Introduction: Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine... Show moreIntroduction: Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions.Methods: A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01, and HLA-B*58:01 were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient's medical records. Carrier frequencies found were compared to a LUMC blood donor population.Results: A total of 13.1% of transplant cohort patients carried at least one of the five HLA risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No HLA-B*15:11 carrier was found. In total nine HLA-B*57:01 carriers received flucloxacillin and seven HLA-B*58:01 carriers within our cohort received allopurinol.Discussion: Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele. Show less
Background The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive... Show moreBackground The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Findings Between March 7, 2017, and June 30, 2020, 41696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001). Interpretation Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. Show less
Aim: To provide a comparison of genotyping for HLA risk alleles versus patch testing to determine which of these two tests is a better diagnostic tool for cutaneous hypersensitivity reactions... Show moreAim: To provide a comparison of genotyping for HLA risk alleles versus patch testing to determine which of these two tests is a better diagnostic tool for cutaneous hypersensitivity reactions caused by anti-seizure medication. Methods: A literature study was performed in PubMed to assess the sensitivity and specificity of HLA genotyping and patch tests for identifying anti-seizure medication induced cutaneous hypersensitivity reactions. Results: This study shows that HLA-B*15:02 genotyping shows high sensitivity for carbamazepine-induced SJS/TEN, especially in Han Chinese and Southeast Asian patients (66.7-100.0%) whereas the sensitivity of patch tests (0.0-62,5%), HLA-A*31:01 (0-50%) and HLA-B*15:11 (18.2-42.9%) are lower. On the contrary, for carbamazepine and phenytoin induced DRESS, patch tests (respectively 70.0-88.9% and 14.3-70.0%) show higher sensitivity than HLA tests (0-66.7% and 0-12.7%). Also for lamotrigine-induced DRESS patch tests perform better than HLA-B*15:02 (33.3-40.0 versus 0%). For anti-seizure medication induced MPE and for oxcarbazepine-induced SCARs more studies are needed. Conclusion: Use of HLA-B genotyping may aid clinicians in the diagnosis of carbamazepine, phenytoin, lamotrigine and oxcarbazepine induced SJS/TEN, particularly in Han Chinese and Southeast Asian patients. On the other hand, patch tests seem to perform better in the diagnosis of carbamazepine and phenytoin induced DRESS. Show less
Manson, L.E.N.; Hout, W.B. van den; Guchelaar, H.J. 2022
Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA... Show moreHuman Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug-gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered. Show less
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... Show moreIntroduction 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 gene - drug interaction guidelines but diagnostic test criteria remain largely unknown. We present an overview of the diagnostic test criteria of the actionable HLA - drug 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. Show less
