Clinical Information

Interferon-free, direct antiviral agent (DAA) drug combination therapy is now a standard of care for patients with chronic hepatitis C virus (HCV) infection. However, poor compliance with therapy and the existence of pretreatment antiviral drug resistance may compromise efficacy of such drug therapy. Naturally occurring (preexisting) or treatment-induced mutations in the viral genomic sequences that are targets of such antiviral agents can lead to antiviral resistance and therapeutic failure. Clinical trials and postmarketing studies of DAA therapy indicated that preexisting, resistance-associated substitutions (RAS) in the relevant HCV genomic regions of certain genotypes or emergence of certain RAS during DAA therapy can lead to treatment failure. Per current recommendations from the US Food and Drug Administration (FDA) and professional society practice guidelines (see Table and Clinical Reference section), use of certain FDA-approved DAA drugs for treating chronic HCV due to genotypes 1a, 1b, and 3 (any subtype) requires pretreatment testing for RAS in the relevant HCV genomic regions to guide selection of optimal DAA combination therapy.

Table.

Trade names of DAA:

(a) Mavyret = Glecaprevir + Pibrentasvir

(b) Zepatier = Elbasvir + Grazoprevir

(c) Vosevi = Sofosbuvir + Velpatasvir + Voxilaprevir

(d) Daklinza = Daclatasvir

(e) Harvoni = Ledipasvir + Sofosbuvir

(f) Epclusa = Sofosbuvir + Velpatasvir

(g) Sovaldi = Sofosbuvir

Antiviral drug RAS in the relevant HCV genomic regions can be detected and identified genotypically using either Sanger sequencing or next-generation sequencing (NGS) methods. Amino acid changes deemed as RAS are predicted by the NS3, NS5A, and NS5B sequences of the patient's HCV strain by comparing them to the expected amino acid at relevant codon positions within a wild-type HCV reference sequence. DAA drug resistance may be predicted for each drug based on the relevant RAS present in the HCV sequences found in the patient's serum. Prediction of HCV antiviral drug resistance in this NGS assay is based on a combination of FDA-approved prescribing information for the drug and professional society practice guidelines (see Table and www.hcvguidelines.org/evaluate/resistance).