Cost-effectiveness analysis of HLA-B*15:02 screening before treatment of epilepsy in Indonesia.

INTRODUCTION: Adverse skin reactions due to drugs such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) occur in 3% of people receiving anti epileptic drugs (AED). Although SJS/TEN has a low incidence, the mortality and morbidity rates are high. Indonesia has not adopted HLA-B*1502 screening prior to administration of carbamazepine (CBZ), although previous studies found a relationship between HLA-B*1502 and SJS/TEN. METHODS: A hybrid decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed focal epilepsy: CBZ direct therapy, levetiracetam (LEV) direct therapy, and therapy based on HLA-B*15:02 test results. From a societal perspective, base case and sensitivity analyses were carried out over a lifetime. RESULTS: Direct administration of CBZ appears to have a slightly lower average cost than the HLA-B*15:02 allele screening strategy. The increase in quality-adjusted life year (QALY) in HLA-B*15:02 screening before treatment related to the cost difference reached 0.519 with an incremental cost-effectiveness ratio (ICER) of around USD 984 per unit of QALY acquisition. Direct treatment of LEV increased treatment costs by almost USD 2000 on average compared to the standard CBZ strategy. The increase in QALY is 0.834 in direct levetiracetam treatment, with an ICER of around USD 2230 for each QALY processing. CONCLUSION: Calculation of the cost-effectiveness of lifetime epilepsy therapy in this study found that the initial screening strategy with the HLA-B*15:02 test was the most cost-effective.

Update on HLA-B*15:02 allele associated with adverse drug reactions.

HLA alleles, part of the major histocompatibility complex, are strongly associated with adverse drug reactions (ADRs). This review focuses on HLA-B*15:02 and explores its association with ADRs in various ethnic populations and with different drugs, aiming to provide insights into the safe clinical use of drugs and minimize the occurrence of ADRs. Furthermore, the review explores the potential mechanisms by which HLA-B*15:02 may be associated with ADRs, aiming to gain new insights into drug modification and identification of haptens. In addition, it analyzes the frequency of the HLA-B*15:02, genotyping methods, cost-effectiveness and treatment measures for adverse reactions, thereby providing a theoretical basis for formulating clinical treatment plans.

Accurate identification of HLA-B*15:02 allele by two-dimensional polymerase chain reaction.

BACKGROUND: HLA-B*15:02 is highly associated with carbamazepine-induced SJS/TEN; however, there is no rapid and accurate detecting method. Here, we present a method to distinguish HLA-B*15:02 from 16 highly homologous HLA-B*15 alleles. METHODS: The high-throughput two-dimensional polymerase chain reaction (2D-PCR) technology was employed to identify HLA-B*15:02 in two-tube reaction. And, 2D-PCR accuracy was verified by PCR-sequence based typing (PCR-SBT). RESULTS: HLA-B*15:02 heterozygotes were identified by 14 melting valleys in the first tube reaction and none in the second, or by 13 melting valleys in the first tube reaction and one in the second. HLA-B*15:02 homozygote was identified by 13 melting valleys in the first tube reaction and none in the second. Three (0.16%) HLA-B*15:02 homozygotes and 84 (4.59%) HLA-B*15:02 heterozygotes were detected in 1830 samples of clinical general population without detecting 16 highly homologous alleles to HLA-B*15:02. The kappa test showed 100% coincidence between the 2D-PCR and PCR-SBT. CONCLUSIONS: 2D-PCR in two-tube reaction method for identifying HLA-B*15:02 was successfully established. Identification of HLA-B*15:02 is necessary prior to taking CBZ based on HLA-B*15:02 allele frequency.

Ultrarapid and high-resolution HLA class I typing using transposase-based nanopore sequencing applied in pharmacogenetic testing.

Nanopore sequencing has been examined as a method for rapid and high-resolution human leukocyte antigen (HLA) typing in recent years. We aimed to apply ultrarapid nanopore-based HLA typing for HLA class I alleles associated with drug hypersensitivity, including HLA-A*31:01, HLA-B*15:02, and HLA-C*08:01. Most studies have used the Oxford Nanopore Ligation Sequencing kit for HLA typing, which requires several enzymatic reactions and remains relatively expensive, even when the samples are multiplexed. Here, we used the Oxford Nanopore Rapid Barcoding kit, which is transposase-based, with library preparation taking less than 1 h of hands-on time and requiring minimal reagents. Twenty DNA samples were genotyped for HLA-A, -B, and -C; 11 samples were from individuals of different ethnicity and nine were from Thai individuals. Two primer sets, a commercial set and a published set, were used to amplify the HLA-A, -B, and -C genes. HLA-typing tools that used different algorithms were applied and compared. We found that without using several third-party reagents, the transposase-based method reduced the hands-on time from approximately 9 h to 4 h, making this a viable approach for obtaining same-day results from 2 to 24 samples. However, an imbalance in the PCR amplification of different haplotypes could affect the accuracy of typing results. This work demonstrates the ability of transposase-based sequencing to report 3-field HLA alleles and its potential for race- and population-independent testing at considerably decreased time and cost.

Impact on carbamazepine usage and cutaneous adverse reactions before and after the reimbursement of HLA-B*1502 genotyping in Taiwan, 2000-2017: A nationwide longitudinal study.

OBJECTIVE: The HLA-B*1502 allele is strongly associated with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in the Han Chinese population. This study investigated the impact of HLA-B*1502 screening on CBZ utilization and rates of severe cutaneous allergic reactions (SCARs) and SJS/TEN over time in Taiwan, where screening for HLA-B*1502 genotyping before prescribing CBZ was reimbursed in June 2010. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed 13 277 457 episodes of seeking treatment for epilepsy or neuralgia between 2000 and 2017. Episodes were categorized into quarters based on treatment time. Propensity score-based stabilized weighting (PSSW) ensured well-balanced covariates. The difference in 3-month SCAR and SJS/TEN rates between phase 2 (2011-2017) and phase 1 (2000-2009) was examined using a one-sample Z-test. Pearson correlation coefficients assessed the association between screening rate, the number of CBZ users and nonusers, and SCAR and SJS/TEN rates after HLA-B*1502 genotyping. RESULTS: CBZ prescriptions reduced from 7% (2000-2003) to 6% (2004-2010) and 4% (2011-2017). The screening rates of CBZ nonusers and CBZ users increased from 0%, .5% in 2011 to .8%, 16% in 2017, respectively. After PSSW, the mean 3-month SCAR incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (6.91 vs. 3.09, p < .0001) and nonusers (1.96 vs. 1.65, p < .0001). SJS/TEN incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (2.94 vs. 1.93, p < .0001) but not for nonusers (.71 vs. .74, p = .1492). In phase 2, SCAR incidence rates were significantly and negatively correlated with the screening rate for both CBZ users (r = -.38, p = .0342) and nonusers (r = -.80, p < .001). No significant correlation was found between SJS/TEN incidence rates and screening rates. SIGNIFICANCE: Recognizing HLA-B*1502 allele and avoiding CBZ therapy in HLA-B*1502-positive patients is critical for preventing CBZ-induced severe adverse events.

The pharmacogenomics of carbamazepine-induced cutaneous adverse drug reaction in the South of Vietnam.

Background: The relationship between HLA-B*15:02 and Severe Cutaneous Adverse Reactions was rigorously examined in Japanese, Han Chinese, Thais, and Caucasians. However, the number of studies about this topic in Vietnamese population is still limited and mostly focuses on the North of Vietnam. Objective: This study aims to clarify the genetic culprit of SCARs in Vietnamese population, particularly in the South of Vietnam, and to validate our result by a meta-analysis about this topic in Vietnamese. Method: A retrospective case-control study with 37 patients treated with carbamazepine monotherapy. Statistical calculation and meta-analysis were performed by R software. Result: HLA-B*15:02 increases the risk of SJS 12.5 times higher in CBZ-treated patients (p-value = 0.017). However, this allele has no impact on MCARs (Mild Cutaneous Adverse Reactions) of CBZ. The number needed to test and the number needed to genotype is two and nine patients respectively. Conclusion: This study recommends more investigations about the cost-effectiveness of this test to accelerate the protection of Southern Vietnamese from SCARs.

Integrating real-world data in cost-effectiveness analysis of universal HLA-B*15:02 screening in Malaysia.

AIMS: Despite the availability of newer antiseizure medications, carbamazepine (CBZ) remains the gold standard. However, patients of Asian ancestry are susceptible to CBZ-related severe cutaneous adverse reactions. Universal HLA-B*15:02 screening is a promising intervention to address this. With the increasing recognition of integrating real-world evidence in economic evaluations, the cost-effectiveness of universal HLA-B*15:02 screening was assessed using available real-world data in Malaysia. METHODS: A hybrid model of a decision tree and Markov model was developed to evaluate 3 strategies for treating newly diagnosed epilepsy among adults: (i) CBZ initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to CBZ initiation; and (iii) alternative prescribing without HLA-B*15:02 screening. The model was populated with real-world inputs derived from the Malaysian population. From a societal perspective, base-case analysis and sensitivity analyses estimated the costs and outcomes over a lifetime. Incremental cost-effectiveness ratios were calculated. RESULTS: In the base-cases analysis, universal HLA-B*15:02 screening yielded the lowest total costs and the highest total quality-adjusted life years (QALYs) gained. Compared with current practice, universal screening was less costly by USD100 and more effective by QALYs increase of 0.1306, while alternative prescribing resulted in 0.1383 QALYs loss at additional costs of USD332. The highest seizure remission rate (56%) was estimated for universal HLA-B*15:02 screening vs. current practice (54%) and alternative prescribing (48%). CONCLUSION: Our study suggests that universal HLA-B*15:02 screening is a cost-effective intervention in Malaysia. With the demonstrated value of real-world evidence in economic evaluations, more relevant standardization efforts should be emphasized to better inform decision-making.

Awareness of HLA-B* 15:02 screening in trigeminal neuralgia and the gene screening policy among dentists in Southern Thailand.

OBJECTIVES: To determine the factors associated with public hospital dentists' awareness of HLA-B*15:02 screening in trigeminal neuralgia (TN) and the national gene screening policy in Thailand. METHODS: Cross-sectional study. A validated questionnaire was distributed to public hospital dentists with at least 1 year of practice in Southern Thailand (n = 760) to assess their knowledge of TN, carbamazepine (CBZ) use, awareness of HLA-B*15:02 screening, and the gene screening policy. RESULTS: A total of 385 dentists participated (50.7% response rate); 81.3% of respondents were aware of HLA-B*15:02 screening. However, 18.7% of dentists were not aware of the importance of gene testing. Furthermore, dentists who were aware of gene screening had significantly better knowledge of TN diagnosis and CBZ use than "unaware" dentists. Awareness of HLA-B*15:02 screening was also significantly associated with dental specialty. Moreover, 80.5% of respondents were not aware of the gene screening policy. The primary problems related to the policy were its inefficient publication, poor implementation, and lack of clinical practice guidelines (CPGs) to encourage dentists to follow the policy and prescribe gene tests. CONCLUSION: While most hospital dentists were aware of the necessity of HLA-B*15:02 screening prior to prescribing CBZ in TN, the majority were unaware of the national gene screening policy. Dental specialty and knowledge were associated with awareness of HLA-B*15:02 screening.

Development of label-free electrochemical impedance spectroscopy for the detection of HLA-B*15:02 and HLA-B*15:21 for the prevention of carbamazepine-induced Stevens-Johnson syndrome.

BACKGROUND: Carbamazepine (CBZ) is an FDA-approved anticonvulsant that is widely used to treat epilepsy, bipolar disorder, trigeminal neuralgia and chronic pain. Several studies have reported a strong association between HLA-B*15:02 and carbamazepine-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). However, the HLA-B75 serotype (HLA-B*15:02, HLA-B*15:08, HLA-B*15:11 and HLA-B*15:21) has been found in patients with carbamazepine-induced SJS/TEN. METHODS: This study aimed to develop label-free electrochemical impedance spectroscopy (EIS) for the detection of HLA-B*15:02 and HLA-B*15:21 after PCR-SSP amplification. A total of 208 DNA samples were tested. The impedance was measured and compared to standard gel electrophoresis. RESULTS: The developed label-free EIS identified HLA-B*15:02 and HLA-B*15:21 alleles with 100% sensitivity (95% CI: 86.773%-100.000%) and 95.05% specificity (95% CI: 90.821%-97.714%), comparable to commercial DMSc 15:02 detection kits. CONCLUSIONS: We successfully developed a novel PCR-SSP associated with signal impedance changes to detect the HLA-B*15:02 allele and HLA-B*15:21 without downstream amplicon size analysis that is suitable for screening individuals before indication of CBZ therapy.

rs144012689 is a highly specific representative marker of HLA-B*15:02 in the Chinese population.

Objective: To develop an accurate and rapid real-time PCR technique for HLA-B*15:02 genotyping and investigate HLA-B*15:02 allele frequency in four ethnic populations in China. Materials & methods: Based on the highly specific representative markers, a real-time PCR assay was developed for HLA-B*15:02 genotyping, and HLA-B*15:02 allele frequencies were screened in four ethnic populations of China. Sequence-based typing was used to validate the accuracy of the assay. Results: The sensitivity and specificity of the assay were 100%, and the detection limit was 0.2 ng. The frequency of HLA-B*15:02 alleles distributed in the Bouyei population was significantly higher than in the Han group (p < 0.01). Neither the Tibetan nor the Uyghur population carried the HLA-B*15:02 haplotype. Conclusion: The authors developed an accurate HLA-B*15:02 genotyping method for evaluating the risk of adverse drug reactions induced by carbamazepine in various ethnic populations in China.

Control of HIV-1 Replication by CD8+ T Cells Specific for Two Novel Pol Protective Epitopes in HIV-1 Subtype A/E Infection.

Although many HIV-1-specific CD8+ T cell epitopes have been identified and used in various HIV-1 studies, most of these epitopes were derived from HIV-1 subtypes B and C. Only 17 well-defined epitopes, none of which were protective, have been identified for subtype A/E infection. The roles of HIV-1-specific T cells have been rarely analyzed for subtype A/E infection. In this study, we identified six novel HLA-B*15:02-restricted optimal HIV-1 subtype A/E epitopes and then analyzed the presentation of these epitopes by HIV-1 subtype A/E virus-infected cells and the T cell responses to these epitopes in treatment-naive HIV-1 subtype A/E-infected HLA-B*15:02+ Vietnamese individuals. Responders to the PolTY9 or PolLF10 epitope had a significantly lower plasma viral load (pVL) than nonresponders among HLA-B*15:02+ individuals, whereas no significant difference in pVL was found between responders to four other epitopes and nonresponders. The breadth of T cell responses to these two Pol epitopes correlated inversely with pVL. These findings suggest that HLA-B*15:02-restricted T cells specific for PolTY9 and PolLF10 contribute to the suppression of HIV-1 replication in HLA-B*15:02+ individuals. The HLA-B*15:02-associated mutation Pol266I reduced the recognition of PolTY9-specific T cells in vitro but did not affect HIV-1 replication by PolTY9-specific T cells in Pol266I mutant virus-infected individuals. These findings indicate that PolTY9-specific T cells suppress replication of the Pol266I mutant virus even though the T cells selected this mutant. This study demonstrates the effective role of T cells specific for these Pol epitopes to control circulating viruses in HIV-1 subtype A/E infection. IMPORTANCE It is expected that HIV-1-specific CD8+ T cells that effectively suppress HIV-1 replication will contribute to HIV-1 vaccine development and therapy to achieve an HIV cure. T cells specific for protective epitopes were identified in HIV-1 subtype B and C infections but not in subtype A/E infection, which is epidemic in Southeast Asia. In the present study, we identified six T cell epitopes derived from the subtype A/E virus and demonstrated that T cells specific for two Pol epitopes effectively suppressed HIV-1 replication in treatment-naive Vietnamese individuals infected with HIV-1 subtype A/E. One of these Pol protective epitopes was conserved among circulating viruses, and one escape mutation was accumulated in the other epitope. This mutation did not critically affect HIV-1 control by specific T cells in HIV-1 subtype A/E-infected individuals. This study identified two protective Pol epitopes and characterized them in cases of HIV-1 subtype A/E infection.

Genetic variants associated with severe cutaneous adverse drug reactions induced by carbamazepine.

AIMS: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients. METHODS: Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined. RESULTS: Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs. CONCLUSION: The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.

The association between HLA-B*15:02 and phenytoin-induced severe cutaneous adverse reactions: a meta-analysis.

Aim: Phenytoin (PHT) is a common anticonvulsant agent known for inducing severe cutaneous adverse reactions (SCARs). HLA-B*15:02 as a risk factor of PHT-induced SCARs was reported in numerous studies with inconsistent results. This meta-analysis aimed to establish pooling evidence of this association. Materials & methods: Pooled odds ratios (ORs) with 95% CIs were estimated using a random-effects model. Results: A total of 11 studies on 1389 patients, were included for the analyses. There was a significant association between HLA-B*15:02 and PHT-induced SCAR (pooled OR = 2.29, 95% CI: 1.25-4.19, p = 0.008). Furthermore, there was a significant association regarding Stevens-Johnson syndrome/toxic epidermal necrolysis (OR = 3.63, 95% CI: 2.15-6.13, p < 0.001) but no association regarding drug reaction with eosinophilia and systemic symptom. Conclusion: The results supported the recommendations of HLA-B*15:02 screening before treatment with PHT.

Association between the HLA-B*1502 gene and mild maculopapular exanthema induced by antiepileptic drugs in Northwest China.

BACKGROUND: The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China. METHODS: We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test. RESULTS: We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found. CONCLUSIONS: In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs.

Characterization of the novel HLA allele: HLA-B*15:437 in a Chinese bone marrow donor.

HLA-B*15:437 shows one nucleotide difference with B*15:02 at position 814 G>A.

Usage Pattern of Carbamazepine and Associated Severe Cutaneous Adverse Reactions in Singapore Following Implementation of HLA-B*15:02 Genotyping as Standard-of-Care.

In April 2013, the Ministry of Health and Health Sciences Authority of Singapore jointly issued recommendations for HLA-B*15:02 genotyping before starting carbamazepine (CBZ) in new patients of Asian ancestry as standard of care. The Ministry of Health also approved a 75% subsidy for HLA-B*15:02 genotyping to all patients on subsidy at public healthcare institutions. To understand the impact of these regulatory decisions, we researched the usage patterns for CBZ and levetiracetam, the trend of Stevens-Johnson syndrome/toxic epidermal necrolysis [Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)] reports associated with antiepileptic drugs and the take-up rates of HLA-B*15:02 tests in Singapore. In the 5-year post-policy period, we found that the annual number of reported SJS/TEN cases associated with all antiepileptic drugs was significantly decreased by 57% (p = 0.015); SJS/TEN cases associated with CBZ and phenytoin reduced by 92% and 42% respectively. New CBZ users decreased by 31% while new levetiracetam users approximately doubled. The annual number of HLA-B*15:02 tests conducted increased from 444 to approximately 1,200. Regulatory recommendations for HLA-B*15:02 genotyping as standard of care coupled with government subsidy for the test had contributed to a reduction in CBZ SJS/TEN in Singapore by >90%, in line with that observed in other Asian countries with similar policies. Additionally, the number of phenytoin-SJS/TEN cases also declined. Taken together, this represents a successful example of precision medicine through implementation of a genotyping program to reduce a rare but serious adverse drug reaction among at-risk individuals, while preserving the availability of an effective and low-cost medicine for the broader population.

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

Cost-effectiveness of screening for HLA-B*1502 prior to initiation of carbamazepine in epilepsy patients of Asian ancestry in the United States.

OBJECTIVE: Carbamazepine, widely used in the treatment of partial and generalized tonic-clonic seizures, has been associated with life-threatening Stevens-Johnson syndrome/toxic epidermal necrolysis among some Asians. The HLA-B*1502 genotype that occurs with varying frequency among Asians is recommended for screening prior to starting carbamazepine. Our goal is to explore the cost-effectiveness of screening for the presence of this genetic allele. METHODS: We constructed a Markov model in a hypothetical cohort of adult Asian patients with epilepsy in the United States being considered for carbamazepine to investigate the cost-effectiveness of two alternative strategies: (1) no HLA-B*1502 gene allele screening and using carbamazepine and (2) HLA-B*1502 gene allele screening and starting levetiracetam in the case of a positive screen. RESULTS: For the lifetime horizon, HLA-B*1502 gene screening was the cost-effective choice compared to no gene screening, with an incremental cost-effectiveness ratio of $27 058 per quality-adjusted life-year (QALY), below the $50 000/QALY threshold in 99.69% of probabilistic sensitivity analyses. Although gene screening strategy was more expensive than a no screening strategy, it was more effective, yielding more QALYs, across all Asian ethnic groups. SIGNIFICANCE: Our analysis confirms the 2007 US Food and Drug Administration recommendation to screen for HLA-B*1502 allele before starting treatment with carbamazepine in patients of Asian ancestry in the United States.

The HLA-B*15:02 polymorphism and Tegretol®-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis.

Tegretol® [carbamazepine (CBZ)], an aromatic drug approved for epilepsy treatment, can induce adverse drug reactions (ADRs) after its administration. Several genetic studies of epilepsy have shown that genetic polymorphisms increase the risk of ADRs, and some interactions between CBZ and other treatments can also induce adverse effects. Thus, to avoid such interactions and to provide an overview of the genetic profiles involved in ADRs with CBZ, for the first time, a systematic review and meta-analysis focusing on epilepsy was performed, using Cochrane Library, Embase and PubMed databases to find studies published between January 1980 and October 2016. Of the eligible studies, those selected were related to the impact of genetic polymorphisms on ADRs in patients receiving antiepileptic treatment. The results of these selected studies are expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), based on data from individual patients. Out of 807 articles, nine were included in the present meta-analysis to assess the association between human leukocyte antigen (HLA)-B*15:02 polymorphisms and CBZ-induced serious cutaneous reactions (SCRs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in epilepsy. It was found that HLA-B*15:02 polymorphisms were significantly associated with CBZ SCR risk (OR: 27.325, 95% CI: 9.933-51.166), while subgroup analyses by ethnicity showed that the association was significant in Han Chinese (OR: 42.059, 95% CI: 9.587-184.514). The HLA-B*15:02 polymorphism was also strongly associated with the CBZ-SJS subgroup (OR: 152.089, 95% CI: 34.737-665.901) and significantly associated with the CBZ-SJS/TEN subgroup (OR: 13.993, 95% CI: 7.291-26.856). Also, the allele was overrepresented in the Han Chinese population (OR: 17.886, 95% CI: 8.411-38.034) within the CBZ-SJS/TEN subgroup. Although the number of studies available in other Asian ethnicities was insufficient for determining publication bias, it nevertheless showed a relationship between the HLA-B*15:02 polymorphism and SCRs. In addition, despite the small number of included studies, the results reveal strong evidence that the HLA-B*15:02 polymorphism can induce SCRs among Asian CBZ users. These findings should prompt physicians to individualize CBZ therapy for patients with epilepsy.