Title: A biomarker panel to predict, diagnose and prevent HLA-mediated serious adverse drug reactions
Funder: Department of Health (England)

Abstract: Purpose Our overall aim is to develop a HLA biomarker panel comprising 22 separate HLA alleles which can be used to predict, prevent and diagnose serious immune-mediated adverse drug reactions. Background HLA genes are involved in predisposing to immune-mediated adverse drug reactions, and have been associated with autoimmune diseases. Immune-mediated adverse drug reactions account for up to 20% of all adverse drug reactions, but are more severe than non-immune adverse reactions. Since 2000, 22 HLA alleles have been implicated in predisposing to adverse drug reactions. This project aims to commercialise this biomarker panel to allow for a cost-effective method of testing HLA alleles with a rapid turnaround time. Pre-treatment testing for some HLA alleles ( B*57:01, B*15:02 ) is already recommended by drug regulatory agencies. Pre-treatment testing has the potential to prevent many of these adverse reactions. The panel however may also be of use for diagnosis of adverse reactions. Plan of investigation We have identified 22 HLA alleles for which there is good evidence of an association with hypersensitivity reactions – we have been involved in identifying some of these associations. Developed and manufactured by MC Diagnostics for BAG Health Care GmbH, the Histo Spot SSO system is an automated sequence specific oligonucleotide (SSO) assay system, which has been applied to HLA typing. The aim here is to convert this widely used platform to develop multiplex amplification (ideally in a single tube), comprising 22 HLA alleles, the results of which can then be run in an automated SSO system, to produce a high resolution result (in terms of the specific allele targets), but maintain the ability to throughput high numbers of samples (288 tests per instrument per day, based on an 8 hour day or 384 tests per day based on 10 hour working day). We will undertake analytical validation of 22 allele panel using DNA from our archive of 400 healthy volunteers for whom high resolution sequence-based HLA-typing for 5 loci (HLA-A,-B, -C, -DRB1, -DQB1) has already been performed. The primary outcome here will be to determine the sensitivity and specificity of the assay. We will undertake economic analysis in order to: i) determine its value-based price, ii) estimate cost-effectiveness under different scenarios of service configurations for national implementation, iii) identify population sub-groups in which routine testing may be (more) cost-effective, iv) estimate future cost-effectiveness in anticipation that hypersensitivity reactions will be linked to HLA alleles for other drugs. The interpretation software available with the Histo Spot SSO system will be modified to aid the interpretation of the HLA allele results, and made available on the internet as a decision support system. We will work with NHSBT (NHS Blood and Transplant) to evaluate the implementation of this test within their system. This is important as it would provide an avenue for making the test available within the NHS in a cost-effective manner, but also make it available through an implementation process which is already available and has been tested for many different diagnostics including single HLA allele testing (for example HLA-B*57:01 to prevent abacavir hypersensitivity). Milestones Month 9 – completion of the development of multiplex HLA biomarker panel. Month 18 – completion of testing of the analytic validity of the HLA biomarker panel Month 20 – completion of decision support system to aid clinicians in making decisions based on the HLA results Month 22 – completion of cost effectiveness testing Month 24 – write up and publications


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE