Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine

Abstract

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotypeguided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotypeguided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Associations of HLA genotypes with antithyroid drug‐induced agranulocytosis: A systematic review and meta‐analysis of pharmacogenomics studies

“…Pharmacogenomics‐guided treatment may be an alternative strategy to prevent ATD‐induced agranulocytosis. For clozapine‐induced agranulocytosis, HLA genotyping prior to clozapine initiation appeared cost‐effective for targeted blood monitoring only in patients with HLA susceptibility alleles . However, whether pharmacogenomics‐guided treatment is cost‐effective needs further investigations.…”

Clozapine Pharmacogenetic Studies in Schizophrenia: Efficacy and Agranulocytosis

“…The sensitivity and specificity of the HLA-DQB1 6672G.>C polymorphism for CIA in patients treated with clozapine, identified though candidate approach, was 21.5 and 98.4%, respectively (Athanasiou et al, 2011 ). The sensitivity and specificity of the HLA-B * 59:01 for CIA, identified by GWAS, was 31.8 and 95.3%, respectively (Saito et al, 2016 ) and the sensitivity and specificity of HLA-B 158T and HLA-DQB1 126Q polymorphisms for CIA, identified by GWAS and whole-exome sequencing (Goldstein et al, 2014 ), was 41 and 85%, respectively (Girardin et al, 2018 ). Clinical application guidelines require HLA allele testing for CIA to have a sensitivity of ~50% (Girardin et al, 2018 ), therefore none of these have reached an acceptable threshold for clinical application.…”

“…The sensitivity and specificity of the HLA-B * 59:01 for CIA, identified by GWAS, was 31.8 and 95.3%, respectively (Saito et al, 2016 ) and the sensitivity and specificity of HLA-B 158T and HLA-DQB1 126Q polymorphisms for CIA, identified by GWAS and whole-exome sequencing (Goldstein et al, 2014 ), was 41 and 85%, respectively (Girardin et al, 2018 ). Clinical application guidelines require HLA allele testing for CIA to have a sensitivity of ~50% (Girardin et al, 2018 ), therefore none of these have reached an acceptable threshold for clinical application. Conversely, we examined the diagnostic performance of non-risk allele (alleles except for HLA-B * 59:01 ) on non-CIA among CIG patients and demonstrated a moderate, positive predictive value for detecting non-CIA subjects in the CIG group without the risk allele, suggesting a potential candidate for re-challenging with clozapine treatment in a Japanese population (Saito et al, 2016 ).…”

Cost‐Effectiveness of Panel Tests for Multiple Pharmacogenes Associated With Adverse Drug Reactions: An Evaluation Framework

“…These are illustrated with a more comprehensive HLA gene panel for preventing ADRs. Additional cost‐utility analyses for HLA‐B*15:02 , HLA‐B*57:01 , HLA‐B (158T) , and HLA‐DQB1 (126Q) were identified from a purposive search of the literature. In this illustrative example, we relaxed assumptions of cost perspective and healthcare setting.…”