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

Épidémiologie de la lèpre en Nouvelle-Calédonie de 1983 à 2017

International audienceNew-Caledonia (NC) is a French community of the Asia-Pacific region where leprosy is still present. The epidemiological study of reported cases from 1983 to 2017 accounts for 342 cases. Since 1988 the overall annual prevalence is less than 1/10,000 inhabitants, the endemicity threshold set by the World Health Organization. Nevertheless, the study reveals an area of overendemia on the island of Bélep (location of the first leprosarium) where the 2007-2017 annual mean detection rate is 126.5/100,000 inhabitants. Over the last 10 years the predomi nance of multibacillary forms and the discovery of new cases of pediatrics leprosy show the persistence of a transmission in NC. Following this study, public health measures and in-depth studies were implemented.La Nouvelle-Calédonie (NC) est une collectivité française de la région Asie-Pacifique où la lèpre est toujours présente. La surveillance épidémiologique des cas notifiés de 1983 à 2017 comptabilise 342 cas. Depuis 1988, la prévalence globale annuelle est inférieure à 1/10 000 habitants, seuil d'endémicité fixé par l'Organisation mondiale de la Santé. Néanmoins, l'étude révèle une zone de surendémie sur l'île de Bélep (lieu d'implantation de la première léproserie) où le taux de détection moyen annuel 2007-2017 est de 126,5/100 000 habitants. Sur les 10 dernières années, la prédominance de formes multibacillaires et la découverte de nouveaux cas de lèpre pédiatriques démontrent la persistance d'une transmission en NC. Suite à cette étude, des mesures de santé publique et des études approfondies ont été mises en place

Épidémiologie de la lèpre en Nouvelle-Calédonie de 1983 à 2017

International audienceNew-Caledonia (NC) is a French community of the Asia-Pacific region where leprosy is still present. The epidemiological study of reported cases from 1983 to 2017 accounts for 342 cases. Since 1988 the overall annual prevalence is less than 1/10,000 inhabitants, the endemicity threshold set by the World Health Organization. Nevertheless, the study reveals an area of overendemia on the island of Bélep (location of the first leprosarium) where the 2007-2017 annual mean detection rate is 126.5/100,000 inhabitants. Over the last 10 years the predomi nance of multibacillary forms and the discovery of new cases of pediatrics leprosy show the persistence of a transmission in NC. Following this study, public health measures and in-depth studies were implemented.La Nouvelle-Calédonie (NC) est une collectivité française de la région Asie-Pacifique où la lèpre est toujours présente. La surveillance épidémiologique des cas notifiés de 1983 à 2017 comptabilise 342 cas. Depuis 1988, la prévalence globale annuelle est inférieure à 1/10 000 habitants, seuil d'endémicité fixé par l'Organisation mondiale de la Santé. Néanmoins, l'étude révèle une zone de surendémie sur l'île de Bélep (lieu d'implantation de la première léproserie) où le taux de détection moyen annuel 2007-2017 est de 126,5/100 000 habitants. Sur les 10 dernières années, la prédominance de formes multibacillaires et la découverte de nouveaux cas de lèpre pédiatriques démontrent la persistance d'une transmission en NC. Suite à cette étude, des mesures de santé publique et des études approfondies ont été mises en place

Functional Assessment of a New PBX1 Variant in a 46,XY Fetus with Severe Syndromic Difference of Sexual Development through CRISPR-Cas9 Gene Editing

International audienceSexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism

Exploring clustering of leprosy in the Comoros and Madagascar: A geospatial analysis

Objectives: To identify patterns of spatial clustering of leprosy. Design: We performed a baseline survey for a trial on post-exposure prophylaxis for leprosy in Comoros and Madagascar. We screened 64 villages, door-to-door, and recorded results of screening, demographic data and geographic coordinates. To identify clusters, we fitted a purely spatial Poisson model using Kulldorff’s spatial scan statistic. We used a regular Poisson model to assess the risk of contracting leprosy at the individual level as a function of distance to the nearest known leprosy patient. Results: We identified 455 leprosy patients; 200 (44.0%) belonged to 2735 households included in a cluster. Thirty-eight percent of leprosy patients versus 10% of the total population live ≤25 m from another leprosy patient. Risk ratios for being diagnosed with leprosy were 7.3, 2.4, 1.8, 1.4 and 1.7, for those at the same household, at 1–<25 m, 25–<50 m, 50–<75 m and 75–<100 m as/from a leprosy patient, respectively, compared to those living at ≥100 m. Conclusions: We documented significant clustering of leprosy beyond household level, although 56% of cases were not part of a cluster. Control measures need to be extended beyond the household, and social networks should be further explored

Population Genomics of Mycobacterium leprae Reveals a New Genotype in Madagascar and the Comoros

Human settlement of Madagascar traces back to the beginning of the first millennium with the arrival of Austronesians from Southeast Asia, followed by migrations from Africa and the Middle East. Remains of these different cultural, genetic, and linguistic legacies are still present in Madagascar and other islands of the Indian Ocean. The close relationship between human migration and the introduction and spread of infectious diseases, a well-documented phenomenon, is particularly evident for the causative agent of leprosy, Mycobacterium leprae. In this study, we used whole-genome sequencing (WGS) and molecular dating to characterize the genetic background and retrace the origin of the M. leprae strains circulating in Madagascar (n = 30) and the Comoros (n = 3), two islands where leprosy is still considered a public health problem and monitored as part of a drug resistance surveillance program. Most M. leprae strains (97%) from Madagascar and Comoros belonged to a new genotype as part of branch 1, closely related to single nucleotide polymorphism (SNP) type 1D, named 1D-Malagasy. Other strains belonged to the genotype 1A (3%). We sequenced 39 strains from nine other countries, which, together with previously published genomes, amounted to 242 genomes that were used for molecular dating. Specific SNP markers for the new 1D-Malagasy genotype were used to screen samples from 11 countries and revealed this genotype to be restricted to Madagascar, with the sole exception being a strain from Malawi. The overall analysis thus ruled out a possible introduction of leprosy by the Austronesian settlers and suggests a later origin from East Africa, the Middle East, or South Asia