Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy

• Published in: Hepatology (Baltimore, Md.) Vol. 48; no. 1; pp. 38 - 47
• Main Authors: El‐Shamy, Ahmed, Nagano‐Fujii, Motoko, Sasase, Noriko, Imoto, Susumu, Kim, Soo‐Ryang, Hotta, Hak
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2008; Wiley
• Subjects: Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - therapeutic use; Biological and medical sciences; Consensus Sequence; Drug Therapy, Combination; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Variation; Genotype; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis C, Chronic - drug therapy; Humans; Interferon alpha-2; Interferon-alpha - therapeutic use; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Mutation; Pharmacology. Drug treatments; Polyethylene Glycols; Predictive Value of Tests; Recombinant Proteins; Ribavirin - therapeutic use; Treatment Outcome; Viral Nonstructural Proteins - genetics; Drug combination; Prognosis; Cytokine; Protein; Ribavirin; Virus; Gastroenterology; Nucleoside analog; Antiviral; Interferon; Combined treatment; Flaviviridae; Inosine monophosphate dehydrogenase inhibitor; Predictive factor; Hepatitis C virus; Hepacivirus
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.22339

A substantial proportion of hepatitis C virus (HCV)‐1b–infected patients still do not respond to interferon‐based therapy. This study aims to explore a predictive marker for the ultimate virological response of HCV‐1b–infected patients treated with pegylated interferon/ribavirin (PEG‐IFN/RBV) combination therapy. Nonstructural protein 5A (NS5A) sequences of HCV in the pretreated sera of 45 patients infected with HCV‐1b were analyzed. The mean number of mutations in the variable region 3 (V3) plus its upstream flanking region of NS5A (amino acid 2334–2379), referred to as IFN/RBV resistance‐determining region (IRRDR), was significantly higher for HCV isolates obtained from patients who later achieved sustained virological response (SVR) by PEG‐IFN/RBV than for those in patients undergoing non‐SVR. The receiver operating characteristic curve analysis estimated six mutations in IRRDR as the optimal threshold for SVR prediction. Indeed, 16 (76%) of 21 SVR, but only 2 (8%) of 24 non‐SVR, had HCV with six or more mutations in IRRDR (IRRDR ≥ 6) (P < 0.0001). All of 18 patients infected with HCV of IRRDR of 6 or greater examined showed a significant (≥1 log) reduction or disappearance of serum HCV core antigen titers within 24 hours after initial dose of PEG‐IFN/RBV, whereas 10 (37%) of 27 patients with HCV of IRRDR of 5 or less did (P < 0.0001). The positive predictive value of IRRDR of 6 or greater for SVR was 89% (16/18; P = 0.0007), with its negative predictive value for non‐SVR being 81% (22/27; P = 0.0008). Conclusion: A high degree (≥6) of sequence variation in IRRDR would be a useful marker for predicting SVR, whereas a less diverse (≤5) IRRDR sequence predicts non‐SVR. (HEPATOLOGY 2008.)