Should prophylaxis against Pneumocystis jirovecii pneumonia be considered in selected patients with leprosy reactions?

Leprosy reactions often require prolonged high-dose steroids or immunosuppressive drugs, putting patients at risk of Pneumocystis jirovecii pneumonia (PJP). However, no PJP cases are reported, possibly due to dapsone treatment for leprosy. In patients with leprosy reactions not receiving dapsone because of toxicity or resistance and requiring long-term immunosuppression, PJP prophylaxis should be considered.

Single-Dose Rifampicin Leprosy Chemoprophylaxis for Household Contacts in Kiribati: An Audit of a Combined Retrospective and Prospective Approach.

Kiribati is a Pacific Island nation with a widely dispersed population and one of the highest rates of leprosy worldwide. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) of leprosy contacts has reduced new case detection rates in controlled trials. In 2018, an SDR-PEP programme was introduced in Kiribati that included screening and chemoprophylaxis of household contacts of leprosy cases retrospectively (2010-2017) and prospectively (2018-2022). We conducted a retrospective audit to determine the comprehensiveness, timeliness and feasibility of the SDR-PEP programme. Overall, 13,641 household contacts were identified (9791 in the retrospective and 3850 in the prospective cohort). In the retrospective cohort, 1044 (11%) contacts were absent, 403 (4%) were ineligible for SDR, and 42 new cases were detected (0.4%) Overall, SDR coverage was 84.7%. In the prospective cohort, 164 (4%) contacts were absent, 251 (7%) were ineligible for SDR, and 23 new cases were diagnosed (0.6%). Overall, SDR coverage was 88.1%. Across both cohorts, there were 23 SDR refusals. The median time to SDR administration was 220 days (IQR 162-468) and 120 days (IQR 36-283) for the retrospective and prospective cohorts, respectively. SDR was readily accepted in both cohorts. The new case detection rate (0.5%) is consistent with that in other studies. Overall SDR coverage in both the retrospective and prospective phases met programmatic expectations.

Leprosy: treatment, prevention, immune response and gene function.

Since the leprosy cases have fallen dramatically, the incidence of leprosy has remained stable over the past years, indicating that multidrug therapy seems unable to eradicate leprosy. More seriously, the emergence of rifampicin-resistant strains also affects the effectiveness of treatment. Immunoprophylaxis was mainly carried out through vaccination with the BCG but also included vaccines such as LepVax and MiP. Meanwhile, it is well known that the infection and pathogenesis largely depend on the host's genetic background and immunity, with the onset of the disease being genetically regulated. The immune process heavily influences the clinical course of the disease. However, the impact of immune processes and genetic regulation of leprosy on pathogenesis and immunological levels is largely unknown. Therefore, we summarize the latest research progress in leprosy treatment, prevention, immunity and gene function. The comprehensive research in these areas will help elucidate the pathogenesis of leprosy and provide a basis for developing leprosy elimination strategies.

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.

Patterns of Occupational Exposure to Human Immunodeficiency Virus and Post-Exposure Prophylaxis Among Health Care Personnel in a Tertiary Care Institute in South India - A Retrospective Case Series.

Background: Post-exposure prophylaxis (PEP) for occupational human immunodeficiency virus (HIV) exposure involves the comprehensive measures used to prevent transmission of blood-borne pathogens such as HIV, hepatitis B virus, and hepatitis C virus through various strategies such as first aid, counseling, risk assessment, relevant laboratory investigations with informed consent, the provision of short-term anti-retroviral drugs, and follow-up testing. Aim and Objectives: We sought to investigate the patterns and causes of occupational exposure in health care workers (HCWs) in our institute and the usage of PEP in our center, a tertiary care hospital in south India. Materials and Methods: The study involved a retrospective analysis of data extracted from the records of PEP usage from the anti-retroviral treatment (ART) center attached to the dermatology, venereology and leprosy out-patient department of a tertiary care center in south India. The data were extracted into a pre-designed proforma and analyzed using descriptive statistics. Results: A total of 352 health care professionals reported to the ART center for PEP from 2010 to 2020. One hundred and thirty-four patients took only the first dose as the source patient later tested to be HIV-negative. Among the 218 remaining patients, 84 were male and 134 were female patients. Only 56 health care workers started the regimen within 2 hours. One hundred and thirty-four patients completed the full course of PEP. Most HCWs (n = 68, 31%) sustained the exposure while doing a procedure on the patient followed by re-capping a needle (n = 64, 29%). Gastritis and drowsiness were the most common adverse effects. Limitations and Conclusions: The study was limited by the retrospective nature of data collection and the lack of detailed interviews with HCWs. Knowledge about PEP, needle safety training, and training of early first aid measures should be increased among health care workers.

Effectiveness of population-wide screening and mass drug administration for leprosy control in Kiribati: the COMBINE protocol.

INTRODUCTION: Progress towards leprosy elimination is threatened by increasing incidence in 'hot-spot' areas where more effective control strategies are urgently required. In these areas, active case finding and leprosy prevention limited to known contacts is insufficient for control. Population-wide active case-finding together with universal prevention through mass drug administration (MDA) has been shown to be effective in 'hot-spot' areas, but is logistically challenging and expensive. Combining leprosy screening and MDA with other population-wide screening activities such as for tuberculosis may increase programme efficiency. There has been limited evaluation of the feasibility and effectiveness of combined screening and MDA interventions. The COMBINE study aims to bridge this knowledge gap. METHODS AND ANALYSIS: This implementation study will assess the feasibility and effectiveness of active leprosy case-finding and treatment, combined with MDA using either single-dose rifampicin or rifamycin-containing tuberculosis preventive or curative treatment, for reducing leprosy incidence in Kiribati. The leprosy programme will run over 2022-2025 in concert with population-wide tuberculosis screening-and-treatment in South Tarawa. The primary research question is to what extent the intervention reduces the annual leprosy new case detection rate (NCDR) in adults and children compared with routine screening and postexposure prophylaxis (PEP) among close contacts (baseline leprosy control activities). Comparisons will be made with (1) the preintervention NCDR separably among adults and children in South Tarawa (before-after study) and (2) the corresponding NCDRs in the rest of the country. Additionally, the postintervention prevalence of leprosy obtained from a survey of a 'hot-spot' sub-population will be compared with prevalence documented during the intervention. The intervention will be implemented in collaboration with the Kiribati National Leprosy Programme. ETHICS AND DISSEMINATION: Approval has been obtained from the Kiribati Ministry of Health and Medical Services (MHMS), the University of Otago (H22/111) and the University of Sydney (2021/127) Human Research Ethics Committees. Findings will be shared with the MHMS, local communities and internationally through publication.

Protocol, rationale and design of BE-PEOPLE (Bedaquiline enhanced exposure prophylaxis for LEprosy in the Comoros): a cluster randomized trial on effectiveness of rifampicin and bedaquiline as post-exposure prophylaxis of leprosy contacts.

BACKGROUND: Leprosy is an ancient infectious disease with an annual global incidence of around 200,000 over the past decade. Since 2018, the World Health Organization (WHO) recommends single-dose rifampicin as post-exposure prophylaxis (SDR-PEP) for contacts of leprosy patients. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial evaluated PEP with a double dose of rifampicin in Comoros and Madagascar. Preliminary results of this trial show some reduction in leprosy incidence in intervention villages but a stronger regimen may be beneficial. The objective of the current Bedaquiline Enhanced ExpOsure Prophylaxis for LEprosy trial (BE-PEOPLE) is to explore effectiveness of a combination of bedaquiline and rifampicin as PEP. METHODS: BE-PEOPLE is a cluster-randomized trial in which 44 clusters in Comoros will be randomized to two study arms. Door-to-door screening will be conducted annually during four years, leprosy patients identified will be offered standard of care treatment. Based on study arm, contacts aged five years and above and living within a 100-meter radius of an index case will either receive bedaquiline (400-800 mg) and rifampicin (150-600 mg) or only rifampicin (150-600 mg). Contacts aged two to four years will receive rifampicin only. Household contacts randomized to the bedaquiline plus rifampicin arm will receive a second dose four weeks later. Incidence rate ratios of leprosy comparing contacts who received either of the PEP regimens will be the primary outcome. We will monitor resistance to rifampicin and/or bedaquiline through molecular surveillance in all incident tuberculosis and leprosy patients nationwide. At the end of the study, we will assess anti-M. leprae PGL-I IgM seropositivity as a proxy for the population burden of M. leprae infection in 8 villages (17,000 individuals) that were surveyed earlier as part of the PEOPLE trial. DISCUSSION: The COLEP trial on PEP in Bangladesh documented a reduction of 57% in incidence of leprosy among contacts treated with SDR-PEP after two years, which led to the WHO recommendation of SDR-PEP. Preliminary results of the PEOPLE trial show a lesser reduction in incidence. The BE-PEOPLE trial will explore whether reinforcing SDR-PEP with bedaquiline increases effectiveness and more rapidly reduces the incidence of leprosy, compared to SDR-PEP alone. TRIAL REGISTRATION: NCT05597280. Protocol version 5.0 on 28 October 2022.

The application of digital health as a nursing solution for leprosy patients during the COVID-19 pandemic: A systematic review.

Objectives: To analyse the effect of using digital health technology on leprosy control programmes. Method: The systematic review comprised search on PubMed, Scopus, ScienceDirect, SAGE and ProQuest databases for interventional studies published in English language from 2013 to 2021 which used digital health technology for leprosy contact tracing, active leprosy detection, monitoring of multi-drug therapy and treatment management during the corona virus disease-2019 pandemic A standard risk of bias tool was used to evaluate bias in the studies, and the Joanna Briggs Institute protocol was used to assess the quality of the studies analysed. RESULTS: Of the 205 studies initially identified, 15(7.3%) were analysed in detail. Quasi-experimental studies had a low risk of bias compared to the rest. The e-leprosy framework was being used along with applications based on smartphones and artificial intelligence Digital health technology was found to be practical, accessible and effective in leprosy control programmes. CONCLUSIONS: Studies reported favourable findings regarding the use of digital health technology in services related to leprosy patients.

Leprosy chemoprophylaxis of household contacts: A survey of Canadian infectious disease and tropical medicine specialists.

BACKGROUND: Leprosy is uncommon in Canada. However, immigration from leprosy-endemic areas has introduced the infection to a Canadian context, in which most doctors have little knowledge of the disease. Although post-exposure chemoprophylaxis (PEP) is reported to decrease leprosy transmission, no Canadian guidelines advise clinical decision making about leprosy PEP. Here, we characterize the practice patterns of Canadian infectious disease specialists with respect to leprosy PEP and screening of household contacts by yearly physical examinations. METHODS: Canadian infectious disease specialists with known experience treating leprosy were identified using university faculty lists. An online anonymous survey was distributed. Certain questions allowed more than one response. RESULTS: The survey response rate was 46.5% (20/43). Thirty-five percent responded that PEP is needed for household contacts, 40.0% responded that PEP is not needed for household contacts, and 25.0% did not know whether PEP is needed (multinomial test p = 0.79). Twenty-five percent responded that PEP should be given to all household contacts, 62.5% responded that PEP should be given to contacts of multibacillary cases, and 25.0% responded that PEP should be given to contacts who are genetically related to the index case. For specialists who prescribe PEP, 57.1% use rifampicin, ofloxacin (levofloxacin), and minocycline; 14.3% prescribe single-dose rifampicin; and 28.6% prescribe multiple doses of rifampicin (multinomial test p = 0.11). In addition, 68.4% recommend yearly screening of household contacts, whereas 31.6% do not (multinomial test p = 0.17). CONCLUSION: Consensus among Canadian infectious diseases specialists is lacking regarding leprosy PEP and screening of household contacts.

HISTORIQUE: La lèpre est peu courante au Canada. Cependant, en raison de l'immigration de régions où la lèpre est endémique, cette infection existe, mais la plupart des médecins du Canada la connaissent peu. Même s'il est établi que la chimioprophylaxie post-exposition (PPE) réduit la transmission de la lèpre, il n'existe aucune directive canadienne pour éclairer les décisions cliniques sur la PPE de la lèpre. Les chercheurs caractérisent les schémas d'exercice des infectiologues canadiens au sujet de la PPE de la lèpre et du dépistage des contacts familiaux par des examens physiques annuels des aspects dermatologiques et nerveux périphériques. MÉTHODOLOGIE: Les chercheurs ont répertorié les infectiologues canadiens qui ont une expérience démontrée du traitement de la lèpre grâce aux listes des professeurs universitaires. Ils ont distribué un sondage anonyme en ligne. Pour certaines questions, les participants pouvaient fournir plus d'une réponse. Ils pouvaient aussi sauter certaines questions. RÉSULTATS: Le taux de réponse au sondage s'élevait à 46,5 % (20 cas sur 43). De cette proportion, 35,0 % ont répondu que les contacts familiaux avaient besoin d'une PPE, 40,0 %, qu'ils n'en avaient pas besoin, et 25,0 %, qu'ils ne le savaient pas (test multinomial, p = 0,79). Sur l'ensemble des répondants, 25,0 % ont répondu que tous les contacts familiaux devraient recevoir une PPE, 62,5 %, qu'elle devait être administrée aux contacts des cas multibacillaires, et 25,0 %, aux contacts génétiquement apparentés au cas de référence. Chez les spécialistes qui prescrivent une PPE, 57,1 % utilisent de la rifampicine, de l'ofloxacine (lévofloxacine) et de la minocycline, 14,3 %, une seule dose de rifampicine, et 28,6 %, de multiples doses de rifampicine (test multinomial p = 0,11). De plus, 68,4 % recommandent le dépistage annuel des contacts familiaux, et 31,6 % ne le recommandent pas (test multinomial p = 0,17). CONCLUSION: Il n'y a pas de consensus chez les infectiologues canadiens au sujet de la PPE de la lèpre et du dépistage des contacts familiaux.

Determining target populations for leprosy prophylactic interventions: a hotspot analysis in Indonesia.

BACKGROUND: Leprosy incidence remained at around 200,000 new cases globally for the last decade. Current strategies to reduce the number of new patients include early detection and providing post-exposure prophylaxis (PEP) to at-risk populations. Because leprosy is distributed unevenly, it is crucial to identify high-risk clusters of leprosy cases for targeting interventions. Geographic Information Systems (GIS) methodology can be used to optimize leprosy control activities by identifying clustering of leprosy cases and determining optimal target populations for PEP. METHODS: The geolocations of leprosy cases registered from 2014 to 2018 in Pasuruan and Pamekasan (Indonesia) were collected and tested for spatial autocorrelation with the Moran's I statistic. We did a hotspot analysis using the Heatmap tool of QGIS to identify clusters of leprosy cases in both areas. Fifteen cluster settings were compared, varying the heatmap radius (i.e., 500 m, 1000 m, 1500 m, 2000 m, or 2500 m) and the density of clustering (low, moderate, and high). For each cluster setting, we calculated the number of cases in clusters, the size of the cluster (km2), and the total population targeted for PEP under various strategies. RESULTS: The distribution of cases was more focused in Pasuruan (Moran's I = 0.44) than in Pamekasan (0.27). The proportion of total cases within identified clusters increased with heatmap radius and ranged from 3% to almost 100% in both areas. The proportion of the population in clusters targeted for PEP decreased with heatmap radius from > 100% to 5% in high and from 88 to 3% in moderate and low density clusters. We have developed an example of a practical guideline to determine optimal cluster settings based on a given PEP strategy, distribution of cases, resources available, and proportion of population targeted for PEP. CONCLUSION: Policy and operational decisions related to leprosy control programs can be guided by a hotspot analysis which aid in identifying high-risk clusters and estimating the number of people targeted for prophylactic interventions.

BCG-induced immunity profiles in household contacts of leprosy patients differentiate between protection and disease.

Leprosy is an infectious disease caused by Mycobacterium leprae leading to irreversible disabilities along with social exclusion. Leprosy is a spectral disease for which the clinical outcome after M. leprae infection is determined by host factors. The spectrum spans from anti-inflammatory T helper-2 (Th2) immunity concomitant with large numbers of bacteria as well as antibodies against M. leprae antigens in multibacillary (MB) leprosy, to paucibacillary (PB) leprosy characterised by strong pro-inflammatory, Th1 as well as Th17 immunity. Despite decades of availability of adequate antibiotic treatment, transmission of M. leprae is unabated. Since individuals with close and frequent contact with untreated leprosy patients are particularly at risk to develop the disease themselves, prophylactic strategies currently focus on household contacts of newly diagnosed patients. It has been shown that BCG (re)vaccination can reduce the risk of leprosy. However, BCG immunoprophylaxis in contacts of leprosy patients has also been reported to induce PB leprosy, indicating that BCG (re)vaccination may tip the balance between protective immunity and overactivation immunity causing skin/nerve tissue damage. In order to identify who is at risk of developing PB leprosy after BCG vaccination, amongst individuals who are chronically exposed to M. leprae, we analyzed innate and adaptive immune markers in whole blood of household contacts of newly diagnosed leprosy patients in Bangladesh, some of which received BCG vaccination. As controls, individuals from the same area without known contact with leprosy patients were similarly assessed. Our data show the added effect of BCG vaccination on immune markers on top of the effect already induced by M. leprae exposure. Moreover, we identified BCG-induced markers that differentiate between protective and disease prone immunity in those contacts.

Preventing leprosy with retrospective active case finding combined with single-dose rifampicin for contacts in a low endemic setting: results of the Leprosy Post-Exposure Prophylaxis program in Cambodia.

Post-exposure prophylaxis (PEP) with single-dose rifampicin (SDR) reduces the risk of developing leprosy among contacts of leprosy patients. Most evidence for the feasibility of the intervention is from highly endemic settings while low-endemic areas present unique challenges including reduced awareness of the disease among the population and in the health system, and the only sporadic occurrence of cases which together make defining any type of routine process challenging. We complemented the retrospective active case finding (RACF) approach with SDR administration to eligible contacts, and piloted the intervention across 31 operational districts in Cambodia. The aim was to demonstrate the feasibility of improving early case detection and administering SDR in a low endemic setting. The intervention focused on leprosy patients diagnosed since 2011 and was implemented between October 2016 - September 2019. The "drives" approach was employed to trace contacts: a trained team systematically contacted all eligible cases in a district, traced and screened contacts, and administered SDR. A total of 555 index patients were traced by the drive team, and 10,410 contacts in their household and 5 immediate neighbor houses listed. Among these contacts, 72.0% could be screened while most others were absent on the screening day. A total of 33 new leprosy cases were diagnosed and 6189 contacts received SDR (82.6% of the screened contacts). Sixty-one contacts refused SDR administration. We conclude that integrating PEP with SDR in RACF campaigns is feasible, and that this approach is appropriate in low resource and low endemic settings. Over time, evidence on whether or not the approach reduced leprosy transmission in Cambodia, may become clear.

Venous thromboembolism prophylaxis in patients with multiple myeloma: where are we and where are we going?

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

The State of Affairs in Post-Exposure Leprosy Prevention: A Descriptive Meta-Analysis on Immuno- and Chemo-Prophylaxis.

OBJECTIVE: Annually, over 200,000 people are diagnosed with leprosy, also called Hansen's disease. This number has been relatively stable over the past years. Progress has been made in the fields of chemoprophylaxis and immunoprophylaxis to prevent leprosy, with a primary focus on close contacts of patients. In this descriptive meta-analysis, we summarize the evidence and identify knowledge gaps regarding post-exposure prophylaxis against leprosy. METHODS: A systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was conducted by searching the medical scientific databases Cochrane, Embase, Pubmed/MEDLINE, Research Gate, Scopus and Web of Science on Jan. 22, 2020, using a combination of synonyms for index terms in four languages: "leprosy" and "population" or "contacts" and "prevention" or "prophylaxis." Subsequently, Infolep.org and Google Scholar were searched and the "snowball method" was used to retrieve other potentially relevant literature. The found articles were screened for eligibility using predetermined inclusion and exclusion criteria. RESULTS: After deduplication, 1,515 articles were screened, and 125 articles were included in this descriptive meta-analysis. Immunoprophylaxis by bacillus Calmette-Guérin (BCG) vaccination is known to provide protection against leprosy. The protection it offers is higher in household contacts of leprosy patients compared with the general population and is seen to decline over time. Contact follow-up screening is important in the first period after BCG administration, as a substantial number of new leprosy patients presents three months post-vaccination. Evidence for the benefit of re-vaccination is conflicting. The World Health Organization (WHO) included BCG in its Guidelines for the Diagnosis, Treatment and Prevention of Leprosy by stating that BCG at birth should be maintained in at least all leprosy high-burden regions. Literature shows that several vaccination interventions with other immunoprophylactic agents demonstrate similar or slightly less efficacy in leprosy risk reduction compared with BCG. However, most of these studies do not exclusively focus on post-exposure prophylaxis. Two vaccines are considered future candidates for leprosy prophylaxis: Mycobacterium indicus pranii (MiP) and LepVax. For chemoprophylaxis, trials were performed with dapsone/acedapsone, rifampicin, and ROM, a combination of rifampicin, ofloxacin, and minocycline. Single-dose rifampicin is favored as post-exposure prophylaxis, abbreviated as SDR-PEP. It demonstrated a protective effect of 57% in the first two years after administration to contacts of leprosy patients. It is inexpensive, and adverse events are rare. The risk of SDR-PEP inducing rifampicin resistance is considered negligible, but continuous monitoring in accordance with WHO policies should be encouraged. The integration of contact screening and SDR-PEP administration into different leprosy control programs was found to be feasible and well accepted. Since 2018, SDR-PEP is included in the WHO Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. CONCLUSION: Progress has been made in the areas of chemoprophylaxis and immunoprophylaxis to prevent leprosy in contacts of patients. Investing in vaccine studies, like LepVax and MiP, and increasing harmonization between tuberculosis (TB) and leprosy research groups is important. SDR-PEP is promising as a chemoprophylactic agent, and further implementation should be promoted. More chemoprophylaxis research is needed on: enhanced medication regimens; interventions in varying (epidemiological) settings, including focal mass drug administration (fMDA); specific approaches per contact type; combinations with screening variations and field-friendly rapid tests, if available in the future; community and health staff education; ongoing antibiotic resistance surveillance; and administering chemoprophylaxis with SDR-PEP prior to BCG administration. Additionally, both leprosy prophylactic drug registration nationally and prophylactic drug availability globally at low or no cost are important for the implementation and further upscaling of preventive measures against leprosy, such as SDR-PEP and new vaccines.

Prolaxis post-exposición para lepra con dosis única de rifampicina: manual para su implementación / Post-exposure prolaxis for leprosy with a single dose of rifampicin: a manual for its implementation

Objetivo: La profilaxis post-exposición de la lepra con dosis única de rifampicina (SDR-PEP) ha demostrado ser efectiva y aplicable y está recomendada por la OMS desde 2018. Esta caja de herramientas SDR-PEP se desarrolló a través de la experiencia de la profilaxis lepra post-eliminación (LPEP). Se ha diseñado para facilitar y estandarizar la implementación del seguimiento de contactos y la administración SDR-PEP en regiones y países que iniciaron la intervención. Resultados: Se desarrollaron cuatro instrumentos, incorporando la evidencia existente actual para SDR-PEP y los métodos y enseñanzas del proyecto LPEP en ocho países. (1) El conjunto de diapositivas Powerpoint política/apoyo que ayudarán a los programadores sobre la evidencia, practicabilidad y recursos necesarios para SDR-PEP, (2) La colección de diapositivas PowerPoint sobre formación e implementación en el campo para formar al personal implicado en el seguimiento de contactos y PEP con SDR, (3) manual genérico de campo SDR-PEP que puede ser usado para formar un protocolo específico de campo para el seguimiento de contactos y SDR-PEP como referencia para el personal directamente implicado. Finalmente, (4) el manual director SDR-PEP, que resume los distintos componentes de la caja de herramientas y contiene las instrucciones para su uso. Conclusión: En respuesta al interés manifestado por varios países de implementar el seguimiento de contactos de lepra con PEP con SDR, con las recomendaciones OMS sobre SDR-PEP, esta caja de herramientas basada en la evidencia concreta pero flexible, ha sido diseñada para servir a los directores de programas nacionales de lepra con un medio práctico para trasladar los planteamientos a la práctica. Está disponible gratuitamente en la página de Infolep y actualizada constantemente: https://www.leprosy-information.org/keytopic/leprosy-post-exposure-prophylaxis-lpep-programme(AU).

Objective: Leprosy post-exposure prophylaxis with single-dose rifampicin (SDRPEP) has proven effective and feasible, and is recommended by WHO since 2018. This SDR-PEP toolkit was developed through the experience of the leprosy post-exposure prophylaxis (LPEP) programme. It has been designed to facilitate and standardise the implementation of contact tracing and SDR-PEP administration in regions and countries that start the intervention. Results: Four tools were developed, incorporating the current evidence for SDRPEP and the methods and learnings from the LPEP project in eight countries. (1) the SDR-PEP policy/advocacy PowerPoint slide deck which will help to inform policy makers about the evidence, practicalities and resources needed for SDR-PEP, (2) the SDR-PEP field implementation training PowerPoint slide deck to be used to train front line staff to implement contact tracing and PEP with SDR, (3) the SDR-PEP generic field guide which can be used as a basis to create a location specific field protocol for contact tracing and SDR-PEP serving as a reference for frontline field staff. Finally, (4) the SDR-PEP toolkit guide, summarising the different components of the toolkit and providing instructions on its optimal use. Conclusion: In response to interest expressed by countries to implement contact tracing and leprosy PEP with SDR in the light of the WHO recommendation of SDRPEP, this evidence-based, concrete yet flexible toolkit has been designed to serve national leprosy programme managers and support them with the practical means to translate policy into practice. The toolkit is freely accessible on the Infolep homepages and updated as required: https://www.leprosy-information.org/keytopic/leprosy-postexposure-prophylaxis-lpep-programme(AU).

Protocol, rationale and design of PEOPLE (Post ExpOsure Prophylaxis for LEprosy in the Comoros and Madagascar): a cluster randomized trial on effectiveness of different modalities of implementation of post-exposure prophylaxis of leprosy contacts.

BACKGROUND: Leprosy is an ancient infectious disease with a global annual incidence that has plateaued above 200,000 new cases since over a decade. New strategies are required to overcome this stalemate. Post-exposure prophylaxis (PEP) with a single dose of Rifampicin (SDR) has conditionally been recommended by the World Health Organization (WHO), based on a randomized-controlled-trial in Bangladesh. More evidence is required. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial will assess effectiveness of different modalities of PEP on the Comoros and Madagascar. METHODS: PEOPLE is a cluster-randomized trial with villages selected on previous leprosy-incidence and randomly allocated to four arms. Four annual door-to-door surveys will be performed in all arms. All consenting permanent residents will be screened for leprosy. Leprosy patients will be treated according to international guidelines and eligible contacts will be provided with SDR-PEP. Arm-1 is the comparator in which no PEP will be provided. In arms 2, 3 and 4, SDR-PEP will be provided at double the regular dose (20 mg/kg) to eligible contacts aged two years and above. In arm 2 all household-members of incident leprosy patients are eligible. In arm 3 not only household-members but also neighbourhood contacts living within 100-m of an incident case are eligible. In arm 4 such neighbourhood contacts are only eligible if they test positive to anti-PGL-I, a serological marker. Incidence rate ratios calculated between the comparator arm 1 and each of the intervention arms will constitute the primary outcome. DISCUSSION: Different trials on PEP have yielded varying results. The pivotal COLEP trial in Bangladesh showed a 57% reduction in incidence over a two-year period post-intervention without any rebound in the following years. A study in a high-incidence setting in Indonesia showed no effect of PEP provided to close contacts but a major effect of PEP provided as a blanket measure to an entire island population. High background incidence could be the reason of the lack of effect of PEP provided to individual contacts. The PEOPLE trial will assess effectiveness of PEP in a high incidence setting and will compare three different approaches, to identify who benefits most from PEP. TRIAL REGISTRATION: Clinicaltrials.Gov. NCT03662022. Initial Protocol Version 1.2, 27-Aug-2018.

Clustering of leprosy beyond the household level in a highly endemic setting on the Comoros, an observational study.

BACKGROUND: The island of Anjouan (Comoros) is highly endemic for leprosy with an annual incidence of 5-10/10,000. In May/June, 2015 single-dose Rifampicin post-exposure prophylaxis (SDR-PEP) was administered to 269 close contacts of 70 leprosy-patients in four villages as a pilot programmatic intervention. Two years later we revisited the villages for follow-up investigations. The main aim of our study was to quantify spatial associations between reported leprosy cases before and after PEP implementation. A secondary aim was to assess the effect of this single round of SDR-PEP at the individual level. METHODS: We conducted door-to-door leprosy screening in all four villages in August/September, 2017. We screened all consenting individuals for leprosy and recorded geographic coordinates of their household. We also recorded whether they had received SDR-PEP and whether they had been diagnosed with leprosy, before or after the 2015 intervention. We fitted a Poisson model with leprosy as outcome and distance to the nearest pre-intervention case and SDR-PEP as predictors. RESULTS: During the survey we found 114 new cases among 5760 contacts screened (2.0% prevalence), in addition to the 39 cases detected in the two preceding years. We found statistically significant associations of incident leprosy with physical distance to index cases ranging from 2.4 (95% confidence interval (95% CI) 1.5-3.6) for household contacts to 1.8 (95% CI 1.3-2.5) for those living at 1-25 m, compared to individuals living at ≥75 m. The effect of SDR-PEP appeared protective but did not reach statistical significance due to the low numbers, with an incidence rate ratio (IRR) of 0.6 (95% CI 0.3-1.2) overall, and 0.5 (95% CI 0.2-1.3) when considering only household contacts. CONCLUSIONS: This pilot demonstrated an increased risk of leprosy in contacts beyond the household, therefore a wider circle should be considered for chemoprophylaxis. Baseline surveys and extended contact definitions are essential for improving SDR-PEP effectiveness.

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).

Population-wide administration of single dose rifampicin for leprosy prevention in isolated communities: a three year follow-up feasibility study in Indonesia.

BACKGROUND: Indonesia ranking third in the world, regarding leprosy burden. Chemoprophylaxis is effective in reducing risk of developing leprosy among contacts. 'Blanket approach' is an operational strategy for leprosy post-exposure prophylaxis in which all members of an isolated community, high endemic for leprosy are screened and given a single dose of rifampicin (SDR) in the absence of signs and symptoms of leprosy. The objective is to assess the operational feasibility of a population-wide 'blanket' administration of SDR for leprosy prevention in isolated communities in a remote island. METHODS: A prospective follow-up study was conducted in the year 2014, 2015 and 2016 in Lingat village of Selaru Island, Indonesia. During the first two visits, screening and SDR were provided, whereas only screening was conducted during the third visit. The demographic and clinical data were used for a descriptive analysis of the project coverage and leprosy epidemiology. RESULTS: During the first two visits, 1671 persons (88%) were screened, 1499 (79%) received SDR, and 213 (11%) were excluded based on the exclusion criteria. During the first two visits, 43 (2.6%) cases were diagnosed with leprosy with a rate of 2263 per 100,000 population. The prevalence was highest in the age groups 15-24 and 25-49 years. Total, 14 (33%) cases had MB and 29 (67%) PB leprosy. Two cases (5%) had grade 2 disability. During the third visit, 10 new leprosy cases, with no grade 2 disability, were detected out of 1481 screened persons at the rate of 484 cases per 100,000 population (n = 2065 population in 2016). Among those screened during the third visit, there was a 50% reduction of leprosy among those who had previously received SDR compared to those who had not. CONCLUSION: With adequate planning and some additional investment, it is feasible to implement a blanket approach of chemoprophylaxis in a remote island of Indonesia, although effort needs to be made to cover as many people as possible in the first visit. Contingency plans need to be made to actively follow this village closely in the coming years and continue leprosy elimination efforts until no new cases are found any more.

Current Situation of Leprosy in India and its Future Implications.

The global leprosy situation has changed significantly over the last four decades after the introduction of multidrug therapy (MDT) in 1982 with a reduction in prevalence from over 5 million cases in the mid-1980s to less than 200,000 at the end of 2016. The programme in India also saw a reduction from a prevalence rate of 57.8/10,000 in 1983 to less than 1/10,000 by the end of 2005 when India declared to have reached the World Health Organization (WHO) target of elimination as a public health problem. Post 2005, major changes in the programme were made by the National leprosy eradication programme (NLEP) and the global leprosy programme, which may have affected the new case detection (NCD), disability, and child leprosy trends, which continue to show no appreciable regression. This article reviews the current global and Indian leprosy scenario to bring out its achievements and successes, including the impact of Leprosy Case Detection Campaigns (LCDC) on leprosy numbers. The basis and expected benefits of recent introduction of chemo and immune-prophylaxis in the programme are also discussed. It also discusses the shortcomings, the areas of concern, and the need for an inclusive strategy in the Indian leprosy programme that includes an intersectoral collaboration within the country for reaching the desired goal of leprosy eradication.