Reappraisal of the importance of mutations in the NS5A-PKR-binding domain of hepatitis C-1b virus in the era of optimally individualized therapy.
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.
Chen
T-M
TM
Division of Hepato-Gastroenterology, Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
Huang
P-T
PT
Wen
C-F
CF
Tung
J-N
JN
Chow
K-C
KC
Chen
Y-P
YP
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D000998:Antiviral Agents / Q000008:administration & dosage*; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C417083:peginterferon alfa-2b