New antiviral therapies for chronic hepatitis C
Tóm tắt
Chronic hepatitis C is an important health issue worldwide. The current standard therapy is based on a combination of pegylated-interferon (pegIFN) and ribavirin (RBV), but this treatment leads to only ~50% sustained virological response (SVR) in patients with HCV genotype 1 and high viral loads, who were mostly null-responders or relapsers. Among HCV genotypes other than HCV genotype 1, especially HCV genotype 4 patients show only 40–70% SVR by this treatment. Although new drugs also depend on the combination of pegIFN and RBV, it appears that these drugs improve not only rapid virological response (RVR) but also early virological response, leading to SVR in these patients. In the near future, we predict higher SVR rates in chronic hepatitis C patients treated with these new drugs.
Tài liệu tham khảo
Thomas DL, Seef LB. Natural history of hepatitis C. Clin Liver Dis 2005;9:383–398
Hoofnagle JH, Seef LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006;355:2444–2451
Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, Kilani A, Areias J, Auperin A, Benhamou JP, Degott C, Eringer S. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon alpha therapy. Ann Intern Med 1997;127:875–881
Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374
Yu JW, Wang GQ, Sun LJ, Li XG, Li SC. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin. J Gastroenterol Hepatol 2007;22:832–836
Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, Ferenci P, Ackrill AM, Willems B. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43:954–960
Di Bisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VH. Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hepat 2007;14:721–729
Bruno R, Sacchi P, Ciappina V, Zochetti C, Patruno S, Maiocchi L, Filice G. Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in native patients with chronic hepatitis C: a randomized, controlled study. Antivir Ther 2004;9:491–497
Silva M, Poo J, Wagner F, Jackson M, Cutler D, Grace M, Bordens R, Cullen C. A randomized trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol 2006;45:204–213
Ferenci P, Laferl H, Scherzer TM, Maieron A, Hofer H, Stauber R, Gschwantler M, Brunner H, Wenisch C, Bischof M, Datz C, Vogel W, Loschenberger K, Steindl-Munda P, Austrian Hepatitis Study Group. Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response. Gastroenterology 2010;138:503–512
Antaki N, Craxi A, Kamal S, Moucari R, Van der Merwe S, Haffar S, Gadano A, Zein N, Lai CL, Pawlotsky JM, Heathcote EJ, Dusheiko G, Marcellin P. The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report. Liver Int 2009;30:342–355
Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL, HALT-C Trial Investigator. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429–2441
Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, Brown RS, Belle SH, Hoofnagle JH, Kleiner DE, Howell CD, Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006;131:470–477
Hepburn MJ, Hepburn LM, Cantu NS, Lapeer MG, Lawitz EJ. Differences in treatment outcome for hepatitis C among ethnic groups. Am J Med 2004;117:163–168
Rodriguez-Torres M, Jeffers LJ, Sheikh MY, Rossaro L, Ankoma-Sey V, Hamzeh FM, Martin P, Latino Study Group. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med 2009;360:257–267
Muir AJ, Bornstein JD, Killenberg PG, Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265–2271
Liu CH, Liu CJ, Lin CL, Liang CC, Hsu SJ, Yang SS, Hsu CS, Tseng TC, Wang CC, Lai MY, Chen JH, Chen PJ, Chen DS, Kao JH. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis 2008;47:1260–1269
Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401
Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109
Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Muller T, Bahlo M, Stewart GJ, Booth DR, George J. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100–1109
Rauch A, Kutalik Z, Descombes P, Cai T, di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Gunthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Mullhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY, Swiss Hepatitis C and HIV Cohort Studies. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure—a genome-wide association study. Gastroenterology 2010;138:1338–1345
Carr C, Hollinger FB, Yoffe B, Wakil A, Phillips J, Bzowej N, Leung J, Mirro K, Poordad F, Moore DH, Gish RG. Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C. Liver Int 2007;67:1957–1974
Jensen DM, Marcellin P. Rationale and design of the REPEAT study: a phase III, randomized, clinical trial of peginterferon alfa-2a (40 kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12 kDa) plus ribavirin. Eur J Gastroentrol Hepatol 2005;43:954–960
Jensen DM, Marcellin P, Freilich B, Andreone P, Di Bisceglie A, Brandão-Mello CE, Reddy KR, Craxi A, Martin AO, Teuber G, Messinger D, Thommes JA, Tietz A. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med 2009;150:528–540
Reddy KR, Shiffman ML, Rodriguez-Torres MR, Abdurakhmanov D, Bakulin I, Silva GF, Cheinquer H, Rabbia M, Depamphilis J, McKenna M, Harrison SA. Standard versus higher induction doses of peginterferon alfa-2a (40kd) and/or higher ribavirin (rbv) in hcv G1 patients with high viral load and body weight ≥85 kg: final results of the progress study. Hepatology 2009;50:330A
Thompson AJV, McHutchison JG. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). J Viral Hepat 2009;16:377–387
Schinazi RF, Bassit L, Gavegnano C. HCV drug discovery aimed at viral eradication. J Viral Hepat 2010;17:77–90
Basu A, Kanda T, Beyene A, Saito K, Meyer K, Ray R. Sulfated homologues of heparin inhibit hepatitis C virus entry into mammalian cells. J Virol 2007;81:3933–3941
Watashi K, Shimotohono K. Chemical genetics approach to hepatitis C virus replication: cyclophilin as a target for anti-hepatitis C virus strategy. Rev Med Virol 2007;17:245–252
Schregel V, Jacobi S, Penin F, Tautz N. Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. Proc Natl Acad Sci USA 2009;106:5342–5347
Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG, Faucher AM, Goudreau N, Kawai SH, Kukolj G, Lagace L, LaPlante SR, Najes H, Poupart MA, Rancourt J, Sentjens RE, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos YS, Weldon SM, Yong CL, Llias-Brunet M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003;426:186–189
Vanwolleghem T, Meuleman P, Libbrecht L, Roskams T, De Vos R, Leroux-Roels G. Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Gastroenterology 2007;133:1144–1155
Kwo P, Lawitz E, McCone J, Schiff ER, Vierling J, Pound D, Davis M, Galati J, Gordon S, Ravendhran N, Rossaro L, Anderson F, Jacobson I, Rubin R, Koury K, Brass C, Chaudhri E, Albrecht J. HCV SPRINT-1 Final results: SVR 24 from a phase 2 study of boceprevir plus pegintron (peginterferon alfa-2b)/ribavirin in treatment-naïve subjects with genotype-1 chronic hepatitis C. J Hepatol 2009;50:S4
Kwo P, Lawitz E, McCone J, Schiff ER, Vierling JM, Pound D, Davis M, Galati JS, Gordon SC, Ravendhran N, Rossaro L, Anderson FH, Jacobson IM, Rubin R, Koury K, Boparai N, Chaudhri EI, Brass CA, Albrecht JK. High sustained virologic response (SVR) in genotype 1 (G1) null responders to peg-interferon alfa-2b (P) plus ribavirin (R) when treated with boceprevir (BOC) combination therapy. Hepatology 2009;50:331A
Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, de Rooij J, McNair L, Purdy S, Kauffman R, Alam J, Jansen PL. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006;131:997–1002
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ, PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–1838
Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourliers M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S, PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850
McHuchison JG, Manns MP, Muir A, Terrault N, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Bsharat M, George S, Adda N, Di Bisceglie AM. PROVE3 final results and 1-year durability of SVR with telaprevir-based regimen in hepatitis C genotype 1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy. Hepatology 2009;50:334A
Foster GR, Hezode C, Bronowicki JP, Carosi G, Weiland O, Verlinden L, van Heeswijk R, Vangeneugden T, Picchio G, Beumont-Mauviel M. Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 2 and 3 hepatitis-c patients: interim results of study C209. J Hepatol 2009;50:S22
Manns M, Reesink H, Moreno C, Berg T, Benhamou Y, Horsmans Y, Dusheiko G, Flisiak R, Meyvisch P, Lenz O, Sekar V, van’t Klooster G, Simmen K, Verloes R. OPERA-1 trial: interim analysis of safety and antiviral activity of tmc435 in treatment-naive genotype 1 HCV patients. J Hepatol 2009;50:S7
Marcellin P, Reesink H, Berg T, Cramp M, Flisiak R, Van Vlierberghe H, Verloes R, Lenz O, Peeters M, Sekar V, De Smedt G. Antiviral activity and safety of TMC435 combined with peginterferon alpha-2a and ribavirin in patients with genotype 1 hepatitis C infection who failed previous IFN-based therapy. J Hepatol 2009;50:S385
Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, Wiedmann R, Hwang P, Quirk E, Silber J, Lee A. MK-7009 significantly improves rapid viral response (RVR) in combination with pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis C (CHC) genotype 1 infection. J Hepatol 2009;50:S384
Kukolj G, Benhamou Y, Manns MP, Bourlière M, Pol S, Schuchmann M, Cartier M, Huang D, Lagacé L, Steinmann G, Stern JO. BI 201335, a potent HCV NS3 protease inhibitor, in treatment-naive and -experienced chronic HCV genotype-1 infection: genotypic and phenotypic analysis of the NS3 protease domain. J Hepatol 2009;50:S347
Pasquinelli C, Eley T, Villegas C, Sandy K, Mathias E, Wendelburg P, Liao S, McPhee F, Scola PM, Sun LQ, Marbury TC, Lawitz E, Goldwater R, Rodriguez-Torres M, DeMicco MP, Ababa M, Wright D, Charlton M, Kraft WK, Lopez-Talavera JC, Grasela DM. Safety, tolerability, pharmacokinetics and antiviral activity following single- and multiple-dose administration of BMS-650032, a novel HCV NS3 inhibitor, in subjects with chronic genotype 1 HCV infection. Hepatology 2009;50:411A
Wang P, Chun BK, Rachakonda S, Du J, Khan N, Shi J, Stec W, Cleary D, Ross BS, Sofia MJ. An efficient and diastereoselective synthesis of PSI-6130: a clinically efficacious inhibitor of HCV NS5B polymerase. J Org Chem 2009;74:6819–6824
Medical News Today (http://www.medicalnewstoday.com/articles/105309.php). Accessed on 3/26/2010
Ali S, Leveque V, Le Pogam S, Ma H, Philipp F, Inocencio N, Smith M, Alker A, Kang H, Najera I, Klumpp K, Symons J, Cammack N, Jiang WR. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob Agents Chemother 2008;52:4356–4369
Nyanguile O, Devogelaere B, Vijgen L, Van den Broeck W, Pauwels F, Cummings MD, de Bondt H, Vos AM, Berke J, Lenz O, Vandercruyssen G, Vermeiren K, Mostmans W, Dehertogh P, Delouvroy F, Vendeville S, Vandyck K, Dockx K, Cleiren E, Raboisson P, Simmen KA, Fanning GC. 1a/1b subtype profiling of non-nucleoside polymerase inhibitors of hepatitis C virus. J Virol 2010;84:2923–2934
Pockros P, Rodriguez-Torres M, Villano S, Maller E, Chojkier M. A phase 2, randomized study of HCV-796 in combination with pegylated-interferon (PEG) plus ribavirin (RBV) versus PEG plus RBV in hepatitis C virus genotype-1 infection. J Hepatol 2009;50:S7–S8
Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D, Carlson J, Reyor LL, Kleyman M, McMahon CM, Birch C, Schulze Zur Wiesch J, Ledlie T, Koehrsen M, Kodira C, Roberts AD, Lauer GM, Rosen HR, Bihl F, Cerny A, Spengler U, Liu Z, Kim AY, Xing Y, Schneidewind A, Madey MA, Fleckenstein JF, Park VM, Galagan JF, Nusbaum C, Walker BD, Lake-Bakaar GV, Daar ES, Jacobson M, Gomperts ED, Edlin BR, Donfield SM, Chung RT, Talal AH, Marison T, Birren BW, Henn MR, Allen TM. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology 2008;48:1769–1778
Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, Kwong AD, Zeuzem S. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007;46:631–639
Tong X, Bogen S, Chase R, Girijavallabhan V, Guo Z, Njoroge FG, Prongay A, Saksena A, Skelton A, Xia E, Ralston R. Characterization of resistance mutations against HCV ketoamide protease inhibitors. Antivir Res 2008;77:177–185
Rustgi VK. Albinterferon alfa-2b, a novel fusion protein of human albumin and human interferon alfa-2b, for chronic hepatitis C. Curr Med Res Opin 2009;25:991–1002
Sulkowski MS, Zeuzem S, Lawitz E, Grigorescu M, Tice AD, Rustgi VK, Rodriguez-Torres M, Lurie Y, Cianciara J, Bacon BR, Bain VG, Kryczka W, Pulkstenis E, Subramanian GM, McHutchison JG. Efficacy and safety of albinterferon alfa-2b in combination with ribavirin in treatment naïve patients with chronic hepatitis C genotype 1. Hepatology 2009;50:333A
Nelson D, Benhamou Y, Chuang WL, Lawitz E, Flisiak R, Rodriguez-Torres M, Bain V, Patel K, Cronin PW, Pulkstenis E, Subramanian GM, McHutchison JG. Efficacy and safety results of albinterferon alfa-2b in combination with ribavirin in interferon-alfa treatment naive patients with genotype 2 or 3 chronic hepatitis C. J Hepatol 2009;50:S378
Brand S, Zitzmann K, Dambacher J, Beigel F, Olszak T, Vlotides G, Eichhorst ST, Goke B, Diepolder H, Auernhammer CJ. SOCS-1 inhibits expression of the antiviral proteins 2′,5′-OAS and MxA induced by the novel interferon-lambdas IL28A and IL-29. Biochem Biophys Res Commun 2005;331:543–548
Pagliaccetti NE, Eduardo R, Kleinstein SH, Mu XJ, Bandi P, Robek MD. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J Biol Chem 2008;283:30079–30089
Dodds MG, Hausman DF, Miller DM. Viral kinetic modeling during treatment with interferon lambda-1A in genotype 1 chronic hepatitis C patients. J Hepatol 2009;50:S342–S343
Wedemeyer H, Schuller E, Schlaphoff V, Stauber RE, Wiegand J, Schiefke I, Firbas C, Jilma B, Thursz M, Zeuzem S, Hofmann WP, Hinrichsen H, Tauber E, Manns MP, Klade CS. Therapeutic vaccine IC41 as late add-onto standard treatment in patients with chronic hepatitis C. Vaccine 2009;27:5142–5151
Fibas C, Boehm T, Buerger V, Schuller E, Sabarth N, Jilma B, Klade CS. Immunogenicity and safety of different injection routes and schedules of IC41, a hepatitis C virus (HCV) peptide vaccine. Vaccine 2010;28:2397–2407
Lin Y, Kwon T, Polo J, Coates S, Crawford K, Dong C, Wininger M, Hall J, Selby M, Coit D, Medina-Selby A, McCoin C, Ng P, Drane D, Chien D, Han J, Vajdy M, Hougton M. Induction of broad CD4+ and CD8+ T-cell responses and cross-neutralizing antibodies against hepatitis C virus by vaccination with Th1-adjuvanted polypeptides followed by defective alphaviral particles expressing envelope glycoproteins gpE1 and gpE2 and nonstructural proteins 3, 4, and 5. J Virol 2008;82:7492–7503
Habersetzer F, Baumert TF, Soll-Keller F. GI-5005, a yeast vector vaccine expressing an NS3-core fusion protein for chronic HCV infection. Curr Opin Mol Ther 2009;11:456–462
Klade CS, Wedemeyer H, Berg T, Hinrichsen H, Cholewinska G, Zeuzem S, Blum H, Buschle M, Jelovcan S, Buerger V, Tauber E, Frisch J, Manns MP. Therapeutic vaccination of chronic hepatitis C nonresponder patients with peptide vaccine IC41. Gastroenterology 2008;134:1385–1395
Firbas C, Jilma B, Tauber E, Buerger V, Jelovcan S, Lingnau K, Frisch J, Klaude CS. Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects. Vaccine 2006;24:4343–4353
McHutchison JG, Jacobson IM, Boyer TD, Schiff ER, Everson GT, Lee WM, Pockros P, Chasen RM, Vierling JM, Lawitz E, Kugelmas M, Tsai N, Armstrong BR, Rodell TC, Apelian D. GI-5005 therapeutic vaccine plus peg-IFN/ribavirin improves end of treatment response at 48 weeks versus peg-IFN/ribavirin in naïve genotype 1 chronic HCV patients. Hepatology 2009;50:LB15
Korba BE, Montero AB, Farrar K, Gaye K, Mukerjee S, Ayers MS, Rossignol JF. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antivir Res 2008;77:56–63
Elazar M, Liu M, McKenna SA, Liu P, Gehrig EA, Puglisi JD, Rossignol JF, Glenn JS. The anti-hepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2α via protein kinase activated by double-stranded RNA activation. Gastroenterology 2009;137:1827–1835
Rossignol JF, Kabil SM, El-Gohary Y, Keeffe EB. Randomized double blind placebo-controlled trial of nitazoxanide in the treatment of patients with chronic hepatitis C genotype 4. J Hepatol 2008;48:S311–S312
Rossignol JF, Kabil SM, El-Gohary Y, Keeffe EB. Randomized controlled trial of nitazoxanide–peginterferon–ribavirin, nitazoxanide–peginterferon and peginterferon–ribavirin in the treatment of patients with chronic hepatitis C genotype 4. J Hepatol 2008;48:S30
Shiffman M, Ahmed A, Jacobson I, Pruitt R, Keeffe E. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide with peginterferon alfa-2a and ribavirin in nonresponders (nr) with chronic hcv genotype 1: week 28 interim analysis. J Hepatol 2009;50:S385–S386
Bacon B, Shiffman M, Lim J, Berman A, Rustgi V, Keeffe E. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in HCV genotype 1 patients: interim analysis shows increase in EVR. J Hepatol 2009;50:S381
Tauskela JS. MitoQ—a mitochondria-targeted antioxidant. IDrugs 2007;10:399–412
Gane EJ, Orr DW, Weilert F, Keogh GF, Gibson M, Murphy MP, Smith RA, Lockhart MM, Frampton CM, Taylor KM. Phase II study of the mitochondrial antioxidant mitoquinone for hepatitis C. J Hepatol 2008;48:S318
Watashi K. Alisporivir, a cyclosporine derivate that selectively inhibits cyclophilin, for the treatment of HCV infection. Curr Opin Investig Drugs 2010;11:213–224
Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporine A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 2003;38:567–572
Nakagawa M, Sakamoto N, Tanabe Y, Koyama T, Itsui Y, Takeda Y, Chen CH, Kakinuma S, Oooka S, Maekawa S, Enomoto N, Watanabe M. Suppression of hepatitis C virus replication by cyclosporine A is mediated by blockade of cyclophilins. Gastroenterology 2005;129:1031–1041
Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 2005;19:111–122
Goto K, Watashi K, Inoue D, Hijikata M, Shimotohno K. Identification of cellular and viral factors related to anti-hepatitis C virus activity of cyclophilin inhibitor. Cancer Sci 2009;100:1943–1950
Ke J, Lawitz E, Rozier R, Marbury T, Nguyen N, Serra D, Dole K, Praestgaard J, Huang M, Evans T. Safety, and tolerability of nim811, a novel cyclophilin inhibitor for hcv, following single and multiple ascending doses in healthy volunteers and hcv-infected patients. J Hepatol 2009;50:S229
Durantel D. Celgosivir, an alpha-glucosidase I inhibitor for the potential treatment of HCV infection. Curr Opin Investig Drugs 2009;10:860–870
Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, Bono A, Cabibi D, Licata G, Porcasi R, Marchesini G, Craxí A. Low vitamin D serum level is related to severe fibrosis and low responsiveness to IFN-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010;51:1158–1167
Abu-Mouch S, Fireman Z, Jarchovsky J, Assy N. The beneficial effect of vitamin D combined peg interferon and ribavirin for chronic HCV infection. Hepatology 2009;50:LB20
Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005;11:791–796
Kanda T, Basu A, Steele R, Wakita T, Ryerse JS, Ray R, Ray RB. Generation of infectious hepatitis C virus in immortalized human hepatocytes. J Virol 2006;80:4633–4639
Cai Z, Zhang C, Chang KS, Jiang J, Ahn BC, Wakita T, Liang TJ, Luo G. Robust production of infectious hepatitis C virus (HCV) from stably HCV cDNA-transfected human hepatoma cells. J Virol 2005;79:13963–13973
Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TJ, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete replication of hepatitis C virus in cell culture. Science 2005;309:623–626
Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 2005;102:9294–9299
Meyer K, Basu A, Przysiecki CT, Lagging LM, Di Bisceglie AM, Conley AJ, Ray R. Complement-mediated enhancement of antibody function for neutralization of pseudotype virus containing hepatitis C virus E2 chimeric glycoprotein. J Virol 2002;76:2150–158
Lohmann V, Körner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999;285:110–113
Iwasaki Y, Shiratori Y, Hige S, Nishiguchi S, Takagi H, Onji M, Yoshida H, Izumi N, Kohgo Y, Yamamoto K, Sato N, Shibuya A, Saito H, Suzuki K, Kaneko S, Moriyama M, Omata M. A randomized trial of 24 versus 48 weeks of peginterferon alpha-2a in patients infected with chronic hepatitis C virus genotype 2 or low viral load genotype 1: a multicenter national study in Japan. Hepatol Int 2009;3:468–479
Ichikawa T, Nakao K, Miyaaki H, Eguchi S, Takatsuki M, Fujimoto M, Akiyama M, Mimura S, Ozawa E, Shibata H, Takeshita S, Kanematsu T, Eguchi K. Hepatitis C virus kinetics during the first phase of pegylated interferon-α-2b with ribavirin therapy in patients with living donor liver transplantation. Hepatol Res 2009;39:856–864
Tseng KH, Chen LH, Chen CY, Chang TT, Chou AL, Wu IC, Cheng PN. Low dose erythropoietin-beta improves anemia and maintains ribavirin dose in chronic hepatitis C patients receiving combination therapy with ribavirin plus pegylated interferon alfa-2b. Hepatol Res 2009;39:539–545
Kanda T, Steele R, Ray R, Ray RB. Small interfering RNA targeted to hepatitis C virus 5′ nontranslated region exerts potent antiviral effect. J Virol 2007;81:669–676
Griffin S, Stgelais C, Owsianka AM, Patel AH, Rowlands D, Harris M. Genotype-dependent sensitivity of hepatitis C virus to inhibitors of p7 ion channel. Hepatology 2008;48:1779–1790
Ciesek S, Steinmann E, Wedemeyer H, Manns MP, Neyts J, Tautz N, Madan V, Bartenschlager R, von Hahn T, Pietschmann T. Cyclosporin A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A. Hepatology 2009;50:1638–1645
Einav S, Gerber D, Bryson PD, Sklan EH, Elazar M, Maerkl SJ, Glenn JS, Quake SR. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 2008;26:1019–1027
Belon CA, High YD, Lin TI, Pauwels F, Frick DN. Mechanism and specificity of a symmetrical benzimidazole-phenyl-carboxamide helicase inhibitor. Biochemistry 2010;49:1822–1832
Nettles E, Chien C, Chung E. BMS-790052 is a first-in-class potent hepatitis C virus (HCV) NS5A inhibitor for patients with chronic HCV infection: results from a proof-of-concept study. Hepatology 2008;48:LB12
McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS, IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–593
Yamada G, Iino S, Okuno T, Omata M, Kiyosawa K, Kumada H, Hayashi N, Sakai T. Virological response in patients with hepatitis C virus genotype 1b and a high viral load: impact of peginterferon-alpha-2a plus ribavirin dose reductions and host-related factors. Clin Drug Investig 2008;28:9–16
Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, Liao LY, Chen CL, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Liu CH, Su WW, Lin CL, Jeng YM, Chen PJ, Chen DS. Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology 2009;136:496–504
Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Solá R, Shafran SD, Barange K, Lin A, Soman A, Zeuzem S, ACCELERATE Investigators. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124–134
Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, Vinelli F, Scotto G, Bacca D, Annese M, Romano M, Zechini F, Sogari F, Spirito F, Andriulli A. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609–2617
El-Zayadi AR, Attia M, Barakat EM, Badran HM, Hamdy H, El-Tawil A, El-Nakeeb A, Selim O, Saied A. Response of hepatitis C genotype-4 naïve patients to 24 weeks of Peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005;100:2447–2452
Roulot D, Bourcier V, Grando V, Deny P, Baazia Y, Fontaine H, Bailly F, Castera L, De Ledinghen V, Marcellin P, Poupon R, Bourlière M, Zarski JP, Roudot-Thoraval F, Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepat 2007;14:460–467
Bonny C, Fontaine H, Poynard T, Hézode C, Larrey D, Marcellin P, Bourlière M, Bronowicki JP, Merle P, Zarski JP, Sapey T, Guillemard C, Ughetto S, Henquell C, Nicolas C, Roche C, Randl K, Bommelaer G, Abergel A. Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study. Aliment Pharmacol Ther 2006;24:593–600
Nguyen NH, Vutien P, Garcia RT, Trinh H, Nguyen H, Nguyen K, Levitt B, Nguyen MH. Response to pegylated interferon and ribavirin in Asian American patients with Chronic hepatitis C genotypes 1 vs 2/3 vs 6. J Viral Hepat 2010 (in press)
Fung J, Lai CL, Hung I, Young J, Cheng C, Wong D, Yuen MF. Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and ribavirin. J Infect Dis 2008;198:808–812