Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy.
Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Julia
J
Dietz
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
Daniel
D
Rupp
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Simone
S
Susser
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Johannes
J
Vermehren
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Kai-Henrik
KH
Peiffer
Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany.
Natalie
N
Filmann
Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany.
Dimitra
D
Bon
Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Switzerland.
Thomas
T
Kuntzen
Zentrum für HIV und Hepatogastroenterologie, Düsseldorf, Germany.
Stefan
S
Mauss
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Georgios
G
Grammatikos
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Dany
D
Perner
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Caterina
C
Berkowski
Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany.
Eva
E
Herrmann
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Stefan
S
Zeuzem
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.|German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
Ralf
R
Bartenschlager
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
Christoph
C
Sarrazin
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases