Resistance mechanisms in HCV: from evolution to intervention

References

• WHO. Hepatitis C – global prevalence (update). Wkly Epidemiol. Rec.74(48), 425 (1999).
   PubMedGoogle Scholar
• Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature436(7053), 933–938 (2005).
   PubMed Web of Science ®Google Scholar
• Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science290(5498), 1972–1974 (2000).
   PubMed Web of Science ®Google Scholar
• Lohmann V, Korner F, Koch J et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science285(5424), 110–113 (1999).
   PubMed Web of Science ®Google Scholar
• Zhong J, Gastaminza P, Cheng G et al. Robust hepatitis C virus infection in vitro. Proc. Natl Acad. Sci. USA102(26), 9294–9299 (2005).
   PubMed Web of Science ®Google Scholar
• Lindenbach BD, Evans MJ, Syder AJ et al. Complete replication of hepatitis C virus in cell culture. Science309(5734), 623–626 (2005).
   PubMed Web of Science ®Google Scholar
• Wakita T, Pietschmann T, Kato T et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med.11(7), 791–796 (2005).
   PubMed Web of Science ®Google Scholar
• Drake JW, Charlesworth B, Charlesworth D, Crow JF. Rates of spontaneous mutation. Genetics148(4), 1667–1686 (1998).
   PubMed Web of Science ®Google Scholar
• Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science282(5386), 103–107 (1998).
   PubMed Web of Science ®Google Scholar
• Martell M, Esteban JI, Quer J et al. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J. Virol.66(5), 3225–3229 (1992).
   PubMed Web of Science ®Google Scholar
• Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature439(7074), 344–348 (2006).
   PubMed Web of Science ®Google Scholar
• Domingo E, Gomez J. Quasispecies and its impact on viral hepatitis. Virus Res.127(2), 131–150 (2007).
   PubMed Web of Science ®Google Scholar
• Schvoerer E, Soulier E, Royer C et al. Early evolution of hepatitis C virus (HCV) quasispecies after liver transplant for HCV-related disease. J. Infect. Dis.196(4), 528–536 (2007).
   PubMed Web of Science ®Google Scholar
• Feliu A, Gay E, Garcia-Retortillo M, Saiz JC, Forns X. Evolution of hepatitis C virus quasispecies immediately following liver transplantation. Liver Transpl.10(9), 1131–1139 (2004).
   PubMed Web of Science ®Google Scholar
• Hughes MG Jr, Rudy CK, Chong TW et al. E2 quasispecies specificity of hepatitis C virus association with allografts immediately after liver transplantation. Liver Transpl.10(2), 208–216 (2004).
   PubMed Web of Science ®Google Scholar
• Quer J, Esteban JI, Cos J et al. Effect of bottlenecking on evolution of the nonstructural protein 3 gene of hepatitis C virus during sexually transmitted acute resolving infection. J. Virol.79(24), 15131–15141 (2005).
   PubMed Web of Science ®Google Scholar
• von Hahn T, Yoon JC, Alter H et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology132(2), 667–678 (2007).
   PubMed Web of Science ®Google Scholar
• Laskus T, Wilkinson J, Gallegos-Orozco JF et al. Analysis of hepatitis C virus quasispecies transmission and evolution in patients infected through blood transfusion. Gastroenterology127(3), 764–776 (2004).
   PubMed Web of Science ®Google Scholar
• Ray SC, Wang YM, Laeyendecker O et al. Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy. J. Virol.73(4), 2938–2946 (1999).
   PubMed Web of Science ®Google Scholar
• Mas A, Ulloa E, Bruguera M et al. Hepatitis C virus population analysis of a single-source nosocomial outbreak reveals an inverse correlation between viral load and quasispecies complexity. J. Gen. Virol.85(Pt 12), 3619–3626 (2004).
   PubMed Web of Science ®Google Scholar
• Farci P, Shimoda A, Coiana A et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science288(5464), 339–344 (2000).
   PubMed Web of Science ®Google Scholar
• Fried MW, Shiffman ML, Reddy KR et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med.347(13), 975–982 (2002).
   PubMed Web of Science ®Google Scholar
• Manns MP, McHutchison JG, Gordon SC et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet358(9286), 958–965 (2001).
   PubMed Web of Science ®Google Scholar
• Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature436(7053), 967–972 (2005).
   PubMed Web of Science ®Google Scholar
• Chayama K, Tsubota A, Kobayashi M et al. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology25(3), 745–749 (1997).
   PubMed Web of Science ®Google Scholar
• Pascu M, Martus P, Hohne M et al. Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused on geographical differences. Gut53(9), 1345–1351 (2004).
   PubMed Web of Science ®Google Scholar
• Farci P, Strazzera R, Alter HJ et al. Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome. Proc. Natl Acad. Sci. USA99(5), 3081–3086 (2002).
   PubMed Web of Science ®Google Scholar
• Chambers TJ, Fan X, Droll DA et al. Quasispecies heterogeneity within the E1/E2 region as a pretreatment variable during pegylated interferon therapy of chronic hepatitis C virus infection. J. Virol.79(5), 3071–3083 (2005).
   PubMed Web of Science ®Google Scholar
• Aus dem Siepen M, Oniangue-Ndza C, Wiese M et al. Interferon-α and ribavirin resistance of HuH7 cells transfected with HCV subgenomic replicon. Virus Res.125(1), 109–113 (2007).
   PubMed Web of Science ®Google Scholar
• Cannon NA, Donlin MJ, Fan X, Aurora R, Tavis JE. Hepatitis C virus diversity and evolution in the full open-reading frame during antiviral therapy. PLoS ONE3(5), e2123 (2008).
   PubMed Web of Science ®Google Scholar
• Hofmann WP, Polta A, Herrmann E et al. Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy. Gastroenterology132(3), 921–930 (2007).
   PubMed Web of Science ®Google Scholar
• Lutchman G, Danehower S, Song BC et al. Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy. Gastroenterology132(5), 1757–1766 (2007).
   PubMed Web of Science ®Google Scholar
• Young KC, Lindsay KL, Lee KJ et al. Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology38(4), 869–878 (2003).
   PubMed Web of Science ®Google Scholar
• Arataki K, Kumada H, Toyota K et al. Evolution of hepatitis C virus quasispecies during ribavirin and interferon-α-2b combination therapy and interferon-α-2b monotherapy. Intervirology49(6), 352–361 (2006).
   PubMed Web of Science ®Google Scholar
• Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology132(5), 1979–1998 (2007).
   PubMed Web of Science ®Google Scholar
• Lamarre D, Anderson PC, Bailey M et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature426(6963), 186–189 (2003).
   PubMed Web of Science ®Google Scholar
• Vanwolleghem T, Meuleman P, Libbrecht L et al. Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Gastroenterology133(4), 1144–1155 (2007).
   PubMed Web of Science ®Google Scholar
• Hinrichsen H, Benhamou Y, Wedemeyer H et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology127(5), 1347–1355 (2004).
   PubMed Web of Science ®Google Scholar
• Reesink HW, Zeuzem S, Weegink CJ et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a Phase Ib, placebo-controlled, randomized study. Gastroenterology131(4), 997–1002 (2006).
   PubMed Web of Science ®Google Scholar
• Sarrazin C, Rouzier R, Wagner F et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon α-2b for genotype 1 nonresponders. Gastroenterology132(4), 1270–1278 (2007).
   PubMed Web of Science ®Google Scholar
• Lu L, Pilot-Matias TJ, Stewart KD et al. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob. Agents Chemother.48(6), 2260–2266 (2004).
   PubMed Web of Science ®Google Scholar
• Lin C, Lin K, Luong YP et al.in vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol. Chem.279(17), 17508–17514 (2004).
   PubMed Web of Science ®Google Scholar
• Courcambeck J, Bouzidi M, Perbost R et al. Resistance of hepatitis C virus to NS3–4A protease inhibitors: mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations. Antivir. Ther.11(7), 847–855 (2006).
   PubMed Web of Science ®Google Scholar
• Mo H, Lu L, Pilot-Matias T et al. Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro. Antimicrob. Agents Chemother.49(10), 4305–4314 (2005).
   PubMed Web of Science ®Google Scholar
• Lin C, Gates CA, Rao BG et al.in vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J. Biol. Chem.280(44), 36784–36791 (2005).
   PubMed Web of Science ®Google Scholar
• Seiwert SD, Hong J, Lim SR et al. Sequence variation of NS3/4A in HCV replicons exposed to ITMN-191 concentrations encompassing those likely to be achieved following clinical dosing. Presented at: 42nd Annual Meeting of the European Association for the Study of the Liver. Barcelona, Spain (2007).
   Google Scholar
• He Y, King MS, Kempf DJ et al. Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrob. Agents Chemother.52(3), 1101–1110 (2008).
   PubMed Web of Science ®Google Scholar
• Zhou Y, Muh U, Hanzelka BL et al. Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon α. J. Biol. Chem.282(31), 22619–22628 (2007).
   PubMed Web of Science ®Google Scholar
• Tong X, Chase R, Skelton A et al. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res.70(2), 28–38 (2006).
   PubMed Web of Science ®Google Scholar
• Kieffer TL, Sarrazin C, Miller JS et al. Telaprevir and pegylated interferon-α-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology46(3), 631–639 (2007).
   PubMed Web of Science ®Google Scholar
• Welsch C, Domingues FS, Susser S et al. Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus. Genome Biol.9(1), R16 (2008).
   Web of Science ®Google Scholar
• Sarrazin C, Kieffer TL, Bartels D et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology132(5), 1767–1777 (2007).
   PubMed Web of Science ®Google Scholar
• Tong X, Bogen S, Chase R et al. Characterization of resistance mutations against HCV ketoamide protease inhibitors. Antiviral Res.77(3), 177–185 (2008).
   PubMed Web of Science ®Google Scholar
• Afdhal NH, Godofsky E, Dienstag J et al. Final Phase I/II trial results for NM283, a new polymerase inhibitor for hepatitis C: antiviral efficacy and tolerance in patients with HCV-1 infection, including previous interferon failures. Hepatology40(Suppl. 1), 726A (2004).
   Google Scholar
• De Francesco R, Tomei L, Altamura S, Summa V, Migliaccio G. Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiviral Res.58(1), 1–16 (2003).
   PubMed Web of Science ®Google Scholar
• Migliaccio G, Tomassini JE, Carroll SS et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem.278(49), 49164–49170 (2003).
   PubMed Web of Science ®Google Scholar
• Dutartre H, Bussetta C, Boretto J, Canard B. General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2´-modified nucleotide analogues. Antimicrob. Agents Chemother.50(12), 4161–4169 (2006).
   PubMed Web of Science ®Google Scholar
• Stuyver LJ, McBrayer TR, Tharnish PM et al. Inhibition of hepatitis C replicon RNA synthesis by β-D-2´-deoxy-2´-fluoro-2´-C-methylcytidine: a specific inhibitor of hepatitis C virus replication. Antivir. Chem. Chemother.17(2), 79–87 (2006).
   PubMedGoogle Scholar
• Olsen DB, Carroll SS, Davies M-E et al. Robust suppression of viral replication in HCV infected chimpanzees by a nucleoside polymerase inhibitor. J. Clin. Virol.36(Suppl. 2), S240–S240 (2006).
   Google Scholar
• Roberts S, Cooksley G, Dore G et al. Results of a Phase 1b, multiple dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV genotype 1 patients. Hepatology44(4), 692A (2006).
   Google Scholar
• Le Pogam S, Jiang WR, Leveque V et al.In vitro selected Con1 subgenomic replicons resistant to 2´-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology351(2), 349–359 (2006).
   PubMed Web of Science ®Google Scholar
• Klumpp K, Leveque V, Le Pogam S et al. The novel nucleoside analog R1479 (4´-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture. J. Biol. Chem.281(7), 3793–3799 (2006).
   PubMed Web of Science ®Google Scholar
• Koev G, Kati W. The emerging field of HCV drug resistance. Expert Opin. Investig. Drugs17(3), 303–319 (2008).
   PubMed Web of Science ®Google Scholar
• Lu L, Mo H, Pilot-Matias TJ, Molla A. Evolution of resistant M414T mutants among hepatitis C virus replicon cells treated with polymerase inhibitor A-782759. Antimicrob. Agents Chemother.51(6), 1889–1896 (2007).
   PubMed Web of Science ®Google Scholar
• Nguyen TT, Gates AT, Gutshall LL et al. Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor. Antimicrob. Agents Chemother.47(11), 3525–3530 (2003).
   PubMed Web of Science ®Google Scholar
• Tomei L, Altamura S, Bartholomew L et al. Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides. J. Virol.78(2), 938–946 (2004).
   PubMed Web of Science ®Google Scholar
• Lu L, Dekhtyar T, Masse S et al. Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro. Antiviral Res.76(1), 93–97 (2007).
   PubMed Web of Science ®Google Scholar
• Le Pogam S, Kang H, Harris SF et al. Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus. J. Virol.80(12), 6146–6154 (2006).
   PubMed Web of Science ®Google Scholar
• Chen CM, He Y, Lu L et al. Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Antimicrob. Agents Chemother.51(12), 4290–4296 (2007).
   PubMed Web of Science ®Google Scholar
• Chandra P, Raible D, Harper D et al. Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in patients with chronic hepatitis C virus: preliminary results from a randomized, double-blind, placebo-controlled, ascending multiple dose study. Gastroenterology130(4), A748–A748 (2006).
   Google Scholar
• McCown MF, Rajyaguru S, Le Pogam S et al. The HCV replicon presents a higher barrier to resistance to nucleoside analogs than to non-nucleoside polymerase or protease inhibitors. Antimicrob. Agents Chemother. (2008).
   PubMedGoogle Scholar
• Howe AYM, Ralston R, Chase R et al. Favorable cross-resistance profile of two novel hepatitis C virus inhibitors, SCH 503034 (Boceprevir) and HCV-796, and enhanced anti-replicon activity mediated by the combined use of both compounds. Presented at: 42nd Meeting of the European Association for the Study of Liver Diseases. Barcelona, Spain (2007).
   Google Scholar
• Kukolj G, McGibbon GA, McKercher G et al. Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase. J. Biol. Chem.280(47), 39260–39267 (2005).
   PubMed Web of Science ®Google Scholar
• Howe AY, Cheng H, Thompson I et al. Molecular mechanism of a thumb domain hepatitis C virus nonnucleoside RNA-dependent RNA polymerase inhibitor. Antimicrob. Agents Chemother.50(12), 4103–4113 (2006).
   PubMed Web of Science ®Google Scholar
• Shi ST, Herlihy KJ, Graham JP et al. In vitro resistance study of AG-021541, a novel nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother.52(2), 675–683 (2008).
   PubMed Web of Science ®Google Scholar
• Middleton T, He Y, Pilot-Matias T et al. A replicon-based shuttle vector system for assessing the phenotype of HCV NS5B polymerase genes isolated from patient populations. J. Virol. Methods145(2), 137–145 (2007).
   PubMed Web of Science ®Google Scholar
• Kuiken C, Yusim K, Boykin L, Richardson R. The Los Alamos hepatitis C sequence database. Bioinformatics21(3), 379–384 (2005).
   PubMed Web of Science ®Google Scholar
• Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J. Virol.67(5), 2832–2843 (1993).
   PubMed Web of Science ®Google Scholar
• Cho YG, Moon HS, Sung YC. Construction of hepatitis C–SIN virus recombinants with replicative dependency on hepatitis C virus serine protease activity. J. Virol. Methods65(2), 201–207 (1997).
   PubMed Web of Science ®Google Scholar
• Colson P, Brouk N, Lembo F et al. Natural presence of substitution R155K within hepatitis C virus NS3 protease from a treatment-naive chronically infected patient. Hepatology47(2), 766–767 (2008).
   PubMed Web of Science ®Google Scholar
• Le Pogam S, Seshaadri A, Kosaka A et al. Existence of hepatitis C virus NS5B variants naturally resistant to nucleoside, but not to non-nucleoside, polymerase inhibitors among untreated patients. J. Antimicrob. Chemother.61(6), 1205–1216 (2008).
   PubMed Web of Science ®Google Scholar
• Cubero M, Esteban JI, Otero T et al. Naturally occurring NS3-protease-inhibitor resistant mutant A156T in the liver of an untreated chronic hepatitis C patient. Virology370(2), 237–245 (2008).
   PubMed Web of Science ®Google Scholar
• Franco S, Parera M, Aparicio E, Clotet B, Martinez MA. Genetic and catalytic efficiency structure of an HCV protease quasispecies. Hepatology45(4), 899–910 (2007).
   PubMed Web of Science ®Google Scholar
• Hoffmann C, Minkah N, Leipzig J et al. DNA bar coding and pyrosequencing to identify rare HIV drug resistance mutations. Nucleic Acids Res.35(13), e91 (2007).
   Web of Science ®Google Scholar
• Margulies M, Egholm M, Altman WE et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature437(7057), 376–380 (2005).
   PubMed Web of Science ®Google Scholar
• Wang C, Mitsuya Y, Gharizadeh B, Ronaghi M, Shafer RW. Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance. Genome Res.17(8), 1195–1201 (2007).
   PubMed Web of Science ®Google Scholar
• Paredes R, Lalama C, Ribaudo H et al. Presence of minor populations of Y181C mutants detected by allele-specific PCR and risk of efavirenz failure in treatment-naive patients: results of an ACTG 5095 case–cohort study. Presented at: 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA (2008).
   Google Scholar
• Ray SC, Fanning L, Wang XH et al. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J. Exp. Med.201(11), 1753–1759 (2005).
   PubMed Web of Science ®Google Scholar
• Timm J, Lauer GM, Kavanagh DG et al. CD8 epitope escape and reversion in acute HCV infection. J. Exp. Med.200(12), 1593–1604 (2004).
   PubMed Web of Science ®Google Scholar
• Timm J, Li B, Daniels MG et al. Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. Hepatology46(2), 339–349 (2007).
   PubMed Web of Science ®Google Scholar
• Neumann-Haefelin C, Frick DN, Wang JJ et al. Analysis of the evolutionary forces in an immunodominant CD8 epitope in hepatitis C virus at a population level. J. Virol.82(7), 3438–3451 (2008).
   PubMed Web of Science ®Google Scholar
• Gaudieri S, Rauch A, Park LP et al. Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection. J. Virol.80(22), 11094–11104 (2006).
   PubMed Web of Science ®Google Scholar
• Yi M, Tong X, Skelton A et al. Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations. J. Biol. Chem.281(12), 8205–8215 (2006).
   PubMed Web of Science ®Google Scholar
• Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon α-2a (40 kd)/ribavirin therapy. Hepatology43(5), 954–960 (2006).
   PubMed Web of Science ®Google Scholar