The Public Health England Hepatitis C Virus Resistance Group provided a consensus review with recommendations on when and how to perform hepatitis C virus (HCV) resistance testing, and how the results should be interpreted, in an article published in the Journal of Infection.

The review panel analyzed data from in vitro studies, phase 2 and phase 3 clinical trials, and real-world studies to provide clinicians with recommendations on treating patients when HCV resistance is a possibility. This panel of experts provided 5 key scenarios as to when they recommend HCV resistance testing should be performed. Currently, HCV infections are treated with highly effective direct acting antiviral therapies, although these drugs do not work against resistant forms of the virus. New second-generation direct acting antiviral therapies may exert activity on resistant viral genotypes, but resistance testing could still enhance treatment decisions.

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There are 2 types of resistance tests that predict resistance based on either the viral genotype or phenotype. Genotypic antiviral resistance testing can be completed in a diagnostic laboratory and detects known drug resistant virus genomes by comparing the sample against a database of known mutations. Phenotypic antiviral resistance testing can only be completed in a research laboratory and directly measures virus resistance by cloning a culture and testing it with concentrated antiviral medication to assess changes. The panel recommended testing resistance by using a genotypic testing method of either the Sanger sequencing or next-generation sequencing methods.

Resistance testing can be performed on either a treatment-naive patient or before a patient tries re-treatment of a direct acting antiviral medication. If re-treatment is necessary, the testing should be done as close to the start date as possible. The possibilities of reinfection or mixed infections need to be assessed at the time of resistance testing and before re-treatment.

Future treatment plans should take into account not only the results of the antiviral resistance testing but also patients’ characteristics, prior treatment history, proposed direct acting antiviral, and concomitant medications. Treatment plans also need to take into consideration the time necessary to complete the resistance test. If the patient is difficult to engage — meaning they have difficulties completing follow-up appointments —  then perhaps resistance testing is not the best first step, and initiating a potent direct acting antiviral medication is the best course of action.

Limitations of this review include using data from a registry that is only in the preliminary form and the fact that these recommendations differ from the European Association of the Study of the Liver and the American Association for the Study of Liver Diseases – Infectious Diseases Society of America.

The panel listed 5 scenarios where they recommend resistance testing before initiating direct acting antiviral therapy. These are as follows: (1) patients who are treatment-naive or those previously exposed to pegylated interferon-ribavirin prior to elbasvir/grazoprevir therapy; (2) patients with compensated cirrhosis prior to sofosbuvir/velpatasvir therapy; (3) patients with decompensated cirrhosis prior to any direct acting antiviral therapy; (4) patients with subtypes not commonly found in high-income countries; and (5) patients with previous exposure to NS3 and/or NS5A inhibitors. 

Reference

Bradshaw D, Mbisa JL, Geretti AM, et al. Public Health England HCV Resistance Group: overview and consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection [published online October 16, 2019]. J Infect. doi: 10.1016/j.jinf.2019.10.007