Abstract
The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The rapid emergence of resistance-associated substitutions (RASs), in particular in the context of incomplete drug pressure, has an impact on sustained virological response (SVR) rates. Several RASs in NS3, NS5A and NS5B have been linked with reduced susceptibility to DAAs. RAS vary based on HCV characteristics and the different drug classes. DAA-resistant HCV variant haplotypes (RVs) are dominant in cases of virological failure. Viruses with resistance to NS3-4A protease inhibitors are only detected in the peripheral blood in a time frame ranging from weeks to months following completion of treatment, whereas NS5A inhibitor-resistant viruses may persist for years. Novel agents have been developed that demonstrate promising results in DAA-experienced patients. The recent approval of broad-spectrum drug combinations with a high genetic barrier to resistance and antiviral potency may overcome the problem of resistance.
Highlights
Basic Conceptshepatitis C virus (HCV) has an estimated half-life that ranges from 2 to 5 h with a high turnover rate
Several direct-acting antiviral (DAA)-based regimens are available for the treatment of chronic HCV infection
Some patients demonstrate treatment failure which has been linked to the detection of resistance-associated substitutions (RASs) at baseline
Summary
HCV has an estimated half-life that ranges from 2 to 5 h with a high turnover rate. 1010–1012 virions are produced and excreted daily in an infected patient. All functional indices that are based on genetic distances assume that genomes that are far apart in sequence space are more likely to have functional differences compared to sequences that are close together This assumption is not fully accepted for viral quasispecies since single mutations in genomes can influence pivotal functional aspects such as resistance against the immune system or antiviral agents [4]. Diversity contraction may result from the emergence of a new haplotype that shares increased fitness compared to the existing mutants, leading eventually to an increase in the viral load accompanied by a temporary reduction in complexity. In the HCV studies, it was crucial to exclude the inhibitory mutations that were not acquired through fitness gain This was made possible by NGS, the multiplicity of infection (MOI)-independent kinetics of virus production in the presence of inhibitors and the maintenance of the resistance phenotype in biological clones of the passaged populations [9]. The long-term replication of the virus in a patient with HCV infection can promote viral fitness to the detriment of treatment efficacy, as observed in clinical practice
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