Hepatitis C virus drug resistance–associated substitutions: State of the art summary

Abstract

Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

“…RAVs can be detected by population sequencing (detects variants that form up to space 15% of viral population), clonal sequencing (variants up to 5%), or ultradeep pyrosequencing (Next Generation sequencing; picks up variants up to 0.5-1%). 26 …”

“…26,27 Replication fitness refers to relative capacity of a viral variant to replicate in a given environment. 25 Though resistance profiles of currently available DAAs have been identified, there are no established standardized commercial assays for testing for resistance.…”

“…Libraries of RAVs have been accumulated by identifying substitutions observed in variants isolated and sequenced from treated patients who experienced on-or post-treatment virologic failure. 26 Most RAVs are quickly lost in the absence of DAAs and detection of RAVs does not necessarily preclude successful treatment, especially with SOF. 28 Treatment-emergent RAVs induced by NS3-4A protease inhibitors (NS3-4A PIs) have low replication efficiency and disappear over 9 to 18 months; however, NS5A-I treatment-emergent RAVs are persistent, being detected up to 2 years or more after end-of-therapy, and pose a clinical challenge when planning re-treatment with regimens including DCV or LDV.…”

Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by thein silicoapproach

“…However, the general consensus is to recommend a cut-off level of 10 – 20%, for detecting RASs within the HCV quasispecies, in order to be of clinical relevance in predicting the viral failures [7,24]. Thus, the population sequencing method (or the next generation sequencing method set at a cut-off level of 10 – 20%) is thought to be the optimal method.…”

“…Sequences were analyzed for the mutation(s) using the SeqScape Software v2.6 from Applied Biosystems® with the NS5B of HCV GT 1a strain H77 (accession number: AF011751) as a reference. Clinically relevant variants between the residues 310 and 564 were inspected and compared to known clinically relevant NS5B NNI class RASs put forth by the HCV drug development advisory group [7,24]. …”