P9, van Brakel WH3

1NLR Nepal; 2 Institute of Tropical Medicine Antwerp; 3NLR IO Netherlands; 4FAIRMED Nepal; 5Health office Morang, 6Health office Sunsari, 7Health office Jhapa, 8Health office Udayapur, 9Leprosy Control and Disability Management Section, Nepal 

*Corresponding author

Banstola NL

ORCID: 0000-0002-8115-7661

Biratnagar, Koshi province

NLR Nepal 

nbastola123@gmail.com

nandlalbanstola@nlrnepal.org.np

Abstract

Background/Introduction

Leprosy control remains a challenge in Nepal. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) shows promise in reducing leprosy incidence among contacts of index cases, contributing to reducing the transmission of Mycobacterium (M.) leprae. This study evaluates the effectiveness of routine SDR-PEP implementation in Nepal in addition to contact screening, focusing on its impact on reducing leprosy risk among contacts and potential population-level effects.

Methodology

We conducted a retrospective cohort study to compare leprosy case notification rates and leprosy risk among close contacts. We compared two districts implementing SDR-PEP (the intervention group) and two without (the control group). Data from 2015 onwards included demographics, index case types, and contact relationships. Statistical analyses, including hazard ratios (HR) and Kaplan-Meier survival curves, assessed the impact of SDR-PEP implementation.

Findings

All four districts showed a decrease in case notification rates since 2015, with the steepest decline in the intervention districts. The risk of developing leprosy among contacts was significantly lower in the intervention districts (HR 0.28, 95% CI 0.18-0.44). SDR-PEP offered 72% protection, consistent over time, as shown in Kaplan-Meier plots. The interaction between intervention and blood-related contact was non-significant (0.29 versus 0.27, p=0.32), and the proportion of MB cases among incident cases was not significantly different post-PEP (51.4% vs. 53.6%, p=0.82).

Conclusions

This study demonstrates the substantial protective effect of integrating SDR-PEP in routine leprosy control programs with contact screening, significantly lowering leprosy risk among contacts. SDR-PEP is equally effective for blood-related contacts and does not preferentially prevent PB cases. While suggesting potential population-level impact, the study design does not allow for firm conclusions at this level. Further research is needed to fully assess SDR-PEP’s effectiveness in diverse contexts and optimize its implementation. Integrating SDR-PEP within well-organized contact screening programs is effective and is expected to reduce leprosy transmission when applied as a rolling intervention.

Keywords: Routine leprosy Control, Single-dose Rifampicin (SDR), Post-exposure Prophylaxis (PEP), SDR-PEP Implementation, Contact Screening,