Abstract
Different highly effective interferon-free treatment options for chronic hepatitis C virus (HCV) infection are currently available. Pre-existence of resistance associated variants (RAVs) to direct antiviral agents (DAAs) reduces sustained virologic response (SVR) rates by 3–53% in hepatitis C virus (HCV) genotype 1 infected patients depending on different predictors and the DAA regimen used. Frequencies of single and combined resistance to NS3, NS5A and NS5B inhibitors and consequences for the applicability of different treatment regimens are unknown. Parallel population based sequencing of HCV NS3, NS5A and NS5B genes in 312 treatment-naïve Caucasian HCV genotype 1 infected patients showed the presence of major resistant variants in 20.5% (NS3), 11.9% (NS5A), and 22.1% (NS5B) with important differences for HCV subtypes. In NS3, Q80K was observed in 34.7% and 2.1% of subtype 1a and 1b patients, respectively while other RAVs to second generation protease inhibitors were detected rarely (1.4%). Within NS5A RAVs were observed in 7.1% of subtype 1a and 17.6% in subtype 1b infected patients. RAVs to non-nucleoside NS5B inhibitors were observed in 3.5% and 44.4% of subtype 1a and 1b patients, respectively. Considering all three DAA targets all subtype 1a and 98.6% of subtype 1b infected patients were wildtype for at least one interferon free DAA regimen currently available. In conclusion, baseline resistance testing allows the selection of at least one RAVs-free treatment option for nearly all patients enabling a potentially cost- and efficacy-optimized treatment of chronic hepatitis C.
Highlights
Detailed characterization of viral proteins with critical functions in the hepatitis C virus (HCV) replication cycle, like the NS3/4A protease, the NS5A protein and the NS5B polymerase together with the invention of a cell culture replication model led to the development of directPLOS ONE | DOI:10.1371/journal.pone.0134395 August 28, 2015Viral Resistance and Optimization of Hepatitis C Therapy
The HCV NS3 protease sequences were analyzed at positions which have previously been reported to be responsible for the emergence of resistance associated variants (RAVs) during treatment with protease inhibitors (PIs)
For the macrocyclic PIs simeprevir, asunaprevir and paritaprevir, which are approved for an interferon-free treatment of chronic hepatitis C, these primary resistance mutations were detected at positions Q80, R155 and D168 [39]
Summary
Detailed characterization of viral proteins with critical functions in the hepatitis C virus (HCV) replication cycle, like the NS3/4A protease, the NS5A protein and the NS5B polymerase together with the invention of a cell culture replication model led to the development of direct. For HCV genotype 1 infected patients combination therapies of a nucleotide NS5B polymerase inhibitor (Sofosbuvir, SOF) with either a NS3 protease inhibitor (Simeprevir, SMV) or a NS5A inhibitor (Daclatasvir, DCV and Ledipasvir, LDV) are available [3,4,5,6,7]. While the NS5B nucleotide analogue Sofosbuvir has a high genetic barrier to resistance and no clinical relevance of pre-existing L159, S282 and V321 variants for IFN-free therapies have been shown so far, for NS3 protease-, NS5A- and non-nucleoside NS5B-inhibitors, RAVs with different levels of resistance to the different available DAAs have been described and found clinically relevant [13,14,15,16,17,18,19,20,21,22,23]. Frequencies of RAVs to currently available NS3, NS5A and NS5B inhibitors have been assessed in 312 Caucasian patients with HCV genotype 1 infection by parallel population-based sequencing for the exploration of the rate of patients with coexistence of RAVs for different dual and triple DAA combination therapies currently available
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