Elsevier

Virology

Volume 443, Issue 2, 1 September 2013, Pages 278-284
Virology

Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: A population and clonal analysis

https://doi.org/10.1016/j.virol.2013.05.013Get rights and content
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Highlights

  • Vaniprevir plus P/R is efficacious in patients with hepatitis CHCV-genotype 1 infection.

  • We detected RAVs in 2 patients before any exposure to protease inhibitors.

  • At the time of virologic failure, RAVs were detectable in all patients tested.

  • Double/triple RAVs were selected in patients remaining viremic on therapy.

Abstract

Background

Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy.

Methods

Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia.

Results

Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing.

Conclusions

RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.

Abbreviations

DAA
directly acting antiviral agent
HCV
hepatitis C virus
IC50
inhibitory concentration 50%
IU/mL
international units per milliliter
LLD
lower limit of detection
LLQ
lower limit of quantification
P/R
peginterferon alfa/ribavirin
SVR
sustained virologic response

Keywords

Vaniprevir
Hepatitis C-genotype 1
Resistance-associated variants

Cited by (0)

The parent study and the current analysis were sponsored and funded by Merck.