Abstract
Numerous genetic polymorphisms have been identified as associated with disease or treatment outcome, but the routine implementation of genotyping into actionable medical care remains limited. Point-of-care (PoC) technologies enable rapid and real-time treatment decisions, with great potential for extending molecular diagnostic approaches to settings with limited medical infrastructure (e.g., CLIA certified diagnostic laboratories). With respect to resource-limited settings, there is a need for simple devices to implement biomarker guided treatment strategies. One relevant example is chronic hepatitis C infection, for which several treatment options are now approved. Single nucleotide polymorphisms (SNPs) in the IL-28B / IFNL3 locus have been well described to predict both spontaneous clearance and response to interferon based therapies. We utilized the Genedrive® platform to develop an assay for the SNP rs12979860 variants (CC, CT and TT). The assay utilizes a hybrid thermal engine, permitting rapid heating and cooling, enabling an amplification based assay with genetic variants reported using endpoint differential melting cure analysis in less than 60 minutes. We validated this assay using non-invasive buccal swab sampling in a prospective study of 246 chronic HCV patients, achieving 100% sensitivity and 100% specificity (95% exact CI: 98.8–100%)) in 50 minutes as compared to conventional lab based PCR testing. Our results provide proof of concept that precision medicine is feasible in resource-limited settings, offering the first CE-IVD (in vitro diagnostics) validated PoC SNP test. We propose that IL-28B genotyping may be useful for directing patients towards lower cost therapies, and rationing use of costly direct antivirals for use in those individuals showing genetic risk.
Highlights
The sequencing of the human genome followed by the subsequent revolution in sequencing technologies heralded an ambition for precision medicine [1]
For patients with hepatitis C virus (HCV), the major clinical question concerns the mode of treatment, with the recent introduction of several direct acting antivirals (DAAs)[6]
Genetic factors have been identified as predictors of response to treatment, in particular polymorphisms of the IL28B gene [8],[9]
Summary
The sequencing of the human genome followed by the subsequent revolution in sequencing technologies heralded an ambition for precision medicine [1]. One challenge has been the implementation of molecular based diagnostics into routine clinical use, with even greater hurdles for resource-limited settings. Point-of-care (PoC) technologies enable rapid and real-time treatment decisions, with potential for extending molecular diagnostic approaches to settings with limited medical infrastructure such as a CLIA (Clinical Laboratory Improvement Amendments) certified diagnostic laboratories or decentralized laboratory settings [4]. The use of diagnostic predictive tests remains relevant for the selection of a suitable treatment plan for each patient, with particular relevance for persons in resource-limited settings. The CC genotype has been demonstrated to predict better virological response rates to interferon based therapies [10], with its utility for DAAs remaining to be defined. Genotyping is currently performed using classical PCR amplification applied to DNA extracted from blood or plasma, with a time to result of 2–3 weeks, limiting its clinical implementation
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