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.

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.

HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.

Drug Eruptions Induced by Allopurinol Associated with HLA-B*5801.

Allopurinol, a drug commonly used for treating gout and hyperuricemia, is a frequent cause of drug eruptions. Recent investigations suggest that HLA‑B*5801 allele is a very strong marker for allopurinol‑induced cutaneous adverse drug reactions (cADRs). In this article we report two cases of allopurinol‑induced drug eruptions in patients carrying the HLA‑B*5801 allele and review the literature on the association between HLA‑B*5801 and allopurinol‑induced cADRs based on a MEDLINE and PubMed search.

Analysis of frequency of HLA-B*5801 in population of Chinese Minnan region / 中国免疫学杂志

Objective: To investigate the gene frequency of HLA-B* 5801 in the population of Chinese Minnan region.Methods:In this study,we enrolled 178 patients requiring allopurinol therapy( including 40 patients with gout,89 patients with hyperuricemia and 49 patients with gouty arthritis) and 100 healthy people.We isolated genomic DNA from their blood and screened for HLA-B*5801 with both PCR and gene sequencing.Results:We found 22%patients and 16%healthy people with HLA-B*5801.The frequencies of HLA-B*5801 in patients and healthy people are 0.13 and 0.09,respectively.The results from PCR and gene sequencing were consistent.Conclusion:The frequency of HLA-B*5801 in the population of Chinese Minnan region is relatively high.Therefore,it is necessary to screen for HLA-B*5801 in allopurinol users before taking the medicine.