Abstract
BackgroundProtease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. A number of pre-treatment resistance associated amino acid variants (RAVs) and polymorphisms have been associated with reduced response to treatment. ObjectivesWe measured the prevalence of RAVs/polymorphisms in a PI treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing. Study designChronically infected, treatment-naïve, HCV genotype 1 patients (n=146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. The NS3/4A region was amplified by nested polymerase chain reaction. The 1.4kb amplified product was sequenced using an ABI 3710XL DNA sequencer. Sequence analysis was performed using web-based ReCall (beta 2.10). Amino acid positions 36, 41, 43, 54, 55, 80, 109, 122, 155, 156, 168 and 170 were analysed for RAVs/polymorphisms. ResultsOverall, 23.29% (34/146) of patients had an RAV or polymorphism detected. Overall, 13.69% (20/146) of patients had HCV virus that contained the Q8 K polymorphism. Other RAVs detected were: V36 M 0.70% (1/146), V36L 0.70% (1/146), T54S 6.85% (10/146), V55A 3.42% (5/146) and V/I170A 0.68% (1/146). Four patients had dual combinations of mutations (T54S+V36L; T54S+V55A and 2 patients with T54S+Q80K). ConclusionsQ80K was the most prevalent baseline polymorphism detected in the Scottish cohort. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant. This highlights the need for baseline sequencing prior to administration of this drug in this population.
Highlights
Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction
Genotype 1HCV infections have been the hardest to treat with sustained virological response (SVR) rates to the standard of care treatment of ribavirin (RBV) co-administered with pegylated-interferon alpha (IFN) in the region of 42–50% [1,2]
We measured the prevalence of natural resistance polymorphisms in a protease inhibitor treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing
Summary
Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. Study design: Chronically infected, treatment-naïve, HCV genotype 1 patients (n = 146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant This highlights the need for baseline sequencing prior to administration of this drug in this population. The development of non-structural protein 3 (NS3) protease inhibitors (PIs) including telaprevir, boceprevir and simeprevir, has substantially improved outcome in these patients with SVR rates approaching 80% in both treatment-naive patients and relapsers [3,4,5,6]. The combination of simeprevir and the NS5B polymerase inhibitor sofosbuvir increased the SVR to over 90% in genotype 1 patients [7]. Further breakthroughs are expected as other combinations of antivirals become available which promise to offer improvements in SVR, shortened duration of treatment and lower pill burden
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