Asians who carry the HLA-B*1502 allele have an elevated risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when treated with the antiepileptic drugs (AEDs) carbamazepine (CBZ) and phenytoin (PHT). With a focus on Singapore, this analysis identifies circumstances in which genotyping and targeted treatment with alternative AEDs that do not induce SJS/TEN is likely to be more cost-effective than 1) treatment with CBZ or PHT without genotyping or 2) providing a more expensive drug that does not induce SJS/TEN to all patients without genotyping.
A decision tree model was developed in TreeAge. The model takes into account costs of epilepsy treatments and genotyping, reductions in quality of life and increased costs resulting from SJS/TEN complications, the prevalence of the risk allele, the positive predictive value (PPV) of genotyping, life expectancy, and other factors.
Compared with no genotyping and providing CBZ to all, genotyping results in an incremental cost-effectiveness ratio of $37,030/quality-adjusted life year (QALY) for Chinese patients, $7,930/QALY for Malays, and $136,630/QALY for Indians in Singapore.
Because of the different population allele frequencies of HLA-B*1502 among different ethnic groups, genotyping for HLA-B*1502 and providing alternate AEDs to those who test positive is cost-effective for Singaporean Chinese and Malays, but not for Singaporean Indians. Population frequency of HLA-B*1502, PPV, duration of treatment relative to life expectancy, and costs of alternative drugs are the key drivers influencing cost-effectiveness.
"In Singapore, the tests are subsidized only up to 25% for government-subsidized (public) patients; private full-paying patients pay for the test in full. A cost-effectiveness study using a decision tree model  suggested that genotyping for HLA-B*1502 and providing alternate anti-epileptic drugs to those who test positive is cost-effective for Singaporean Chinese and Malays, but not for Singaporean Indians. However, the limitations of the study  included both PHT and CBZ being used interchangeably in the model rather than CBZ alone, and the costs of long-term sequelae, especially ocular sequelae not being considered in the model. "
[Show abstract][Hide abstract] ABSTRACT: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions (SCAR) to drugs which are associated with significant morbidity and mortality. High risk drugs in Asia are similar to those reported worldwide. Human leukocyte antigen (HLA)-related risk alleles for carbamazepine and allopurinol SCAR are unique to Asians. Although prognostic scoring systems like the SCORTEN have been used for more than a decade, pitfalls and caveats need to be recognized, in particular in patients with multiple medical co-morbidities and systemic features in SJS/TEN. In centres without a tertiary Burns Centre, SJS/TEN patients can still be managed successfully in general and dermatology wards with well-executed supportive/nursing care. Controversy remains regarding the effectiveness of immunomodulation in reducing SJS/TEN morbidity, mortality and hastening re-epithelialization. Despite paucity of robust evidence, intravenous immunoglobulins and ciclosporin remain the most commonly used modalities worldwide. Acute and long-term ocular effects are an important source of morbidity for which emerging ophthalmic therapies appear promising. Quality of life issues have now become an important outcome in patients with SJS/TEN as they often impact survivors' future attitudes towards pharmacotherapy. Even though pharmacogenetic testing for high-risk drugs appears to be the panacea for preventing carbamazepine- and allopurinol-induced SJS/TEN in ethnic Asians, many issues remain before health regulators in our region can conclusively determine whether testing should be made mandatory or highly recommended as standard of care.
[Show abstract][Hide abstract] ABSTRACT: Background
Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01.
To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population.
A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01.
The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results. Conclusions: High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs.
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