HLA-B*13:01 screening shows strong association with Dapsone Hypersensitivity Syndrome in leprosy patientsGenetic testing may help identify patients at risk for leprosy side effects

BACKGROUND: Dapsone Hypersensitivity Syndrome (DHS) is a serious debilitating condition which can develop after 2-8 weeks of dapsone treatment in varying proportions between genetically diverse populations. Approximately 10% of the affected individuals die, and DHS patients often spend weeks to months in the hospital, which impacts health and psychological morbidity and household financial burden. In recent years, a human leukocyte antigen, HLA-B*13:01, has been consistently associated with up to 85% of DHS cases across international population studies; however, the necessity of next generation sequencing (NGS) severely limits clinical applications in low resource contexts. METHODOLOGY/PRINCIPAL FINDING: To investigate HLA-B*13:01 associations with DHS among Nepalese leprosy cases, retrospective and active DHS cases and dapsone-tolerant controls treated at least for 3 months with multi-drug therapy (MDT) were sampled and screened by HLA-B*13:01 qPCR. In the present study we enrolled 34 DHS cases and 82 dapsone tolerant controls and found that the association is maintained in a multi-ethnic Nepali population with an Odds Ratio of 50.1 (95% CI: 15.0-166.6). A previously validated qPCR-based commercial kit was used in the study, and we revalidated the methodology (23 negative and 35 positives by commercial qPCR) using Next Generation sequencing (NGS) method and found a concordance rate of 98.3%. We meta-analyzed all eligible HLA-B*13:01 and DHS association studies and found a summary Odds Ratio of 61.86 (95% CI 32.60 - 117.4). As 23.5% of the DHS cases were HLA-B*13:01 negative in our study, further analyses of the HLA-B*13:01 positive and negative study participants revealed that HLA-B*13:01 positive DHS cases were significantly younger than HLA-B*13:01 negative DHS cases (35.5 years vs. 66 years, p = 0.0018). The positive predictive value of the HLA test in the Nepalese population was ~ 24. CONCLUSION: The study validates the association between HLA-B*13:01 and DHS in Nepalese leprosy population. Inclusion of a genetic screening test before starting MDT could potentially prevent significant proportion of DHS occurring in leprosy cases, especially in South Asian and Southeast countries.