Cost-effectiveness analysis of HLA-B*13:01 screening for the prevention of co-trimoxazole-induced severe cutaneous adverse reactions among HIV-infected patients in Thailand.

Studies found a strong association between HLA-B*13:01 allele and co-trimoxazole-induced severe cutaneous adverse reactions (SCARs). Genetic screening before initiation of co-trimoxazole may decrease the incidence of co-trimoxazole-induced SCARs. This study aims to evaluate the cost-effectiveness of HLA-B*13:01 screening before co-trimoxazole initiation in HIV-infected patients in Thailand. A combination of a decision tree model and a Markov model was used to estimate lifetime costs and outcomes of two strategies including 1) HLA-B*13:01 screening before co-trimoxazole initiation and 2) usual practice from a societal perspective. Alternative drugs are not considered because dapsone (the second-line drug) also presents a genetic risk. Input parameters were obtained from literature, government documents, and part of the TREAT Asia HIV Observational Database (TAHOD). One-way sensitivity analyses and probabilistic analyses were performed to determine robustness of the findings. HLA-B*13:01 screening resulted in 0.0061 quality-adjusted life years (QALYs) loss with an additional cost of 370 THB ($11.84). At the cost-effectiveness threshold of 160,000 THB ($5,112.85), the probability of the genetic screening strategy being cost-effective is 9.54%. This analysis demonstrated that HLA-B*13:01 allele screening before initiation of co-trimoxazole among HIV-infected patients is unlikely to be cost-effective in Thailand. Our findings will help policymakers make an evidence-informed decision making.

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.

A lifetime economic research of universal HLA-B*58:01 genotyping or febuxostat initiation therapy in Chinese gout patients with mild to moderate chronic kidney disease.

OBJECTIVE: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system. METHODS: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed. RESULTS: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results. CONCLUSION: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.

A low-cost, sensitive and specific PCR-based tool for rapid clinical detection of HLA-B*35 alleles associated with delayed drug hypersensitivity reactions.

HLA (HLA) alleles are risk factors for CD8+ T-cell-mediated drug hypersensitivity reactions. However, as most HLA associations are incompletely predictive and/or involve risk alleles at low frequency, costly sequence-based typing can elude an economically productive cost: benefit ratio for clinical validation studies and diagnostic and/or preventative screening. Hence rapid and low-cost detection assays are now required, both for single alleles but also across risk loci associated with broader multi-disease risk; exemplified by associations with diverse alleles in HLA-B*35, including HLA-B*35:01 and green tea- or co-trimoxazole-induced liver injury. Here, we developed a cost-effective (<$10USD) qPCR assay for rapid (<2.5 h) clinical detection of HLA-B*35 alleles. The assay was validated using 430 DNA samples with previous American society for histocompatibility and immunogenetics-accredited sequence-based high-resolution HLA typing, positively detecting all HLA-B*35 allelic variants in our cohort, and as expected by primer design, the six samples that expressed low-frequency B*78:01. The assay did not result in positive detection for any negative control allele. With expected detection of B*35 and B*78, our assay sensitivity (95% CI, 95.07%-100.00%) and specificity (95% CI, 98.97%-100.00%) of 100% using as low as 10 ng of DNA provides a reliable HLA-B*35 screening tool for clinical validation and HLA-risk-based prevention and diagnostics.

Assessment of HLA-B genetic variation with an HLA-B leader tool and implications in clinical transplantation.

Sequence variation in the HLA-B gene is critically linked to differential immune responses. A dimorphism at -21 of HLA-B exon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease, relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-B leader, an HLA-BLeader Assessment Tool (BLEAT) was developed to automate the assignment of leader genotypes, define HLA-B leader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9 417 614 registered donors from the Be The Match Registry with HLA-B typing. Among these donors, the performance of BLEAT was assessed in 1 098 358 donors with sequence data for HLA-B exon 1 (2 196 716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-B leader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

Low Hydrophobic Mismatch Scores Calculated for HLA-A/B/DR/DQ Loci Improve Kidney Allograft Survival.

We evaluated the impact of human leukocyte antigen (HLA) disparity (immunogenicity; IM) on long-term kidney allograft survival. The IM was quantified based on physicochemical properties of the polymorphic linear donor/recipient HLA amino acids (the Cambridge algorithm) as a hydrophobic, electrostatic, amino acid mismatch scores (HMS\AMS\EMS) or eplet mismatch (EpMM) load. High-resolution HLA-A/B/DRB1/DQB1 types were imputed to calculate HMS for primary/re-transplant recipients of deceased donor transplants. The multiple Cox regression showed the association of HMS with graft survival and other confounders. The HMS integer 0-10 scale showed the most survival benefit between HMS 0 and 3. The Kaplan-Meier analysis showed that: the HMS=0 group had 18.1-year median graft survival, a 5-year benefit over HMS>0 group; HMS ≤ 3.0 had 16.7-year graft survival, a 3.8-year better than HMS>3.0 group; and, HMS ≤ 7.8 had 14.3-year grafts survival, a 1.8-year improvement over HMS>7.8 group. Stratification based on EMS, AMS or EpMM produced similar results. Additionally, the importance of HLA-DR with/without -DQ IM for graft survival was shown. In our simulation of 1,000 random donor/recipient pairs, 75% with HMS>3.0 were re-matched into HMS ≤ 3.0 and the remaining 25% into HMS≥7.8: after re-matching, the 13.5 years graft survival would increase to 16.3 years. This approach matches donors to recipients with low/medium IM donors thus preventing transplants with high IM donors.

Impact of HLA polymorphisms among cadaveric donors on kidney graft allocation.

This study provides data on HLA-A, -B, and -DRB1 frequencies among 861 end-stage renal disease (ESRD) patients from Croatia and estimates the benefit of the kidney exchange program by comparing HLA distribution and assessing HLA mismatches (MMs) within a group of ESRD patients who received kidney grafts from 707 cadaveric donors (422 from Croatia and 285 from Eurotransplant). Patients positive for HLA-B*07, -B*08, or -B*44 genes more often received a kidney from ET donors, while HLA-DRB1*11 and -DRB1*16 positive patients more frequently received a kidney from CRO donors. ABDR MM 000 was more frequently present in the case of transplantation from ET donors, while MM 222 was significantly more frequent when the donor was from Croatia. Sensitized patients received kidney more frequently from ET donors (P < .0001). A large pool of organ donors with different HLA gene distributions allows for a higher probability of transplantation from HLA highly matched donor.

Cost-effectiveness of sequential urate lowering therapies for the management of gout in Singapore.

Aims: Allopurinol is the most common urate lowering therapy (ULT) used to treat gout but may cause life-threatening severe cutaneous adverse reactions (SCAR) in a small number of patients. Risk of SCAR is increased for patients with the HLA-B*58:01 genotype. When alternative ULT is required, febuxostat or probenecid are recommended. The aim of this study was to conduct a cost-utility analysis of sequential ULT treatment strategies for gout, including strategies with and without HLA-B*58:01 genotyping prior to treatment initiation, with a view to inform optimal gout management in Singapore.Materials and methods: A Markov model was developed from the Singapore healthcare payer perspective. Reflecting local practice, 12 different treatment strategies containing at least one ULT (allopurinol, febuxostat, probenecid) were evaluated in adults with gout. Response rates (SUA < 6mg/dL) were derived from an in-house network meta-analysis and from published literature. Incremental cost-effectiveness ratios (ICERs) were calculated over a 30-year time horizon, with costs and benefits discounted at 3% per annum. Sensitivity analyses were conducted to explore uncertainties.Results: Sequential treatment of allopurinol 300 mg/day-allopurinol 600 mg/day-probenecid ("standard of care") was cost-effective compared to no ULT, with an ICER of SGD1,584/QALY. Allopurinol300-allopurinol600-probenecid-febuxostat sequence compared to allopurinol300-allopurinol600-probenecid had an ICER of SGD11,400/QALY. All other treatment strategies were dominated by preceding strategies. Treatment strategies incorporating HLA-B*58:01 genotyping before ULT use were dominated by the corresponding non-genotyping strategy.Conclusions: Current standard of care (allopurinol300-allopurinol 600-probenecid) for gout is cost-effective compared with no ULT in the local context. Febuxostat is unlikely to be cost-effective in Singapore at current prices unless it is used last-line.

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.

Utility evaluation of HLA-B*13:01 screening in preventing trichloroethylene-induced hypersensitivity syndrome in a prospective cohort study.

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.

Assessment by Extended-Coverage Next-Generation Sequencing Typing of DPA1 and DPB1 Mismatches in Siblings Matching at HLA-A, -B, -C, -DRB1, and -DQ Loci.

Allogeneic hematopoietic stem cell transplant from an HLA matched sibling donor is usually the preferable choice. The use of next-generation sequencing (NGS) for HLA typing in clinical practice provides broader coverage and higher resolution of HLA genes. We evaluated the frequency of DPB1 crossing-over events among patients and potential related donors typed with NGS. From July 2016 to January 2018, 593 patients and 2385 siblings were typed. We evaluated sibling matching status in 546 patients, and 44.8% of these patients had siblings that matched at HLA-A, -B, -C, -DRB1, and -DQB1 loci. In 306 patient-HLA matched sibling pairs, we found 6 pairs (1.96%) with 1 DPB1 mismatch, and 5 of these pairs included an additional mismatch in DPA1. No additional mismatches were observed at the low expression loci. Using the T cell epitope algorithm, 4 of these DP mismatches were classified as permissive, 1 as nonpermissive in the host-versus-graft direction, and 1 as nonpermissive in the graft-versus-host direction. The frequency of DPB1 and DPA1 mismatches is low, and their impact in related donor transplants is not well established. Although DP typing in related transplants goes beyond guidelines, it is especially relevant for sensitized patients. NGS-based HLA typing provides full gene coverage, and its use in clinical practice can enable better donor selection.

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

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 genotype-guided 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 genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

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

The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multigene panel, including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T), and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of £378 (US $491), and a quality-adjusted life year gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01), and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)), but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels.

Epigallocatechin-3 Gallate Inhibits STAT-1/JAK2/IRF-1/HLA-DR/HLA-B and Reduces CD8 MKG2D Lymphocytes of Alopecia Areata Patients.

BACKGROUND: Alopecia areata (AA) is associated with Interferon- γ (IFN-γ) mediated T-lymphocyte dysfunction and increased circulating Interleukine-17 (IL-17) levels. Epigallocatechin-3-gallate (EGCG) specifically inhibits IFN-γ pathways and unlike Janus Kinase 1 and 2 (JAK1/JAK2) inhibitors (tofacitinib, ruxolitinib), EGCG is safer, more cost-effective, and is a topically active agent. Our objective is to test the mode of action of EGCG in vitro and ex vivo using HaCat, Jurkat cell lines, and peripheral blood mononuclear cells (PBMCs) of AA patients and healthy controls (HCs), respectively. METHODS: distribution of T helper cells (Th1, Th17), and cytotoxic cells (CD8) in PBMCs isolated from 30 AA patients and 30 HCs was investigated by flowcytomterty. In vitro treatment of HaCat and Jurkat cells with 40 µm EGCG for 48 h was performed to measure the level of phosphorylation of signal transducer and activator of transcription protein STAT1, and replicated in ex vivo model using PBMCs of AA patients. RESULTS: Interestingly, 40 µm EGCG is capable of completely inhibiting phosphorylation of STAT1 after 48 h in HaCat and Jurkat cells and ex vivo in PBMCs of AA patients. Based on QPCR data, the action of EGCG on p-STAT1 seems to be mediated via downregulation of the expression of JAK2 but not JAK1 leading to the inhibition of human leukocyte antigens (HLA-DR and HLA-B) expression probably via IRF-1. On the other hand, AA patients have significantly increased levels of Th1, Th17, and CD8 cells and the production of IFN-γ and IL-17 by PBMCs in AA patients was significantly higher compared to HC; p = 0.008 and p = 0.006, respectively. Total numbers of CD8+ cells were not significantly different between treated and untreated samples. However, CD8+ cells with positive Natural killer group 2 member D (NKG2D) transmembrane receptor (CD8+ NKG2D+ subset) was significantly reduced when PBMCs were treated with 20 µm EGCG for 48 h. CONCLUSION: These results suggest that EGCG has a synergistic action that inhibits expression of HLA-DR and HLA-B molecules via the IFN-γ pathway to maintain immune privilege in HF; also it reduces CD8+ NKG2D+ subset.

A retrospective investigation of HLA-B*5801 in hyperuricemia patients in a Han population of China.

BACKGROUND: Hyperuricemia and gout have become increasingly prevalent in China. Allopurinol is an effective urate-lowering therapy, but it has severe side effects. HLA-B*5801 is highly associated with the allopurinol-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. PATIENTS AND METHODS: In this retrospective report, we had genotyped HLA-B*5801 in 253 cases of hyperuricemia and gout patients in a Han population in Shenzhen and analyzed the clinical management of medications. RESULTS: We found 30 carriers of the HLA-B*5801 allele in 253 cases of hyperuricemia or gout patients in the population (11.9%). Allopurinol was prescribed in both HLA-B*5801-positive and HLA-B*5801-negative groups. The evaluation of four models with or without genetic screening and management of allopurinol or febuxostat indicated that the HLA-B*5801 screening had significant cost benefit for clinical management. CONCLUSION: For appropriate management and cost-effectiveness, the HLA-B*5801 allele should be screened in all patients with hyperuricemia and gout in the Chinese population.