Validation Study of HLA-B*13:01 as a Biomarker of Dapsone Hypersensitivity Syndrome in Leprosy Patients in Indonesia

Importance: Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy (MDT) which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, leprosy is still a problem. Furthermore, there had been reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. HLA-B*13:01 has been found to be associated with DHS and prospective screening has proven its ability to prevent DHS in the Chinese population, but has not been validated in Indonesians. Objective: To validate HLA-B*13:01 as a biomarker for DHS in the Indonesian population. Design: This is a case-control study. Setting: Population-based, multi-district recruitment from primary care centers in two of the top 3 most prevalent provinces in Indonesia, Papua and West Papua. Participants: Leprosy patients who presented themselves with DHS were recruited as case subjects (34 cases) and leprosy patients without DHS were recruited as control subjects (52 controls). Exposure: Leprosy patients who had undergone multi-drug treatment for leprosy under the standard WHO guideline, consisting of rifampicin, dapsone and clofazamine. Main Outcome and Measures: The association of HLA-B*13:01 to DHS based on difference in allele frequencies between cases and controls. HLA-B alleles were typed using the gold-standard Sequence Based Typing method. Results were analyzed using logistic regression and risk assessment was carried out. Results: The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio=247.6 and P-value=4.81E-9, confirming the strong association of HLA-B*13:01 to DHS in the Indonesian population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. Conclusions and Relevance: HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future. Keywords: HLA-B*13:01, dapsone hypersensitivity syndrome, leprosy, dapsone, adverse drug reaction, Papua, Indonesia