Global Frequencies of Clinically ImportantHLAAlleles and Their Implications For the Cost-Effectiveness of Preemptive Pharmacogenetic Testing

Abstract

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01,HLA-B*15:02,HLA-A*31:01, andHLA-B*58:01constitute established risk factors and preemptive genotyping of theseHLAalleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptiveHLAtesting has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidatedHLAgenotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing ofHLA-B*57:01in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping ofHLA-B*15:02is only cost-effective across most of East and South Asia, whereasHLA-A*31:01testing is likely to be cost-effective globally. Testing ofHLA-B*58:01is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.