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.).

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

Genome-Wide Analysis of Protein-Coding Variants in Leprosy.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

Clinical features of relapse after multidrug therapy for leprosy in China.

BACKGROUND: Although the World Health Organization (WHO) has defined relapse in leprosy, it is often difficult to confirm a relapse, especially in paucibacillary (PB) patients. OBJECTIVE: To study features of relapse cases in order to determine the information needed to allow better management of relapses in the leprosy control programme. DESIGN: A retrospective survey by questionnaire was carried out at national level at the end of 2012. RESULTS: There were 40 relapsed patients on register. The clinical form of leprosy was TT5, BT4, BB5, BL13 and LL13. Twenty-eight patients had had a positive skin smear test at the start of MDT, with a BI ranging from 0.83 to 6.0. At the time of completing MDT, the skin smear test remained positive in seven patients. After completion of MDT, other family members of 13 patients were identified as new leprosy patients. All relapse cases showed one or more active skin lesions. There were 33 patients with a positive skin smear test at the time of relapse. A total of 23 patients had a biopsy at the time of relapse, including seven patients with a negative skin smear test. The histological features of relapsed BB-LL patients included granulomas containing macrophages or epithelioid cells with sparse lymphocytes and acid-fast bacilli. The histological features of seven patients with negative skin smears showed epithelioid cell granulomas with dense lymphocytes surrounding the granuloma, but without distinct edema in the dermis. The average interval from completion of MDT to the diagnosis of relapse was 168.5 ± 92.6 months with a range of 21-322 months. During the study, nine patients were tested for rifampicin resistance, but none showed any mutation. CONCLUSIONS: Leprosy relapse after MDT usually occurred late and all relapse cases had new active skin lesions. Most patients relapsed with a positive skin smear after previously reaching negative BI status. Relapse with a negative skin smear test should be confirmed very cautiously.

Survey on child leprosy patients and problems resulted from the disease in China.

OBJECTIVES: To understand the situation of child leprosy patients in the low prevalence situation pertaining in China. METHOD: A retrospective survey by questionnaire was carried out in all 32 provinces of mainland of China in 2011. All data concerning child cases detected from January 2005 to December 2009 were collected by professional health workers working at county level. RESULTS: During the study, only 165 questionnaires were collected for analysis. Among 165 child cases, 96 were boys, 69 were girls with an average age of 11-7 years old. 80% of child cases were members of families with other leprosy affected people. 145 (85%) child cases took their MDT secretly (nobody outside the family knew the child suffered from leprosy), and three (1.8%) children died, one each from dapsone syndrome, suicide and severe pneumonia. During follow-up, four child cases developed new disability increasing the Grade 2 disability rate to 13.3% (22/165). At end of the study, 8.2% of children had discontinued their study at school, and 7.5% had moved to a remote place to do casual work, while 6.3% stayed at home. 31% of child patients thought that leprosy caused a negative impact on their daily life. Two children had a hostile attitude toward society due to the stigma caused by leprosy. CONCLUSIONS: In both high and low endemic areas, as long as there is an infectious source of leprosy in the family, there is a possibility for children to develop leprosy. Contact surveys should be done to detect early disease, especially when there are children in the household.

Six years' follow-up of multibacillary leprosy patients treated with uniform multi-drug therapy in China.

OBJECTIVE: This study was conducted to evaluate the effectiveness of uniform multi-drug therapy (UMDT) in patients with multibacillary (MB) leprosy. METHODS: Newly detected MB leprosy patients were treated with six months of UMDT as recommended by the World Health Organization (WHO). The effectiveness of treatment was evaluated by clinical status and skin smear tests. RESULTS: At the start, 114 patients were recruited, examined, and treated. These patients were re-examined and followed annually for up to six years. A total of 75 (65.8%) patients completed six years of follow-up. Dropouts were attributable to death, severe drug reactions, and other reasons. The mean ± standard deviation bacteriological index (BI) of all patients decreased from 3.01 ± 1.50 before treatment to 0.02 ± 1.84 at the end of year 6, reflecting a mean annual decrease of 0.50. The rate of smear negativity in all patients was 98.7% at the end of year 6 of follow-up. A total of 53 leprosy reactions were observed. One patient relapsed 13 months after the cessation of treatment. CONCLUSIONS: A 6-month administration of UMDT is effective in MB leprosy patients. The changes in BI values and the frequency of leprosy reactions were similar to those cited in reports in the literature of patients treated with 1- or 2-year regimens of MDT. However, further research should be conducted to confirm the present results.

Rifampicin-resistant Mycobacterium leprae in an elderly leprosy patient in the people's Republic of China.

The reported number of registered leprosy patients worldwide declined with the introduction of multidrug therapy. However, the emergence of rifampicin resistance in leprosy patients engenders difficulties for an individual patient, and its dissemination could pose a threat to leprosy control. This study reports an elderly patient who was diagnosed with rifampicin-resistant lepromatous leprosy. This case indicates that inadequate treatment and poor compliance may eventually result in rifampicin resistance in Mycobacterium leprae and clinical relapse.

Bacteriological results and leprosy reactions among MB leprosy patients treated with uniform multidrug therapy in China.

OBJECTIVES: To investigate the changes of bacteriological index and leprosy reactions among Multi-bacillary (MB) patients treated with uniform multi-drug therapy (UMDT). METHODS: Newly diagnosed leprosy patients were recruited after taking informed consent in three districts in Guizhou Province and one district in Yunnan Province China during November 2003 to June 2005 and were treated with Uniform Multidrug Therapy. All patients were followed up once a year for 3 years after completion of treatment. All data on bacteriological index (BI) and the frequencies of leprosy reaction were collected and analysed. RESULTS: A total of 166 patients were recruited for UMDT trial. Among them 114 patients had positive BI smear, and 83 patients had been followed up for 42 months. The mean BI of 83 patients decreased from 2.84 before treatment to 0.33 at the end of 42 months follow-up. At the end of this period, 61 patients (73.5%) had become BI negative. There were 13 (14.6%) patients who had a Type I reaction during 24 months of follow-up. One patient in the study group relapsed 13 months after stopping treatment of the UMDT. CONCLUSION: There was a significant decrease in the mean BI and 73.5% of patients treated with UMDT became BI negative during 3 years' follow-up. The frequency of Type I reaction seemed a little higher among patients treated with UMDT, but the numbers of patients enrolled were too few to determine statistical significance. Future studies on U-MDT should also study Type I reactions in these patients.

Dapsone hypersensitivity syndrome among leprosy patients in China.

OBJECTIVE: To Study the incidence and clinical characteristics of dapsone hypersensitivity syndrome (DHS) among MDT-treated leprosy patients from 2006 to 2009 in China. METHODS: A retrospective survey was carried out throughout China using a specially designed questionnaire. RESULTS: From 2006 to 2009, there were 63 new patients reported to have DHS with an incidence of 1.0%. Among these patients, 13 were complete types of DHS, the others were incomplete ones. The average age of patients with DHS was 38 years and the male to female ratio was 2.15. The average incubation period from taking dapsone to DHS onset was 32.8 days (2-6 weeks). There were 60 (95.2%) patients who presented with various skin lesions, 56 (88.9%) with fever, 40 (63.5%) with hepatic damage and 22 (34.9%) with lymphopathy. Seven patients died with a death rate of 11.1% among all patients with DHS. CONCLUSIONS: DHS is a serious adverse event resulted from dapsone. It can occur in a small number of new leprosy patients treated with dapsone containing regimen. Some patients may die of DHS if not taking timely and adequate management. Therefore local doctors should pay an attention to DHS among leprosy patients newly treated with the dapsone-containing MDT regimen.

[Historical comparisons on related features among newly registered leprosy patients in the endemic areas of Wenshan district, Yunnan province].

OBJECTIVE: To analyze the current situation and prevalence of leprosy in Wenshan district, Yunnan province. METHODS: To collect various data on leprosy reported by the health workers at the county level. RESULTS: The number of newly registered patients did not decrease significantly in 1989, 1999 and 2009, respectively. The mean age of patients at detection was 33 - 35 years old. Time of delay between the disease onset and being diagnosed was shortened from 35.2 months in 1989 to 15.9 months in 2009. However, the proportion of patients with more than 12 months of delay still accounted for nearly 50%. The proportion of Grade II disability fluctuated between 15.2% - 17.7% and the proportion of child cases increased from 8.1% in 1989 to 13.1% in 2009. Clinics for skin diseases were the main locations for case detection. The proportion of new cases detected through 'active case finding' program accounted for 44.3% in 1999 and 42.6% in 2009, both higher than 17.7% in 1989. CONCLUSION: The situation of leprosy in Wenshan district, Yunnan province, was still serious and the reason for the occurrence of new cases was related to the fact that the infectious source of leprosy had not been under full control.

Causes of death among active leprosy patients in China.

We analyzed the causes of death among active leprosy patients in China, to better understand the disease and improve the quality of services, by performing a retrospective study involving 24 provinces of China. Information about patients with active leprosy who were not clinically cured and died between January 1, 2000, and December 31, 2005, was collected by professionals at county levels. A total of 524 deaths were analyzed. The leading cause of death was suicide. There were 86 patients (16%) who died at a mean of 21 ± 19 months after starting multi-drug therapy (MDT). The second and third leading causes of death were cardiovascular disease and organ failure associated with advanced age, respectively. Two hundred and twenty-one patients (42%) died within one year of beginning MDT. The second month of MDT was the riskiest for newly treated patients; approximately 20% of patients succumbed to liver failure, 33% to dapsone (diaminodiphenylsulfone/DDS) allergy, and 27% to renal insufficiency during this period. Among 143 deaths related to leprosy, 37 (26%) occurred within three months of starting MDT. We recommend that newly diagnosed patients should be provided with no more than two months of MDT blister packs.

[Epidemiological analysis on leprosy in China, 2009].

OBJECTIVE: To study the epidemiological characteristics of leprosy and to provide evidence for specific strategies development on leprosy control. METHODS: Descriptive analysis of data from the national leprosy surveillance system was carried out in 2009. RESULTS: A total number of 1597 new cases were detected in 2009 with a case detection rate of 0.120 per 100 000 population. The proportions of children under 15, multibacillary and disability grade 2 were 2.4%, 84.3% and 22.8% respectively. A total number of 148 relapse cases were reported in 2009, among which 69 cases were those relapsed after multi-drug therapy. The existing cases were 6603 by the end of 2009 with a prevalence rate of 0.049 per 10 000 populations, among which 3332 cases were on multi-drug therapy. CONCLUSION: The overall leprosy situation is considered to be at low endemic in China but the distribution is unequal, with pocket areas in Yunnan, Sichuan and Guizhou. In order to reach the target on leprosy elimination, which was considered as a public health and social problem, the input and efforts are needed for many years to come.

A big challenge in case finding at low endemic situation: analysis on 1462 new leprosy patients detected in China in 2007.

OBJECTIVE: To understand the characteristics of newly detected leprosy patients at low endemic situation in China in order to provide information for better leprosy control. METHODS: A study was carried out using a designed questionnaire in a retrospective method in China in 2007. RESULTS: Among 1462 new patients studied, the average age at diagnosis was 41.5 +/- 15.8 years. Nearly half of new patients were detected by a passive method at the skin clinic. This might relate to a long delay between disease onset and diagnosis (3.23 +/- 45 years) as well as a high rate of disability Grade 2 among new patients (22.6%). There were 363 (24.8%) patients who came from non-leprosy endemic areas, 844 (57.7%) patients who came from non-leprosy families and 409 (28.0%) patients who came from villages where leprosy outbreaks had never occurred before. CONCLUSION: Case finding within low endemic areas of China is a big challenge in leprosy control. Maintaining sustainable leprosy control and strengthening leprosy training among dermatologists may be the important strategy in the future.

Occurrence and management of leprosy reaction in China in 2005.

BACKGROUND: Leprosy reactions are a major cause of disability before, during and after anti-bacterial treatment. Prompt diagnosis and correct management of reaction is a crucial matter for improving the quality of leprosy health services. OBJECTIVES: To describe the pattern of leprosy reaction and its management in China during 2005. METHODS: A retrospective survey using a questionnaire was carried out in all the provinces of China at the beginning of 2006. Patients included were those presenting with leprosy reaction between 1 January and 31 December 2005. RESULTS: 452 questionnaires from 25 provinces were analysed. There were 313 male and 139 female patients who had 159 Type I reactions, 273 Type II reactions and 20 Type I and II mixed reaction. 72.4% of reactions occurred in the first year of MDT and 27.6% of patients during the second year of MDT. The highest frequency of reaction was during the first 6 months of MDT; 57.3% of patients developed new nerve impairment during and after MDT. CONCLUSIONS: New nerve function impairment and disability still occurs among patients during and after MDT. The early detection and management of leprosy reaction remains important.

Analysis on value of household contact survey in case detection of leprosy at a low endemic situation in China.

BACKGROUND: Leprosy is at a low endemic situation in China, the value of house contact survey in case detection of leprosy becoming a dispute. AIMS: To evaluate the value of household contact survey in the case detection of leprosy at a low endemic situation in China. METHODS: A study was carried out using a designed questionnaire in a retrospective method to analyze the value of household contact survey in case detection in Southwest and East China. RESULTS: A total of 2135 index leprosy patients were collected from January 1, 1996 to December 31, 2005 in six provinces of China. The number of index patients accounted for 22.0 and 14.1% of newly registered patients in the Southwest and East of China, respectively. The household contact survey (36.1%) and the skin clinic (62.0%) ranked first in methods of case detection in Southwest and East China, respectively. Within 5 years after primary leprosy patients were detected, 24.8 and 16.1% of the index patients in Southwest China and East China had been detected, respectively. CONCLUSION: The authors conclude that at the time of a low leprosy endemic situation, the household contact survey is still a useful method for case detection in China.

[A long-term evolution on the epidemiological characteristics of leprosy, towards the goal of its elimination in 1949 - 2007 in China].

OBJECTIVE: To understand the epidemiological characteristics of leprosy during the evolution of the disease, towards the goal of elimination for the past 50 years and longer, so as to provide experiences for accelerating eradication of leprosy in China. METHODS: Data were collected from National Surveillance System of Leprosy which was composed annually of all the data from county-based leprosy unit reporting system. All the data were reviewed retrospectively. RESULTS: A total number of 487 900 leprosy patients were reported from 1949 to 2007 in China. The case detection rate reduced from the highest of 5.56/100 000 in 1958 to the lowest of 0.12/100 000 in 2007. Leprosy patients mainly distributed in mountain areas in Yunnan, Guizhou, Sichuan, Guangdong Guangxi, Hunan and Jiangxi provinces with warm and damp climate and underdeveloped economy. After more than 50 years of leprosy control efforts, the case detection rate declined quickly in provinces in the eastern and the southern parts but very slowly in provinces in the western and the southwestern part of China. The ratio of relapsed patients to newly detected ones increased from 1:139 in 1960s' to 1:10 after 1980s', annually. The proportion of child cases among newly detected patients had been 3% - 4% since 1968. In the recent 20 years, the proportion of new patients with positive skin smear gradually increased and the rate of disability grade two reached 20% and more. The average age of new patients upon diagnosis was 45 years old in the east coastal provinces but only 38 years old in the southwest provinces. A new finding was that some new patients detected in the east coastal provinces were immigrants from the southwestern provinces. CONCLUSION: With continuous socio-economic development and active efforts on leprosy control, the prevalence of leprosy gradually declined despite the long evolution period. Some negative events seemed to have influenced the trend of case detection.

Current situation of leprosy colonies/leprosaria and their future in P.R. China.

OBJECTIVE: To identify the current situation of leprosy colonies/leprosaria and make some recommendations for improving the quality of life of people affected by leprosy in China. METHODS: A national survey using designed forms was carried out in 2004. The forms were filled in by local heads responsible for the management of leprosy colonies/leprosaria and sent to Provincial and National Centres for analysis. RESULTS: China had 605 leprosy colonies/leprosaria with 555 active leprosy patients (on treatment) and 18,175 ex-patients (people affected by leprosy) living in them at the end of 2004. Among 18,730 patients and people affected by leprosy, 13,430 (71.7%) had grade 2 disabilities. Among those with visible disability, 6392 (47.6%) lost the ability to take care of themselves due to serious deformity. Because of a decrease in health workers working at leprosy colonies and a shortage of medical materials, the health care quality of these people was neglected. Most colonies/leprosaria were located at remote and isolateS places with difficult transportation, and most buildings/houses were in danger of collapse because the colonies/leprosaria were built in the 1950's. Those affected by leprosy were in great need of help. CONCLUSION: The authors recommend that small, remote and isolated leprosy colonies should be closed. New leprosaria at District, Provincial or National levels should be established or some old leprosaria with good transportation should be reconstructed to house those affected by leprosy from closed leprosy colonies/leprosaria. The newly established or reconstructed leprosaria could act as centres for reference, training, rehabilitation and research on leprosy.

Relapse in MB leprosy patients treated with 24 months of MDT in south west China: a short report.

This study investigates the relapse rate among multibacillary leprosy patients treated with 24 months of MDT in south west China. A retrospective relapse survey was conducted in the southwest of China. A detailed questionnaire was designed to collect the data on relapse among MB patients who completed 2 years of the WHO/MB regimen, from 1989 to 2000. The data about 2517 multibacillary leprosy patients in 27 counties in the southwest of China were collected. Among 2517 MB patients, 235 patients died or were lost to follow-up and 2374 were followed up for more than 3 years after completion of MDT. The total duration of follow-up was 20,825 person-years, with a mean duration of 8.27 years per patient. Five patients with relapse were identified with an accumulated relapse rate of 0.21/1000 person-years. Their initial BIs ranged from 1.8 to 5. The patients with relapse occurred 48-158 months after the completion of MDT. The relapse rate of MB patients treated with 24 months of the WHO/MB regimen was observed to be very low after long-term follow-up.