Diagnostic Test Criteria for HLA Genotyping to Prevent Drug Hypersensitivity Reactions: A Systematic Review of Actionable HLA Recommendations in CPIC and DPWG Guidelines

Abstract

Introduction: Certain HLA variants are associated with an increased risk of hypersensitivity reactions to specific drugs. Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have issued actionable HLA genedrug interaction guidelines but diagnostic test criteria remain largely unknown. We present an overview of the diagnostic test criteria of the actionable HLAdrug pairs. Methods: A systematic literature search was conducted in PubMed, Embase, Web of Science and Cochrane Library. Original case-control and cohort studies were selected and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and number needed to genotype (NNG) were calculated for the actionable HLA-drug pairs. Results: In general, the HLA tests show high specificity and NPV for predicting hypersensitivity reactions. The sensitivity of HLA tests shows a wide range, from 0-33% for HLA-B*1502 testing to predict lamotrigine induced SJS/TEN up to 100% for HLA-B*5701 to predict immunologically confirmed abacavir hypersensitivity syndrome (ABC-HSR). PPV is low for all tests except for HLA-B*5701 and ABC-HSR which is approximately 50%. HLA-B*5701 to predict ABC-HSR shows the lowest NNG followed by HLA-B*5801 for allopurinol induced severe cutaneous adverse drug reactions and HLA-B*1502 for carbamazepine induced SJS/TEN. Discussion: This is the first overview of diagnostic test criteria for actionable HLA-drug pairs. Studies researching HLA genes and hypersensitivity are scarce for some of the HLA-drug pairs in some populations and patient numbers in studies are small. Therefore, more research is necessary to calculate the diagnostic test criteria more accurately.

Ibuprofen induced Stevens-Johnson syndrome and liver injury in children: a case report

“…Some studies have reported a close genetic relationship between HLA alleles and drug allergy susceptibility (5,6). These genetic associations may be drug-specific.…”

“…These genetic associations may be drug-specific. For example, HLA-B*1502 is related to SJS induced by carbamazepine (6), HLA-B*55:01 is related to penicillin allergy (7), and HLA-B*5801 is related to severe skin adverse reactions induced by allopurinol (6).…”

Review and Consensus on Pharmacogenomic Testing in Psychiatry

“…Polygenic risk scores derived from schizophrenia and depression GWAS have been associated with lithium response [39,40], but none of these findings have been replicated. The immunologic genes HLA-A and HLA-B are robustly linked to rare, but potentially fatal, severe cutaneous adverse reactions (SCARs) (e. g., Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) following exposure to carbamazepine, oxcarbazepine, and phenytoin [41]. Specifically, HLA-A * 31:01 and HLA-B * 15:02 alleles are associated with a higher risk of SCARs if exposed to carbamazepine [12], while only the HLA-B * 1502 allele is linked to a higher risk of SCARs following exposure to oxcarbazepine and phenytoin [42].…”

2021 Asia‐Pacific League of Associations for Rheumatology clinical practice guideline for treatment of gout

“…A retrospective cohort study 70 The frequency of the HLA-B*5801 allele carriers among Asians is about 10% to 20% but may further vary. 71,72 Testing for HLA-B*5801 among Asians had a high sensitivity (88%-100%) and specificity (82%-94%) in the population with allopurinol-induced severe cutaneous adverse reaction (SCAR) cases. 71 A cohort study (n = 4346) demonstrated that patients who tested positive for HLA-B*5801 and were not prescribed allopurinol had a lower risk of SCAR up to 2 months after ULT initiation compared with those who were not tested but were given allopurinol.…”