Cost-effectiveness of HLA-B*58:01 testing to prevent Stevens-Johnson syndrome/toxic epidermal necrolysis in Vietnam.

Background: HLA-B*58:01 is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. Methods: A model was developed to compare three strategies: no screening, use allopurinol; HLA-B*58:01 screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Results: Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0.0069 with the incremental cost of Vietnam dong (VND) 14,283,633 (US$617), yielding an incremental cost-effectiveness ratio of VND 2,070,459,122 (US$89,398) per quality-adjusted life-year. Therefore, 'screening' was unlikely to be cost-effective under the current willingness-to-pay. Testing's cost-effectiveness may change with targeted high-risk patients, reimbursed febuxostat or lower probenecid prices. Conclusion: The implementation of nationwide HLAB*58:01 testing before the use of allopurinol is not cost-effective, according to this analysis. This may be due to the lack of quality data on the effectiveness of testing and costing data in the Vietnamese population.

DNA methylation of ITGB2 contributes to allopurinol hypersensitivity.

BACKGROUNDS: HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR. OBJECTIVE: To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing. STUDY DESIGN: The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021. RESULTS: The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083). CONCLUSIONS: Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.

Allopurinol-Induced Stevens-Johnson Syndrome in Javanese Men With Positive HLA-B*58:01.

Background: Allopurinol is the most commonly used drug for the treatment of gout arthritis. However, the use of allopurinol is associated with severe cutaneous adverse reactions (SCARs) and life-threatening immune-mediated reactions that include Stevens-Johnson syndrome (SJS). SJS induced by allopurinol is strongly linked with the presence of HLA-B*58:01 in the Asian population. Such a study has not been conducted in Indonesia. We present two cases with clinical diagnosis of SJS. These patients had Javanese ethnicity, for which evidence on the genetic predisposition of allopurinol-induced SJS/TEN had not been established. Testing for the presence of the HLA-B∗58:01 allele was positive in both cases. Our case report confirms findings from studies in Asian countries that link HLA-B*58:01 and allopurinol-induced SJS/TEN. A larger study is needed to elicit evidence that the HLA-B*58:01 allele can potentially be used as a genetic marker for allopurinol-induced SCARs among different ethnicities in Indonesia.

[HLA-B58.01 and allopurinol hypersensitivity renal vasculitis in a Chinese patient]. / HLA-B58.01 et vascularite rénale d'hypersensibilité à l'allopurinol chez un patient chinois.

INTRODUCTION: Allopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations. OBSERVATION: We report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations. DISCUSSION: . The identification of this allele should be proposed before prescribing allopurinol in patients originating from certain regions of Asia, and the imputability of allopurinol should be evoked in case of necrotizing renal vasculitis, even without associated cutaneous involvement.

Allopurinol-induced severe cutaneous adverse reactions in Vietnamese: the role of HLA alleles and other risk factors.

Aim: To reveal the association of three class I HLA alleles, including HLA-A*33:03, HLA-B*58:01 and HLA-C*03:02, and allopurinol-induced severe cutaneous adverse reactions (SCARs) in Vietnamese patients. Methods: A case-control study on 100 allopurinol-induced SCARs patients, 183 tolerant controls and 810 population controls was performed. The HLA-A*33:03 and HLA-C*03:02 alleles were detected with the nested allele-specific PCR method; the HLA-B*58:01 allele was detected with the sequence-specific primer PCR method. Results: There were strong associations between HLA-B*58:01 and HLA-C*03:02 and allopurinol-induced SCARs. Specific associations were found between HLA-B*58:01 and Stevens-Johnson syndrome/toxic epidermal necrolysis and between HLA-C*03:02 and drug reaction with eosinophilia and systemic symptoms, with a gene dosage effect. The multivariate regression analysis indicated two significant independent risk factors: HLA-B*58:01/HLA-C*03:02 and estimated glomerular filtration rate <60 ml/min/1.73 m2. The specificity, positive predictive value and negative predictive value of HLA-B*58:01 testing were higher than the HLA-C*03:02 or the multiplex testing, especially in patients with impaired renal function. Conclusion: The results supported pre-treatment HLA-B*58:01 testing in Vietnamese patients with declined renal function to prevent SCARs.

HLA-B*58:01 screening to prevent allopurinol-induced severe cutaneous adverse reactions in Chinese patients with chronic kidney disease.

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.

Predominant HLA Alleles and Haplotypes in Mild Adverse Drug Reactions Caused by Allopurinol in Vietnamese Patients with Gout.

Allopurinol (ALP) is commonly used as a drug for gout treatment. However, ALP is known to cause cutaneous adverse reactions (CARs) in patients. The HLA-B*58:01 allele is considered a biomarker of severe CAR (SCAR) in patients with gout, with symptoms of Stevens Johnson syndrome, and with toxic epidermal necrolysis. However, in patients with gout and mild cutaneous adverse drug reactions (MCARs), the role of HLA-allele polymorphisms has not been thoroughly investigated. In this study, 50 samples from ALP-tolerant patients and ALP-induced MCARs patients were genotyped in order to examine the polymorphisms of their HLA-A and HLA-B alleles. Our results showed that the frequencies of HLA-A*02:01/HLA-A*24:02 and HLA-A*02:01/HLA-A*29:01, the dual haplotypes in HLA-A, in patients with ALP-induced MCARs were relatively high, at 33.3% (7/21), which was HLA-B*58:01-independent, while the frequency of these dual haplotypes in the HLA-A locus in ALP-tolerant patients was only 3.45% (1/29). The HLA-B*58:01 allele was detected in 38% (8/21) of patients with ALP-induced MCARs, and in 3.45% (1/29) of ALP-tolerant patients. Notably, although HLA-B*58:01 may be a cause for the occurrence of MCARs in patients with gout, this correlation was not as strong as that previously reported in patients with SCAR. In conclusion, in addition to the HLA-B*58:01 allele, the presence of the dual haplotypes of HLA-A*02:01/HLA-A*24:02 and/or HLA-A*02:01/HLA-A*29:01 in the HLA-A locus may also play an important role in the appearance of ALP-induced MCARs in the Vietnamese population. The obtained primary data may contribute to the development of suitable treatments for patients with gout not only in Vietnam but also in other Asian countries.

Clinical Aspects of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis With Severe Ocular Complications in South Korea.

This review describes the current knowledge regarding genetic susceptibilities and treatment strategies for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with ocular complications, in Korea. In a case-control study, the gene frequencies of both HLA-A*0206 (20.0%) and HLA-Cw*0304 (15.0%) increased but the gene frequency of HLA-Cw*0303 (1.3%) decreased with cold medicine (CM)-SJS/TEN with severe ocular complications (SOCs). In a case-series, positive genotyping of HLA-B*5801 was 80.0% in allopurinol-induced SJS/TEN without SOCs. In a genome-wide association study, HLA-A*0206 was substantially related to CM-SJS/TEN with SOCs. Both HLA-A*0206 and prostaglandin-E receptor 3 (PTGER3) single nucleotide polymorphism (SNP) rs1327464 exert a synergistic effect on SOCs in CM-SJS/TEN. In the acute stage, conventional procedures, amniotic membrane transplantation or suture-less amniotic contact lenses are applied. Applications of intravenous Immunoglobulin (IVIG) or mega-dose steroids are attempted in patients with high acute ocular and systemic involvement scores. In the chronic stage, keratolimbal transplantation and penetrating keratoplasty are the standard procedures. Either autologous nasal or oral mucosal grafts, or biomaterial-free cultured oral mucosal epithelial cell sheets are transplanted as alternative therapies. Deep anterior lamellar keratoplasty is attempted. Combined photodynamic therapy with intrastromal bevacizumab injection or intense pulse laser are used to resolve chronic ocular complication. Corneoscleral contact lenses are available for a visual rehabilitation. As a last resort, Seoul-type keratoprosthesis had been transplanted. There are unmet needs to standardize nationwide ocular grading system and to correct tarsal scarring using mucosal grafting. This review provides a perspective on the current practices to treat ocular complications in SJS/TEN.

Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study.

OBJECTIVE: The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. METHODS: All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8-40.1], P < 0.0001), female sex (OR 333 [40-43,453], P < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120-125,847], P < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101-122], P < 0.0001), diuretics intake (OR 304 [35-40,018], P < 0.0001), eGFR < 60 ml/min/1.73 m2 (OR 100 [32-353], P < 0.0001), history of allopurinol-induced skin reaction (OR 78 [6-10,808], P = 0.004), and HLA-B*58:01 carriage (OR 147 [45-746], P < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs (n = 74), risk factors were eGFR < 60 ml/min/1.73 m2 (OR 4.9 [1.61-14.6], P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2-3777], P = 0.01), and asymptomatic hyperuricemia (OR 27 [2-3777], P = 0.01). CONCLUSION: This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.

Is HLA-B*58:01 genotyping cost effective in guiding allopurinol use in gout patients with chronic kidney disease?

Aim: Concerns for fatal severe cutaneous adverse reactions (SCARs) hamper allopurinol use. Methods and material: We adopted a health system perspective to evaluate the cost-effectiveness of HLA-B*58:01 genotyping before allopurinol initiation. A decision tree compared three treatment strategies in gout patients with chronic kidney disease who have higher risk for SCAR. They were standard allopurinol treatment followed by febuxostat in nonresponders, test-positive patients receive febuxostat while test-negative receive allopurinol and universal use of febuxostat. Results: The first strategy was the most cost effective. Genotyping dominated universal febuxostat use. Time horizon and SCAR incidence were the most influential factors on the incremental cost-effectiveness ratio. Conclusion: HLA-B*58:01 genotyping compared with standard allopurinol-febuxostat sequential treatment does not provide good value for money in gout with chronic kidney disease.

HLA-B*58:01 and rs9263726 have a linkage, but not absolute linkage disequilibrium in Han Chinese population.

HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Due to the conflict results, in this study, we aim to demonstrate whether the rs9263726 allele is a surrogate biomarker for HLA-B*58:01 in Han Chinese population. A total of 353 samples (200 cases from the south and 153 cases from the north) were selected to detect HLA-B*58:01 and rs9263726 allele. The HLA-B*58:01 was identified by sequencing-based method, and the rs9263726 allele was identified by Taqman SNP Genotyping Assays. The results showed that the two alleles had a linkage, but not absolute linkage disequilibrium in Han Chinese population.

Rapid, Reliable, and Inexpensive HLA-B*58:01 Detection Method Using DNA Binding Dye-based Duplex Allele-specific Melting Curve Analysis.

BACKGROUND: Allopurinol is the most commonly used drug for the treatment of gout and also one of the most common causes of severe cutaneous adverse reactions (SCARs). Human leukocyte antigen-B*58:01 (HLA-B*58:01) is strongly associated with allopurinol-induced SCARs. The aim of the present study was to develop and validate a rapid and economic screening method for HLA-B*58:01. METHODS: The accuracy of duplex allele-specific melting curve analysis using DNA-binding dye for HLA-B*58:01 was evaluated in 150 blood samples with sequence-based typing (SBT) as the reference method. RESULTS: Fifty HLA-B*58:01-positive and 100 negative results obtained by duplex allele-specific melting curve analysis were completely in agreement with the SBT results. CONCLUSION: Duplex allele-specific melting curve analysis is a rapid, reliable and inexpensive assay that is appropriate for screening for the HLA-B*58:01 allele.

Cost-effectiveness Analysis of HLA-B*58:01 Gene Polymorphism Detection before Gout Patients Using Allopurinol or Febuxostat / 中国药房

OBJECTIVE:To provide reference for optimizing gout drug therapy plan. METHODS:A total of 107 patients met gout clinical diagnosis criteria in the Affiliated Hospital of Putian University during Jul. 1st,2016- Jul. 1st,2017 were divided into group A and B according to carrying out HLA-B*58:01 gene detection or not. Group A was divided into positive and negative subgroup according to the results of gene detection. Positive subgroup was given febuxostat 40 mg,qd. Negative subgroup was given allopurinol 300 mg,tid with a treatment course for 2 weeks,the level of uric acid was detected after a treatment course;febuxostat was given instead if the level of uric acid was not up to the standard. Group B was given allopurinol;after a treatment course,the level of uric acid was detected;febuxostat was given instead (usage and dosage as group A) if the level of uric acid was not up to the standard. Both groups were treated for 6 months. The levels of uric acid were investigated in 2 groups before and after treatment so as to evaluate up-to-standard rate of treatment. European 5-D health scale of 2 groups were followed up with telephone to calculate therapeutic efficacy by QALY. Cost-effectiveness of 2 groups were calculated,and sensitivity analysis was conducted. RESULTS:Before treatment,there was no statistical significance in urine acid levels between 2 groups (P>0.05). After treatment,urine acid levels of 2 groups were significantly lower than before treatment with statistical significance(P<0.05). Therapeutic effectiveness was 0.818 QALY in group A and 0.808 QALY in group B,without statistical significance between 2 groups(P>0.05). The cost of group A was 3932.46 yuan,and that of group B was 2174.92 yuan. Cost-effectiveness ratio of 2 groups were 4807.41 and 2691.73,and group A was significantly higher than group B. The therapy plan of group B showed that cost-effectiveness advantage. Sensitivity analysis supported the results. There was no statistical significance in the incidence of ADR between 2 groups (P>0.05). CONCLUSIONS:It shows cost-effectiveness advantage to directly use allopurinol without gene detection in gout patients.

Relationship between HLA-B*5801 Gene Polymorphism and Allopurinol-induced ADR in Han Population of Hainan Province / 中国药房

OBJECTIVE:To investigate the relationship between HLA-B*5801 gene polymorphism and allopurinol-induced ADR in the Han population of Hainan Province. METHODS:The in-situ hybridization fluorescence staining analysis technique was used to detect HLA-B*5801 allele of 149 inpatients receiving allopurinol in Hainan Provincial People's Hospital during Sept. 2015-Sept. 2017.They were divided into tolerance group and ADR group according to ADR.Woolf's formula was used to calculate OR. The correlation of HLA-B*5801 allele with the occurrence of allopurinol-induced ADR was analyzed. RESULTS:Of 149 patients,there were 133 cases in tolerance group,among which 17.29%(23/133)carried HLA-B*5801 allele.There were 16 cases in ADR group,among which 93.75%(15/16)carried HLA-B*5801 allele. Among 16 ADR patients,13 patients suffered from lesion of skin and its appendents;1 patient suffered from systemic damage;1 patient suffered from gastrointestinal systemic damage;1 patient suffered from central and peripheral nervous system damage. The risk of ADR in patients with HLA-B*5801 allele was significantly higher than patients without HLA-B*5801 allele(OR:71.74,95%CI:9.02-570.55,P<0.000). The lesion of skin and its appendents was strongly associated with HLA-B*5801 allele(OR:57.39,95%CI:7.11-463.50,P<0.000). CONCLUSIONS:HLA-B*5801 allele is strongly associated with allopurinol-induced ADR. It is suggested that HLA-B*5801 allele of Han patients should be detected before taking allopurinol,which helps to reduce the incidence of allopurinol-induced ADR.

Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis.

BACKGROUND: Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain. METHODS: The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated. RESULTS: In nine population-control studies, HLA-B*5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR-, DOR and AUC were 0.78 (95% CI = 0.71-0.85), 0.96 (95% CI = 0.96-0.97), 14.23 (95% CI = 7.89-25.63), 0.29 (95% CI = 0.16-0.54), 83.5 (95% CI = 50.7-137.4), and 0.97 (95% CI = 0.95-0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3-672.0), Japanese (78.8; 95% CI = 30.4-203.9), and Caucasian (58.4; 95% CI = 16.9-201.5) populations. Overall, HLA-B*5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50-60% sensitivity (pooled sensitivity 56%), compared to the 80-100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations. CONCLUSIONS: The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B*5801 for detecting allopurinol-induced TEN/SJS is universal. Screening of HLA-B*5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (≥ 5%) risk allele frequency.

Cost effectiveness analysis of HLA-B*58:01 genotyping prior to initiation of allopurinol for gout.

Objective: To determine whether prospective testing for HLA-B*58:01, as a strategy to prevent serious adverse reactions to allopurinol in patients with gout, is cost-effective from the perspective of the National Health Service in the UK. Methods: A systematic review and meta-analysis for the association of HLA-B*58:01 with cutaneous and hypersensitivity adverse drug reactions informed a decision analytic and Markov model to estimate lifetime costs and outcomes associated with testing vs standard care (with febuxostat prescribed for patients who test positive). Scenario analyses assessed alternative treatment assumptions and patient populations. Results: The number of patients needed to test to prevent one case of adverse drug reaction was 11 286 (95% central range (CR): 2573, 53 594). Cost and quality-adjusted life-year (QALY) gains were small, £103 (95% CR: £98, £106) and 0.0023 (95% CR: -0.0006, 0.0055), respectively, resulting in an incremental cost-effectiveness ratio (ICER) of £44 954 per QALY gained. The probability of testing being cost-effective at a threshold of £30 000 per QALY was 0.25. Reduced costs of testing or febuxostat resulted in an ICER below £30 000 per QALY gained. The ICER for patients with chronic renal insufficiency was £38 478 per QALY gained. Conclusion: Routine testing for HLA-B*58:01 in order to reduce the incidence of adverse drug reactions in patients being prescribed allopurinol for gout is unlikely to be cost-effective in the UK; however testing is expected to become cost-effective with reductions in the cost of genotyping, and with the future availability of cheaper, generic febuxostat.

Cost-effectiveness Analysis for Genotyping before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug Reactions.

OBJECTIVE: Patients with an HLA-B*58:01 allele have an increased risk of developing severe cutaneous adverse drug reactions (SCAR) when treated with allopurinol. Although one-off pharmacogenetic testing may prevent life-threatening adverse drug reactions, testing prior to allopurinol initiation incurs additional costs. The study objective was to evaluate the cost-effectiveness of HLA-B*58:01 screening compared with using other available urate-lowering agents (ULA). METHODS: A decision-analytical model was used to compare direct medical costs and effectiveness [including lifetime saved, quality-adjusted life-yrs (QALY) gained] in treating new patients with the following options: (1) genetic screening followed by allopurinol prescribing for noncarriers of HLA-B*58:01, (2) prescribing benzbromarone without screening, (3) prescribing febuxostat without screening, and (4) prescribing allopurinol without screening. A 1-year time frame and third-party payer perspective were modeled for both the entire cohort (base-case) and for the subgroup of patients with chronic kidney disease (CKD). RESULTS: The incremental cost-effectiveness ratio of genetic screening prior to ULA therapy was estimated as New Taiwan (NT) $234,610 (US$7508) per QALY gained in the base-case cohort. For patients with CKD, it was estimated as NT$230,925 (US$7390) per QALY. The study results were sensitive to the probability of benzbromarone/febuxostat-related hypersensitivity, and a negative predicted value of genotyping. CONCLUSION: HLA-B*58:01 screening gave good value for money in preventing allopurinol-induced SCAR in patients indicated for ULA therapy. In addition to the costs of genotyping, it is important to monitor ULA safety closely in adopting HLA-B*58:01 screening in practice.

Allopurinol-induced severe cutaneous adverse reactions: A report of three cases with the HLA-B*58:01 allele who underwent lymphocyte activation test.

Allopurinol-induced severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are reportedly associated with the HLA-B*58:01 genotype. Three patients who developed SCARs after allopurinol administration were subjected to HLA-B genotyping and lymphocyte activation test (LAT) to evaluate genetic risk and to detect the causative agent, respectively. All three patients given allopurinol to treat gout were diagnosed with DRESS syndrome. Symptom onset commenced 7-24 days after drug exposure; the patients took allopurinol (100-200 mg/d) for 2-30 days. HLA-B genotyping was performed using a polymerase chain reaction (PCR)-sequence-based typing (SBT) method. All patients had a single HLA-B*58:01 allele: HLA-B*13:02/*58:01 (a 63-year-old male), HLA-B*48:01/*58:01 (a 71-year-old female), and HLA-B*44:03/*58:01 (a 22-year-old male). Only the last patient yielded a positive LAT result, confirming that allopurinol was the causative agent. These findings suggest that patients with HLA-B*58:01 may develop SCARs upon allopurinol administration. Therefore, HLA-B genotyping could be helpful in preventing serious problems attributable to allopurinol treatment, although PCR-SBT HLA-B genotyping is time consuming. A simple genotyping test is required in practice. LAT may help to identify a causative agent.

Allopurinol-induced severe cutaneous adverse reactions: A report of three cases with the HLA-B*58:01 allele who underwent lymphocyte activation test

Allopurinol-induced severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are reportedly associated with the HLA-B*58:01 genotype. Three patients who developed SCARs after allopurinol administration were subjected to HLA-B genotyping and lymphocyte activation test (LAT) to evaluate genetic risk and to detect the causative agent, respectively. All three patients given allopurinol to treat gout were diagnosed with DRESS syndrome. Symptom onset commenced 7-24 days after drug exposure; the patients took allopurinol (100–200 mg/d) for 2-30 days. HLA-B genotyping was performed using a polymerase chain reaction (PCR)-sequence-based typing (SBT) method. All patients had a single HLA-B*58:01 allele: HLA-B*13:02/*58:01 (a 63-year-old male), HLA-B*48:01/*58:01 (a 71-year-old female), and HLA-B*44:03/*58:01 (a 22-year-old male). Only the last patient yielded a positive LAT result, confirming that allopurinol was the causative agent. These findings suggest that patients with HLA-B*58:01 may develop SCARs upon allopurinol administration. Therefore, HLA-B genotyping could be helpful in preventing serious problems attributable to allopurinol treatment, although PCR-SBT HLA-B genotyping is time consuming. A simple genotyping test is required in practice. LAT may help to identify a causative agent.

Impact of HLA-B*58:01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies.

Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). Recently, HLA-B*58:01 allele was identified as a strong genetic marker for allopurinol-induced CADRs in Han Chinese. However, the magnitude of association and diagnosis value of HLA-B*58:01 in allopurinol-induced CADRs remain inconclusive. To investigate this inconsistency, we conducted a meta-analysis of 21 pharmacogenetic studies, including 551 patients with allopurinol-induced CADRs, and 2,370 allopurinol-tolerant controls as well as 9,592 healthy volunteers. The summary OR for allopurinol-induced CADRs among HLA-B*58:01 carriers was 82.77 (95% CI: 41.63 - 164.58, P < 10-5) and 100.87 (95% CI: 63.91 - 159.21, P < 10-5) in matched and population based studies, respectively. Significant results were also observed when stratified by outcomes and ethnicity. Furthermore, the summary estimates for quantitative analysis of HLA-B*58:01 allele carriers in allopurinol-induced CADRs screening were as follows: sensitivity, 0.93 (95% CI: 0.85 - 0.97); specificity, 0.89 (95% CI: 0.87 - 0.91); positive likelihood ratio, 8.24 (95% CI: 6.92 - 9.81); negative likelihood ratio, 0.084 (95% CI: 0.039 - 0.179); and diagnostic odds ratio, 98.59 (95% CI: 43.31 - 224.41). The AUSROC was 0.92 (95% CI: 0.89-0.94), indicating the high diagnostic performance. Our results indicated that allopurinol-SCAR is strongly associated with HLA-B*58:01, and HLA-B*58:01 is a highly specific and effective genetic marker for the detection allopurinol-induced CADRs, especially for Asian descents.