Immunopharmacogenomics: Mechanisms of HLA‐Associated Drug Reactions
Year: 2021
Type: article
Abstract: The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug-induced T-cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T-cell-mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA-associated drug reactions and the implications for future translation into clinical care.
DOI: 10.1002/cpt.2343
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Health and Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences
Awards: Improving Prediction of Drug Action, Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors, Genomic and Transcriptomic Influences on Heparin-Induced Thrombocytopenia, Single Cell definition of pathogenic T cells in Drug-induced Stevens-Johnson-Syndrome/Toxic epidermal necrolysis, Training in Environmental Toxicology of Human Disease, Immune-mediated adverse drug reactions to HIV and TB treatments in South Africa: predict, prevent and improve long-term outcomes (IMARI SA study), NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
OpenAlex ID: W3168727558