Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

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.

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.

Leprosy and tuberculosis control scenario of the national program for the improvement of access and quality of primary care in Brazil.

BACKGROUND: In Brazil, despite advances in public health policies aimed at eliminating and controlling infectious and parasitic diseases, the incidence of neglected diseases is still high. The epidemiological scenario in Brazil of diseases such as tuberculosis and leprosy evidences a public policy agenda that has not been resolute in terms of control, nor in terms of elimination. OBJECTIVE: To analyze the actions of diagnosis and treatment of leprosy and tuberculosis in the context of primary health care. METHODS: In this ecological study, data from the third cycle of the Program for the Improvement of Access and Quality of Primary Care were extracted from electronic address of the Primary Health Care Secretariat of Brazil in the area of Actions, Programs and Strategies. A total of 37,350 primary health care teams were that answered the questionnaire were eligible, with variables extracted from leprosy and tuberculosis control actions. The municipalities were grouped according to the characteristic of the Brazilian municipality. The partition chi-square and the Residuals Test were used to assess whether there was a difference in the proportion of tuberculosis and leprosy actions between types of municipalities. Statistics were carried out using Minitab 20 and Bioestat 5.3. RESULTS: Regarding the leprosy treatment location, there is a higher proportion of people referred to be treated at the reference in adjacent rural (p = 0.0097) and urban (p < 0.0001) municipalities; monitoring of people with leprosy referred to the service network (p. = 0.0057) in remote rural areas. Lower proportion of teams requesting bacilloscopy in remote rural areas (p = 0.0019). Rural areas have a higher proportion of teams that diagnose new cases (p = 0.0004). Regarding the actions of diagnosis and treatment of tuberculosis. There is a higher proportion of teams that carry out consultations at the unit itself in rural areas when compared to adjacent intermediaries (p = 0.0099) and urban (p < 0.0001); who requested sputum smear microscopy in adjacent intermediaries (p = 0.0021); X-ray in adjacent intermediaries (p < 0.0001) and urban (p < 0.0001); collection of the first sputum sample in urban (p < 0.0001) and adjacent rural areas (p < 0.0001); directly observed treatment (p < 0.0001) in adjacent rural municipalities. CONCLUSION: There are inequalities in the diagnosis and treatment of leprosy and tuberculosis among the types of municipalities.

Clinico-Epidemiological profile of new leprosy cases detected in leprosy case detection campaign in North Maharashtra during 2018-2020.

Leprosy is a leading cause of disability in India. The percentage of disability and deformity can be reduced by diagnosing leprosy at an early stage. In order to detect the hidden leprosy cases, leprosy case detection campaigns, on line with Pulse Polio Campaign have been introduced specifically for high endemic districts, by the Central Leprosy Division. Records of cases from 2018 to 2020 were evaluated retrospectively to study the trend of new cases. The present study denotes the presence of hidden undiagnosed cases in the community and will require an intensification of leprosy control activities through contact tracing and active case detection. Continued quality surveillance is required for early detection, timely management, and prevention of the spread of the disease.

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.

Correlates of GLA family adjuvants' activities.

Lipopolysaccharide (LPS) is a well-defined agonist of Toll-like receptor (TLR) 4 that activates innate immune responses and influences the development of the adaptive response during infection with Gram-negative bacteria. Many years ago, Dr. Edgar Ribi separated the adjuvant activity of LPS from its toxic effects, an effort that led to the development of monophosphoryl lipid A (MPL). MPL, derived from Salmonella minnesota R595, has progressed through clinical development and is now used in various product-enabling formulations to support the generation of antigen-specific responses in several commercial and preclinical vaccines. We have generated several synthetic lipid A molecules, foremost glucopyranosyl lipid adjuvant (GLA) and second-generation lipid adjuvant (SLA), and have advanced these to clinical trial for various indications. In this review we summarize the potential and current positioning of TLR4-based adjuvant formulations in approved and emerging vaccines.

Cost-effectiveness of incorporating Mycobacterium indicus pranii vaccine to multidrug therapy in newly diagnosed leprosy cases for better treatment outcomes & immunoprophylaxis in contacts as leprosy control measures for National Leprosy Eradication Programme in India.

Background & objectives: The elimination goal for leprosy as a public health problem at the national level was achieved in 2005 in India. However, the number of new cases reporting annually remained nearly the same during the last 10-15 years. Moreover, a substantial number of these new cases reported disabilities for the first time. Therefore, besides multidrug therapy (MDT), newer strategies with focus on effectively decreasing the number of new cases, optimizing the treatment of detected cases, averting disabilities and arresting the transmission of the disease are required. So the objective of this study was to assess the cost-effectiveness of Mycobacterium indicus pranii (MIP) vaccine implementation in National Leprosy Eradication Programme (NLEP) for newly diagnosed leprosy patients as well as their contacts to arrest/decrease the transmission and occurrence of new cases. Methods: This was a model-based estimation of incremental costs, total quality-adjusted life years (QALYs) gained, new cases averted, deaths averted, incremental cost-effectiveness ratio (ICER) and budget impact of the vaccination intervention. This model included the addition of MIP treatment intervention to the newly detected leprosy patients as well as vaccination with MIP to their contacts. Results: Using the societal perspective, discounted ICER was estimated to be ₹73,790 per QALY gained over a five-year time period. Probabilistic sensitivity analysis (PSA) was assessed by varying the values of input parameters. Majority (96%) of simulations fell in North East quadrant of cost-effectiveness plane, which were all below the willingness to pay threshold. Interpretation & conclusions: Introduction of MIP vaccination in the NLEP appears to be a cost-effective strategy for India. Significant health gains were reduction in the number of new leprosy cases, decreased incidence and severity of reactions during treatment, and after release from treatment, prevention of disabilities, thus reducing the cost as well as stigma of the disease.

Surveillance of Leprosy in Kiribati, 1935-2017.

In Kiribati, unlike most countries, high and increasing numbers of cases of leprosy have been reported despite the availability of multidrug therapy and efforts to improve case finding and management. Historic records show that 28 cases had been identified by 1925. A systematic population survey in 1997 identified 135 new cases; the mean incidence rate for 1993-1997 was 7.4/10,000 population. After administering mass chemoprophylaxis, the country reached the elimination threshold (prevalence <1/10,000), but case numbers have rebounded. The mean annualized rate of new cases in 2013-2017 was 15/10,000 population, with the highest new case rates (>20/10,000 population) in the main population centers of South Tarawa and Betio. Spread is expected to continue in areas where crowding and poor socioeconomic conditions persist and may accelerate as sea levels rise from climate change. New initiatives to improve social conditions are needed, and efforts such as postexposure chemoprophylaxis should be implemented to prevent spread.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

Trends of the leprosy control indicators in Benin from 2006 to 2018.

BACKGROUND: Leprosy, or Hansen's disease, is a chronic infectious disease caused by Mycobacterium leprae. The purpose of this study was to describe the epidemiological characteristics of leprosy in Benin from 2006 to 2018. METHODS: This descriptive retrospective study included data from January 2006 to December 2018. The data of all patients treated in the leprosy treatment centres (LTCs) of the Republic of Benin were obtained from the LTC registers and analysed using Stata/SE 11.0 software. Quantum GIS (Geographic Information System) version 2.18.23 software was used for mapping. The main indicators of leprosy were calculated according to the World Health Organization (WHO) recommendations. RESULTS: During the study period, a total of 2785 (annual average of 214) new cases of leprosy were diagnosed. The median age of the patients was 38 years, with extremes ranging from 6 to 88 years. The sex ratio (males/females) was 1.18 (1509/1276). The departments of Plateau, Atacora, and Zou were the most endemic; their leprosy detection rate per 100,000 population during these thirteen years were 6.46 (479/7414297), 5.38 (534/9932880) and 5.19 (526/10134877), respectively. The leprosy detection rate declined from 3.8 to 1.32 per 100,000 inhabitants. The proportion of paediatric cases varied from 8.56 to 2.67% as the proportion of multibacillary forms increased from 72.95 to 90%. From 2006 to 2018, 622 leprosy patients detected had grade 2 disability (G2D) at screening, indicating an average rate of 5.06 (622/122877474) cases with G2D per million population. The proportion of grade 2 disabilities increased from 21.23 to 32% during the study period. The majority of new leprosy cases among foreign-born persons were Nigerian (85.71%). The completion of multidrug therapy (MDT) for paucibacillary (PB) and multibacillary (MB) leprosy cases ranged from 96.36 to 95.65% and from 90.53 to 94.12%, respectively. CONCLUSION: In Benin, leprosy remains a major health challenge; it is important to revitalize the epidemiological surveillance system to achieve its elimination by 2030.

Setting targets for HIV/AIDS-What lessons can be learned from other disease control programmes?

In a Collection Review, Richard Hayes and colleagues discuss metrics for assessing progress in control of the HIV/AIDS epidemic in the context of prior disease control programmes.

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.

Policy Lessons From Quantitative Modeling of Leprosy.

Recent mathematical and statistical modeling of leprosy incidence data provides estimates of the current undiagnosed population and projections of diagnosed cases, as well as ongoing transmission. Furthermore, modeling studies have been used to evaluate the effectiveness of proposed intervention strategies, such as postleprosy exposure prophylaxis and novel diagnostics, relative to current approaches. Such modeling studies have revealed both a slow decline of new cases and a substantial pool of undiagnosed infections. These findings highlight the need for active case detection, particularly targeting leprosy foci, as well as for continued research into innovative accurate, rapid, and cost-effective diagnostics. As leprosy incidence continues to decline, targeted active case detection primarily in foci and connected areas will likely become increasingly important.

Factors associated with the delay of diagnosis of leprosy in north-eastern Colombia: a quantitative analysis.

OBJECTIVES: To determine the average time in months between the beginning of symptoms and the diagnostic confirmation of leprosy by the health system and to investigate factors associated with diagnostic delay. METHODS: A total of 249 patients older than 15 years diagnosed with leprosy between 2011 and 2015, in 20 endemic municipalities of north-eastern Colombia, provided informed consent and were interviewed face-to-face. Clinical histories from health centres or hospitals where study participants were treated for leprosy were also reviewed. RESULTS: The mean delay in diagnosis of leprosy was 33.5 months. About 14.9% of patients showed a visible deformity or damage (disability grade 2, DG2) at the time of diagnosis. In multivariable regression analysis, five or more consultancies required to confirm the diagnosis and not seeking care immediately after noticing first symptoms were associated with longer diagnostic delay. CONCLUSIONS: Our study found a significant delay in diagnosis of leprosy in north-eastern Colombia, which might explain the continuously high rate of DG2 among new cases being notified in the country. Both patient- and health system-related factors were associated with longer diagnostic delay. Interventions to increase awareness of disease among the general population and timely referral to a specialised health professional are urgently needed in our study setting.