ABSTRACT
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.
Subject(s)
Dapsone/adverse effects , Drug Hypersensitivity Syndrome/prevention & control , HLA-B13 Antigen/genetics , Leprostatic Agents/adverse effects , Leprosy/drug therapy , Adult , Alleles , China , Clofazimine/administration & dosage , Cohort Studies , Dapsone/administration & dosage , Drug Hypersensitivity Syndrome/epidemiology , Drug Hypersensitivity Syndrome/etiology , Drug Therapy, Combination , Female , Humans , Incidence , Leprostatic Agents/administration & dosage , Male , Middle Aged , Prospective Studies , Rifampin/administration & dosageABSTRACT
BACKGROUND: A significant association between single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes and leprosy has been reported in a previous genome-wide association study of leprosy in the Chinese Han population. However, it remains unknown whether this association exists among the Chinese Yi population. The aim of this study was to investigate whether single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes are associated with leprosy among the Chinese Yi population in China. METHODS: We genotyped rs9302752, rs7194886, rs8057341, and rs3135499 in the NOD2 gene; rs3764147 and rs10507522 in the C13orf31 gene; and rs3088362 and rs9533634 in the CCDC122 gene in a Chinese Yi cohort comprised of 319 patients with leprosy and 355 ethnic-matched controls. The differences between the patients and healthy controls were analyzed using chi-squared analysis. RESULTS: Significant differences of rs3135499 in NOD2, rs3764147 and rs10507522 in C13orf31, and rs3088362 and rs9533634 in CCDC122 were observed between the patients and the healthy control groups in the cohort. The allelic P values and odd ratios were as follows: rs3135499, 1.0 × 10(-8) and 2.55; rs3764147, 1.7 × 10(-7) and 1.88; rs10507522, 1.16 × 10(-5) and 1.95; rs3088362, 8.2 × 10(-4) and 1.51; rs9533634, 5.34 × 10(-5) and 1.73. No significant differences were found in the distributions of rs9302752, rs7194886, and rs8057341 between the patients and healthy controls. CONCLUSIONS: We demonstrated that genetic variants in the NOD2, C13orf31, and CCDC122 genes are closely associated with leprosy among the Chinese Yi population, which implicates the pathogenic role of NOD2, C13orf31, and CCDC122 genes in a different ethnicity.