Reappraisal of the importance of mutations in the NS5A-PKR-binding domain of hepatitis C-1b virus in the era of optimally individualized therapy

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http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2893.2010.01287.x/abstract

Reappraisal of the importance of mutations in the NS5A-PKR-binding domain of

hepatitis C-1b virus in the era of optimally individualized therapy

T.-M. Chen1,2, P.-T. Huang1, C.-F. Wen3, J.-N. Tung3, K.-C. Chow4, Y.-P.

Chen3,4Article first published online: 2 MAR 2010

DOI: 10.1111/j.1365-2893.2010.01287.x

© 2010 Blackwell Publishing Ltd

Issue

Journal of Viral Hepatitis

Volume 18, Issue 2, pages 119–128, February 2011

Summary.  Past studies have reported that mutations in the protein kinase

R-binding domain (PKRBD) sequences of hepatitis C virus (HCV) NS5A proteins are

correlated with response to fixed-duration interferon (IFN)-based therapy in

patients infected with HCV-1b. In this study, we investigated whether the

substitutions in PKRBD, including the IFN sensitivity-determining region (ISDR)

and 26 additional downstream amino acids from ISDR, will have effects upon

patients infected with chronic HCV-1b in the era of individualized therapy with

peginterferon and ribavirin. Thirty-seven patients were treated with optimally

tailored therapy guided by baseline viral load combined with rapid and early

virological responses while 23 patients were treated without guidance and/or

assigned suboptimal treatment duration. The amino acid sequences of the PKRBD

were determined by PCR and sequencing. The overall sustained virological

response (SVR) rate of patients who received optimally individualized therapy

was 78.4%, which was better than the SVR rate of patients who received

suboptimal therapy (47.8%, P = 0.015). Multivariate analysis showed that

optimally individualized therapy (P = 0.019) and 80/80/80 adherence (P = 0.006)

were independent favourable predictors of SVR in the entire cohort. Further

sub-analysis of the predictive factors of SVR in patients treated with optimally

individualized therapy showed that mutations in the 26-amino acid downstream

from the ISDR (P = 0.024) were the only independent predictor of SVR. We

concluded that mutations in 26-amino acid downstream portion from the ISDR

remained a prognosticator of SVR in the era of optimally tailored therapy.