In hepatitis C virus (HCV), sofosbuvir (SOF) displays potent antiviral activity across a diverse range of HCV clinical isolates belonging to 6 genotypes, according to study results published in Antiviral Research.

SOF is a direct-acting antiviral agent in HCV treatment that targets NS5B polymerase and has a high barrier to resistance and antiviral activity across all genotypes. The objective of this study was to evaluate SOF susceptibility of HCV genotypes 1 to 6 in untreated patients and to evaluate SOF susceptibility in NS5B nucleoside/nucleotide inhibitor (NI) mutants.

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In this study, researchers used 3 NS5B replicon vectors in a transient transfection susceptibility assay to evaluate SOF susceptibility of HCV in genotypes 1 to 6. The NS5B NI mutants evaluated in this study were selected based on NS5B polymorphisms that emerged during in vitro SOF selection studies. They also included patients who received NI treatments in other clinical studies. The samples tested were collected at baseline from direct-acting antiviral treatment-naïve patients enrolled in a number of sponsored studies.


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To characterize patient isolates, researchers added restriction sites to existing NS5B replicon vectors. A subtype 1b vector was used for patient samples of all genotypes with the exception of 4 and 6, for which subtypes 4a or 6a were used, respectively. SOF susceptibility to chimeric replicons carrying full-length NS5B coding region was assessed in 479 treatment-naïve patients with HCV, including 15 subtypes in genotypes 1 to 6. Researchers also evaluated SOF susceptibility in 331 replicons with engineered NS5B NI resistance-associated substitutions (RAS). RAS substitutions were defined as any substitution conferring >2.5-fold reduced susceptibility to any NS5B NI in vitro in one or more HCV genotypes, or that emerged in patients who failed SOF-based therapies.

Results revealed that HCV replicons containing S282T had low levels of resistance to SOF. SOF 50% effective concentration (EC₅₀) values (mean±SD) ranged from 32±9.0 nM for subtype 2a (n=15) to 130±29 nM for genotype 4. Low to moderate variation in SOF susceptibility within genotype was observed with differences between the 95th and 5th percentiles ranging between 1.6-fold and 6.5-fold. The 95th percentile for any genotype was never higher than 189 nM. The levels of resistance to SOF in S282T replicons were between 2.4- (subtype 2a) and 18-fold (subtype 5a) change in EC₅₀, and there were no other RAS that conferred greater than a 2.3-fold reduction in SOF susceptibility in any subtype.

The study researchers concluded that of the 160 NS5B substitutions evaluated, S282T is the only known RAS that confers resistance to SOF in vitro, and that SOF displays potent antiviral activity across a wide range of NS5B mutants and HCV clinical isolates belonging to genotypes 1 to 6.

Disclosure: This clinical trial was supported by Gilead Sciences. Please see the original reference for a full list of authors’ disclosures.

Reference

Han B, Martin R, Xu S, et al. Sofosbuvir susceptibility of genotype 1 to 6 HCV from DAA-naïve subjects [published online August 5, 2019]. Antiviral Res. doi: 10.1016/j.antiviral.2019.104574