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Scientifica  2012 

Direct Acting Antivirals for the Treatment of Chronic Viral Hepatitis

DOI: 10.6064/2012/478631

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The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives. 1. Introduction Conservative estimates of the number of individuals worldwide who are thought to be chronically infected with either HBV or HCV are placed at over 350 [1] and 200 [2] million, respectively. It has long been established through epidemiological surveys that these patients are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). About 1 million people die per year as a result of HBV-related liver pathologies [3]. In resource-limited countries, HBV infection accounts for 30% of cirrhotic patients and 53% of those with HCC [4]. On the other hand, HCV is responsible for approximately 350000 deaths every year [5]. The only means of preventing these un-necessary deaths is therapeutic intervention through the use of immune modulators and direct acting antivirals (DDAs). The ultimate goals of treatment are to achieve a sustainable suppression of replication and remission of liver disease in the case of HBV, and complete eradication of the virus from the liver in the case of HCV. For many years, the only choice for treatment was interferon alpha (IFNα), lymphoblastoid initially and recombinant subsequently, both of which have more recently been superceded by the pegylated form (PegIFN), which requires intramuscular injection only once a week as opposed to three times a week with the previous forms. Interferon has not only immunomodulatory, but also antiproliferative and antiviral effects. It acts by promoting cytotoxic T-cell activity for lysis of infected hepatocytes and by stimulating cytokine production for control of viral replication. DDAs on the other hand constitute a more recent development based on increasing

References

[1]  W. M. Lee, “Hepatitis B virus infection,” New England Journal of Medicine, vol. 337, no. 24, pp. 1733–1745, 1997.
[2]  “Global surveillance and control of hepatitis C,” Journal of Viral Hepatitis, vol. 6, no. 1, pp. 35–47, 1999.
[3]  T. M. Block, H. Guo, and J. T. Guo, “Molecular Virology of Hepatitis B Virus for Clinicians,” Clinics in Liver Disease, vol. 11, no. 4, pp. 685–706, 2007.
[4]  J. F. Perz, G. L. Armstrong, L. A. Farrington, Y. J. F. Hutin, and B. P. Bell, “The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide,” Journal of Hepatology, vol. 45, no. 4, pp. 529–538, 2006.
[5]  A. Hatzakis, S. Wait, J. Bruix et al., “The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference,” Journal of Viral Hepatitis, vol. 18, supplement 1, pp. 1–16, 2011.
[6]  C. Seeger and W. S. Mason, “Hepatitis B virus biology,” Microbiology and Molecular Biology Reviews, vol. 64, no. 1, pp. 51–68, 2000.
[7]  D. Ganem and R. J. Schneider, “Hepadnaviridae: the viruses and their replication,” in Fields Virology, D. M. Knipe, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman, and S. E. Straus, Eds., pp. 2923–2969, Lippincott Williams & Wilkins, Philadelphia, 4th edition, 2001.
[8]  H. Norder, A. M. Courouce, and L. O. Magnius, “Molecular basis of hepatitis B virus serotype variations within the four major subtypes,” Journal of General Virology, vol. 73, no. 12, pp. 3141–3145, 1992.
[9]  H. Norder, A. M. Courouce, and L. O. Magnius, “Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes,” Virology, vol. 198, no. 1, pp. 489–503, 1994.
[10]  M. Lindh, A. S. Andersson, and A. Gusdal, “Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus—large-scale analysis using a new genotyping method,” Journal of Infectious Diseases, vol. 175, no. 6, pp. 1285–1293, 1997.
[11]  H. Naumann, S. Schaefer, C. F. T. Yoshida, A. M. C. Gaspar, R. Repp, and W. H. Gerlich, “Identification of a new hepatitis B virus (HBV) genotype from Brazil that expresses HBV surface antigen subtype adw4,” Journal of General Virology, vol. 74, no. 8, pp. 1627–1632, 1993.
[12]  C. J. Chu, E. B. Keeffe, S. H. Han et al., “Hepatitis B virus genotypes in the United States: results of a nationwide study,” Gastroenterology, vol. 125, no. 2, pp. 444–451, 2003.
[13]  M. Nassal, “Hepatitis B viruses: reverse transcription a different way,” Virus Research, vol. 134, no. 1-2, pp. 235–249, 2008.
[14]  A. R. Neurath, S. B. H. Kent, N. Strick, and K. Parker, “Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus,” Cell, vol. 46, no. 3, pp. 429–436, 1986.
[15]  A. R. Neurath, B. Seto, and N. Strick, “Antibodies to synthetic peptides from the preS1 region of the hepatitis B virus (HBV) envelope (env) protein are virus-neutralizing and protective,” Vaccine, vol. 7, no. 3, pp. 234–236, 1989.
[16]  N. Paran, B. Geiger, and Y. Shaul, “HBV infection of cell culture: evidence for multivalent and cooperative attachment,” EMBO Journal, vol. 20, no. 16, pp. 4443–4453, 2001.
[17]  J. S. Tuttleman, C. Pourcel, and J. Summers, “Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells,” Cell, vol. 47, no. 3, pp. 451–460, 1986.
[18]  S. Locarnini and C. Birch, “Antiviral chemotherapy for chronic hepatitis B infection: lessons learned from treating HIV-infected patients,” Journal of Hepatology, vol. 30, no. 3, pp. 536–550, 1999.
[19]  J. Summers and W. S. Mason, “Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate,” Cell, vol. 29, no. 2, pp. 403–415, 1982.
[20]  A. Kramvis and M. C. Kew, “Structure and function of the encapsidation signal of hepadnaviridae,” Journal of Viral Hepatitis, vol. 5, no. 6, pp. 357–367, 1998.
[21]  M. Nassal and H. Schaller, “Hepatitis B virus replication—an update,” Journal of Viral Hepatitis, vol. 3, no. 5, pp. 217–226, 1996.
[22]  F. Zoulim and C. Seeger, “Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase,” Journal of Virology, vol. 68, no. 1, pp. 6–13, 1994.
[23]  M. Weber, V. Bronsema, H. Bartos, A. Bosserhoff, R. Bartenschlager, and H. Schaller, “Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription,” Journal of Virology, vol. 68, no. 5, pp. 2994–2999, 1994.
[24]  R. A. Crowther, N. A. Kiselev, B. Bottcher et al., “Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy,” Cell, vol. 77, no. 6, pp. 943–950, 1994.
[25]  T. Gerelsaikhan, J. E. Tavis, and V. Bruss, “Hepatitis B virus nucleocapsid envelopment does not occur without genomic DNA synthesis,” Journal of Virology, vol. 70, no. 7, pp. 4269–4274, 1996.
[26]  L. O. Magnius and H. Norder, “Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene,” Intervirology, vol. 38, no. 1-2, pp. 24–34, 1995.
[27]  L. Mimms, “Hepatitis B virus escape mutants: 'pushing the envelope' of chronic hepatitis B virus infection,” Hepatology, vol. 21, no. 3, pp. 884–887, 1995.
[28]  W. F. Carman, M. R. Jacyna, S. Hadziyannis et al., “Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection,” Lancet, vol. 2, no. 8663, pp. 588–591, 1989.
[29]  M. R. Brunetto, M. Stemler, F. Schodel et al., “Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis,” Italian Journal of Gastroenterology, vol. 21, no. 3, pp. 151–154, 1989.
[30]  P. P. Scaglioni, M. Melegari, and J. R. Wands, “Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame,” Virology, vol. 233, no. 2, pp. 374–381, 1997.
[31]  H. Okamoto, F. Tsuda, Y. Akahane et al., “Hepatitis B virus with mutations in the core promoter for an e antigen- negative phenotype in carriers with antibody to e antigen,” Journal of Virology, vol. 68, no. 12, pp. 8102–8110, 1994.
[32]  V. E. Buckwold, Z. Xu, M. Chen, T. S. B. Yen, and J. H. Ou, “Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication,” Journal of Virology, vol. 70, no. 9, pp. 5845–5851, 1996.
[33]  P. Karayiannis, M. J. F. Fowler, and A. S. F. Lok, “Detection of serum HBV-DNA by molecular hybridisation. Correlation with HBeAg/anti-HBe status, racial origin, liver histology and hepatocellular carcinoma,” Journal of Hepatology, vol. 1, no. 2, pp. 99–106, 1985.
[34]  S. Hadziyannis, “Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment,” Viral Hepatitis Reviews, vol. 1, pp. 7–36, 1985.
[35]  J. P. Zarski, P. Marcellin, M. Cohard, J. M. Lutz, C. Bouche, and A. Rais, “Comparison of anti-HBe-positive and HBe-antigen-positive chronic hepatitis B in France,” Journal of Hepatology, vol. 20, no. 5, pp. 636–640, 1994.
[36]  M. R. Brunetto, M. M. Giarin, F. Oliveri et al., “Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 10, pp. 4186–4190, 1991.
[37]  H. S. Margolis, M. J. Alter, and S. C. Hadler, “Hepatitis B: evolving epidemiology and implications for control,” Seminars in Liver Disease, vol. 11, no. 2, pp. 84–92, 1991.
[38]  P. Coursaget, B. Yvonnet, and J. Chotard, “Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal),” Journal of Medical Virology, vol. 22, no. 1, pp. 1–5, 1987.
[39]  B. J. McMahon, W. L. M. Alward, and D. B. Hall, “Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state,” Journal of Infectious Diseases, vol. 151, no. 4, pp. 599–603, 1985.
[40]  N. C. Tassopoulos, G. J. Papaevangelou, and M. H. Sjogren, “Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults,” Gastroenterology, vol. 92, no. 6, pp. 1844–1850, 1987.
[41]  A. A. Evans and W. T. London, “Epidemiology of hepatitis B,” in Viral Hepatitis, A. J. Zuckerman and H. C. Thomas, Eds., pp. 107–114, Churchill livingstone, London, UK, 1998.
[42]  S. J. Hadziyannis and G. V. Papatheodoridis, “Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment,” Seminars in Liver Disease, vol. 26, no. 2, pp. 130–141, 2006.
[43]  C. L. Lai, H. J. Lin, E. K. Yeoh, A. S. F. Lok, P. C. Wu, and C. Y. Yeung, “Placebo-controlled trial of recombinant α2-interferon in Chinese HBsAg-carrier children,” Lancet, vol. 2, no. 8564, pp. 877–880, 1987.
[44]  A. S. F. Lok, C. L. Lai, P. C. Wu et al., “Treatment of chronic hepatitis B with interferon: experience in Asian patients,” Seminars in Liver Disease, vol. 9, no. 4, pp. 249–253, 1989.
[45]  T. Nguyen, P. Desmond, and S. Locarnini, “The role of quantitative hepatitis B serology in the natural history and management of chronic hepatitis B,” Hepatology International, supplement 1, pp. 5–15, 2009.
[46]  J. Jaroszewicz, B. C. Serrano, K. Wursthorn et al., “Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective,” Journal of Hepatology, vol. 52, no. 4, pp. 514–522, 2010.
[47]  R. P. Perrillo, “Treatment of chronic hepatitis B with interferon: experience in western countries,” Seminars in Liver Disease, vol. 9, no. 4, pp. 240–248, 1989.
[48]  P. Karayiannis, “Serum HBsAg levels and their utility as a predictor of sustained virological response after antiviral treatment,” Hepatitis Monthly, vol. 12, no. 7, pp. 420–422, 2012.
[49]  G. Fattovich, F. Bortolotti, and D. Francesco, “Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors,” Journal of Hepatology, vol. 48, no. 2, pp. 335–352, 2008.
[50]  G. K. K. Lau, T. Piratvisuth, X. L. Kang et al., “Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B,” New England Journal of Medicine, vol. 352, no. 26, pp. 2682–2695, 2005.
[51]  P. Marcellin, G. K. K. Lau, F. Bonino et al., “Peginterferon Alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B,” New England Journal of Medicine, vol. 351, no. 12, pp. 1206–1217, 2004.
[52]  H. L. A. Janssen, M. Van Zonneveld, H. Senturk et al., “Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial,” Lancet, vol. 365, no. 9454, pp. 123–129, 2005.
[53]  H. L. Y. Chan, N. W. Y. Leung, A. Y. Hui et al., “A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-α2b and lamivudine with lamivudine alone,” Annals of Internal Medicine, vol. 142, no. 4, pp. 240–250, 2005.
[54]  E. H. C. J. Buster, H. J. Flink, Y. Cakaloglu et al., “Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon α-2b,” Gastroenterology, vol. 135, no. 2, pp. 459–467, 2008.
[55]  P. Marcellin, F. Bonino, G. K. K. Lau et al., “Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon Alfa-2a,” Gastroenterology, vol. 136, no. 7, pp. 2169–2179, 2009.
[56]  N. C. Tassopoulos, R. Volpes, G. Pasture et al., “Efficacy of lamivudine in patients with hepatitis B e antigen- negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B,” Hepatology, vol. 29, no. 3, pp. 889–896, 1999.
[57]  F. Bonino, P. Marcellin, G. K. K. Lau et al., “Predicting response to peginterferon α-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B,” Gut, vol. 56, no. 5, pp. 699–705, 2007.
[58]  R. Moucari, V. Mackiewicz, O. Lada et al., “Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients,” Hepatology, vol. 49, no. 4, pp. 1151–1157, 2009.
[59]  M. R. Brunetto, F. Moriconi, F. Bonino et al., “Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B,” Hepatology, vol. 49, no. 4, pp. 1141–1150, 2009.
[60]  G. Moraleda, J. Saputelli, C. E. Aldrich, D. Averett, L. Condreay, and W. S. Mason, “Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus,” Journal of Virology, vol. 71, no. 12, pp. 9392–9399, 1997.
[61]  N. Cammack, P. Rouse, C. L. P. Marr et al., “Cellular metabolism of (?) enantiomeric 2′-deoxy-3′-thiacytidine,” Biochemical Pharmacology, vol. 43, no. 10, pp. 2059–2064, 1992.
[62]  C. N. Chang, V. Skalski, J. H. Zhou, and Y. C. Cheng, “Biochemical pharmacology of (+)- and (?)-2′,3′-dideoxy-3′-thiacytidine as anti-hepatitis B virus agents,” Journal of Biological Chemistry, vol. 267, no. 31, pp. 22414–22420, 1992.
[63]  S. L. Doong, C. H. Tsai, R. F. Schinazi, D. C. Liotta, and Y. C. Cheng, “Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 19, pp. 8495–8499, 1991.
[64]  A. S.-F. Lok, M. Hussain, C. Cursano et al., “Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy,” Hepatology, vol. 32, no. 5, pp. 1145–1153, 2000.
[65]  S. W. Cho, K. B. Hahm, and J. H. Kim, “Reversion from precore/core promoter mutants to wild-type hepatitis B virus during the course of lamivudine therapy,” Hepatology, vol. 32, no. 5, pp. 1163–1169, 2000.
[66]  F. Zoulim and C. Trépo, “Is lamivudine effective on precore/core promoter mutants of hepatitis B virus?” Hepatology, vol. 32, no. 5, pp. 1172–1174, 2000.
[67]  R. Y. M. Chen, R. Edwards, T. Shaw et al., “Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudineresistant HBV in vitro,” Hepatology, vol. 37, no. 1, pp. 27–35, 2003.
[68]  J. L. Dienstag, E. R. Schiff, T. L. Wright et al., “Lamivudine as initial treatment for chronic hepatitis B in the United States,” New England Journal of Medicine, vol. 341, no. 17, pp. 1256–1263, 1999.
[69]  C. L. Lai, R. N. Chien, N. W. Y. Leung et al., “A one-year trial of lamivudine for chronic hepatitis B,” New England Journal of Medicine, vol. 339, no. 2, pp. 61–68, 1998.
[70]  S. W. Schalm, D. F. Gray, J. Heathcote et al., “Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial,” Gut, vol. 46, no. 4, pp. 562–568, 2000.
[71]  Y. F. Liaw, N. W. Y. Leung, T. T. Chang et al., “Effects of extended lamivudine therapy in asian patients with chronic hepatitis B,” Gastroenterology, vol. 119, no. 1, pp. 172–180, 2000.
[72]  N. W. Y. Leung, C. L. Lai, T. T. Chang et al., “Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy,” Hepatology, vol. 33, no. 6, pp. 1527–1532, 2001.
[73]  J. G. P. Reijnders, M. J. Perquin, N. Zhang, B. E. Hansen, and H. L. A. Janssen, “Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B,” Gastroenterology, vol. 139, no. 2, pp. 491–498, 2010.
[74]  B. C. Song, D. J. Suh, H. C. Lee, Y. H. Chung, and Y. S. Lee, “Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea,” Hepatology, vol. 32, no. 4, pp. 803–806, 2000.
[75]  A. S. F. Lok, “The maze of treatments for hepatitis B,” New England Journal of Medicine, vol. 352, no. 26, pp. 2743–2746, 2005.
[76]  E. B. Keeffe, D. T. Dieterich, S. H. B. Han et al., “A Treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 Update,” Clinical Gastroenterology and Hepatology, vol. 6, no. 12, pp. 1315–1341, 2008.
[77]  M. Rizzetto, “Efficacy of lamivudine in HBeAg-negative chronic hepatitis B,” Journal of Medical Virology, vol. 66, no. 4, pp. 435–451, 2002.
[78]  T. Santantonio, M. Mazzola, T. Iacovazzi, A. Miglietta, A. Guastadisegni, and G. Pastore, “Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine,” Journal of Hepatology, vol. 32, no. 2, pp. 300–306, 2000.
[79]  S. J. Hadziyannis, G. V. Papatheodoridis, E. Dimou, A. Laras, and C. Papaioannou, “Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B,” Hepatology, vol. 32, no. 4 I, pp. 847–851, 2000.
[80]  D. T. Lau, M. Farooq Khokhar, E. Doo et al., “Long-term therapy of chronic hepatitis B with lamivudine,” Hepatology, vol. 32, no. 4 I, pp. 828–834, 2000.
[81]  M. Rizzetto, R. Volpes, and A. Smedile, “Response of pre-core mutant chronic hepatitis B infection to lamivudine,” Journal of Medical Virology, vol. 61, no. 3, pp. 398–402, 2000.
[82]  G. V. Papatheodoridis, E. Dimou, A. Laras, V. Papadimitropoulos, and S. J. Hadziyannis, “Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease,” Hepatology, vol. 36, no. 1, pp. 219–226, 2002.
[83]  G. Scotto, V. Fazio, F. Campanozzi, and A. D'Adduzio, “Efficacy of treatment with lamivudine in patients with chronic active e- minus variant hepatitis B virus infection: a nonrandomized, open-label study,” Current Therapeutic Research, vol. 61, no. 6, pp. 321–330, 2000.
[84]  Y. Suzuki, H. Kumada, K. Ikeda et al., “Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection,” Journal of Hepatology, vol. 30, no. 5, pp. 743–748, 1999.
[85]  Y.-O. Kweon, Z. D. Goodman, J. L. Dienstag et al., “Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B,” Journal of Hepatology, vol. 35, no. 6, pp. 749–755, 2001.
[86]  Y. F. Liaw, J. J. Sung, W. C. Chow, et al., “Lamivudine for patients with chronic hepatitis B and advanced liver disease,” The New England Journal of Medicine, vol. 351, pp. 1521–1531, 2004.
[87]  M. F. Yuen, W. K. Seto, D. H. F. Chow et al., “Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease,” Antiviral Therapy, vol. 12, no. 8, pp. 1295–1303, 2007.
[88]  M. Buti, M. Cotrina, R. Jardi et al., “Two years of lamivudine therapy in anti-HBe-positive patients with chronic hepatitis B,” Journal of Viral Hepatitis, vol. 8, no. 4, pp. 270–275, 2001.
[89]  R. N. Chien, Y. F. Liaw, and M. Atkins, “Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B,” Hepatology, vol. 30, no. 3, pp. 770–774, 1999.
[90]  R. P. Perrillo, S. W. Schalm, E. R. Schiff, et al., “Predictors of HBsAg seroconversion in chronic hepatitis B patients treated with lamivudine,” Hepatology, vol. 30, article 317A, 1999.
[91]  Y. F. Liaw, R. N. Chien, C. T. Yeh, S. L. Tsai, and C. M. Chu, “Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy,” Hepatology, vol. 30, no. 2, pp. 567–572, 1999.
[92]  M. M. Bartholomew, R. W. Jansen, L. J. Jeffers et al., “Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation,” Lancet, vol. 349, no. 9044, pp. 20–22, 1997.
[93]  O. Poch, I. Sauvaget, M. Delarue, and N. Tordo, “Identification of four conserved motifs among the RNA-dependent polymerase encoding elements,” EMBO Journal, vol. 8, no. 12, pp. 3867–3874, 1989.
[94]  M. I. Allen, M. Deslauriers, C. Webster Andrews et al., “Identification and characterization of mutations in hepatitis B virus resistant to lamivudine,” Hepatology, vol. 27, no. 6, pp. 1670–1677, 1998.
[95]  K. P. Fischer and D. L. J. Tyrrell, “Generation of duck hepatitis B virus polymerase mutants through site- directed mutagenesis which demonstrate resistance to lamivudine [(?)-β-L-2′,3′-dideoxy-3′-thiacytidine] in vitro,” Antimicrobial Agents and Chemotherapy, vol. 40, no. 8, pp. 1957–1960, 1996.
[96]  K. Chayama, Y. Suzuki, M. Kobayashi et al., “Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy,” Hepatology, vol. 27, no. 6, pp. 1711–1716, 1998.
[97]  P. Honkoop, H. G. M. Niesters, R. A. M. De Man, A. D. M. E. Osterhaus, and S. W. Schalm, “Lamivudine resistance in immunocompetent chronic hepatitis B. Incidence and patterns,” Journal of Hepatology, vol. 26, no. 6, pp. 1393–1395, 1997.
[98]  R. Ling, D. Mutimer, M. Ahmed et al., “Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine,” Hepatology, vol. 24, no. 3, pp. 711–713, 1996.
[99]  G. A. Tipples, M. M. Ma, K. P. Fischer, V. G. Bain, N. M. Kneteman, and D. L. J. Tyrrell, “Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo,” Hepatology, vol. 24, no. 3, pp. 714–717, 1996.
[100]  H. G. M. Niesters, P. Honkoop, E. B. Haagsma, R. A. De Man, S. W. Schalm, and A. D. M. E. Osterhaus, “Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine treatment,” Journal of Infectious Diseases, vol. 177, no. 5, pp. 1382–1385, 1998.
[101]  M. Melegari, P. P. Scaglioni, and J. R. Wands, “Hepatitis B virus mutants associated with 3TC and Famciclovir administration are replication defective,” Hepatology, vol. 27, no. 2, pp. 628–633, 1998.
[102]  S. K. Ono, N. Kato, Y. Shiratori et al., “The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance,” Journal of Clinical Investigation, vol. 107, no. 4, pp. 449–455, 2001.
[103]  T. T. Aye, A. Bartholomeusz, T. Shaw et al., “Hepatitis B virus polymerase mutations during antiviral therapy in a patient following liver transplantation,” Journal of Hepatology, vol. 26, no. 5, pp. 1148–1153, 1997.
[104]  H. L. Tillmann, C. Trautwein, T. Bock et al., “Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation,” Hepatology, vol. 30, no. 1, pp. 244–256, 1999.
[105]  C. T. Yeh, R. N. Chien, C. M. Chu, and Y. F. Liaw, “Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy,” Hepatology, vol. 31, no. 6, pp. 1318–1326, 2000.
[106]  S. Villet, C. Pichoud, G. Billioud et al., “Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure,” Journal of Hepatology, vol. 48, no. 5, pp. 747–755, 2008.
[107]  R. A. Heijtink, G. A. De Wilde, J. Kruining et al., “Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection,” Antiviral Research, vol. 21, no. 2, pp. 141–153, 1993.
[108]  A. J. Nicoll, D. L. Colledge, J. J. Toole, P. W. Angus, R. A. Smallwood, and S. A. Locarnini, “Inhibition of duck hepatitis B virus replication by 9-(2- phosphonylmethoxyethyl)adenine, an acyclic phosphonate nucleoside analogue,” Antimicrobial Agents and Chemotherapy, vol. 42, no. 12, pp. 3130–3135, 1998.
[109]  X. Xiong, C. Flores, H. Yang, J. J. Toole, and C. S. Gibbs, “Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro,” Hepatology, vol. 28, no. 6, pp. 1669–1673, 1998.
[110]  R. Perrillo, E. Schiff, E. Yoshida et al., “Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants,” Hepatology, vol. 32, no. 1, pp. 129–134, 2000.
[111]  R. J. C. Gilson, K. B. Chopra, A. M. Newell et al., “A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection,” Journal of Viral Hepatitis, vol. 6, no. 5, pp. 387–395, 1999.
[112]  M. Tsiang, J. F. Rooney, J. J. Toole, and C. S. Gibbs, “Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy,” Hepatology, vol. 29, no. 6, pp. 1863–1869, 1999.
[113]  M. G. Peters, G. Singer, T. Howard et al., “Fulminant hepatic failure resulting from lamivudine- resistant hepatitis B virus in a renal transplant recipient: durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin,” Transplantation, vol. 68, no. 12, pp. 1912–1914, 1999.
[114]  Y. Benhamou, M. Bochet, V. Thibault et al., “Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study,” Lancet, vol. 358, no. 9283, pp. 718–723, 2001.
[115]  D. Mutimer, B. H. Feraz-Neto, R. Harrison et al., “Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir,” Gut, vol. 49, no. 6, pp. 860–863, 2001.
[116]  K. M. Walsh, T. Woodall, P. Lamy, D. G. D. Wight, S. Bloor, and G. J. M. Alexander, “Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus,” Gut, vol. 49, no. 3, pp. 436–440, 2001.
[117]  S. Mukherjee and P. Marcellin, “Adefovir dipivoxil for hepatitis B e antigen-positive chronic hepatitis B,” New England Journal of Medicine, vol. 348, no. 24, p. 2468, 2003.
[118]  E. R. Schiff, C. L. Lai, S. Hadziyannis et al., “Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients,” Hepatology, vol. 38, no. 6, pp. 1419–1427, 2003.
[119]  S. J. Hadziyannis, N. C. Tassopoulos, E. J. Heathcote et al., “Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B,” New England Journal of Medicine, vol. 348, no. 9, pp. 800–807, 2003.
[120]  P. Angus, R. Vaughan, S. Xiong et al., “Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase,” Gastroenterology, vol. 125, no. 2, pp. 292–297, 2003.
[121]  S. J. Hadziyannis, N. C. Tassopoulos, E. J. Heathcote et al., “Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis b for up to 5 years,” Gastroenterology, vol. 131, no. 6, pp. 1743–1751, 2006.
[122]  M. Seifer, R. K. Hamatake, R. J. Colonno, and D. N. Standring, “In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir,” Antimicrobial Agents and Chemotherapy, vol. 42, no. 12, pp. 3200–3208, 1998.
[123]  E. V. Genovesi, L. Lamb, I. Medina et al., “Efficacy of the carbocyclic 2′-deoxyguanosine nucleoside BMS-200475 in the woodchuck model of hepatitis B virus infection,” Antimicrobial Agents and Chemotherapy, vol. 42, no. 12, pp. 3209–3217, 1998.
[124]  S. F. Innaimo, M. Seifer, G. S. Bisacchi, D. N. Standring, R. Zahler, and R. J. Colonno, “Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus,” Antimicrobial Agents and Chemotherapy, vol. 41, no. 7, pp. 1444–1448, 1997.
[125]  C. L. Lai, M. Rosmawati, J. Lao et al., “Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection,” Gastroenterology, vol. 123, no. 6, pp. 1831–1838, 2002.
[126]  T. T. Chang, R. G. Gish, R. De Man et al., “A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B,” New England Journal of Medicine, vol. 354, no. 10, pp. 1001–1010, 2006.
[127]  N. Leung, C. Y. Peng, H. W. Hann et al., “Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir,” Hepatology, vol. 49, no. 1, pp. 72–79, 2009.
[128]  D. Shouval, C. L. Lai, T. T. Chang et al., “Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy,” Journal of Hepatology, vol. 50, no. 2, pp. 289–295, 2009.
[129]  C. L. Lai, D. Shouval, A. S. Lok et al., “Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B,” New England Journal of Medicine, vol. 354, no. 10, pp. 1011–1020, 2006.
[130]  T. T. Chang, C. L. Lai, S. K. Yoon et al., “Entecavir treatment for up to 5 years in patients with hepatitis b e antigen-positive chronic hepatitis B,” Hepatology, vol. 51, no. 2, pp. 422–430, 2010.
[131]  T. T. Chang, Y. F. Liaw, S. S. Wu et al., “Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B,” Hepatology, vol. 52, no. 3, pp. 886–893, 2010.
[132]  R. G. Gish, T. T. Chang, C. L. Lai, et al., “Hepatitis B surface antigen loss in antiviral treated patients with HBeAg(+) chronic hepatitis B infection: observation from antiviral-naive patients treated with entecavir and lamivudine,” Hepatology, vol. 44, supplement 1, p. 558A, 2006.
[133]  J. G. P. Reijnders, K. Deterding, J. Petersen et al., “Antiviral effect of entecavir in chronic hepatitis B: influence of prior exposure to nucleos(t)ide analogues,” Journal of Hepatology, vol. 52, no. 4, pp. 493–500, 2010.
[134]  T. T. Chang, Y. C. Chao, V. V. Gorbakov et al., “Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-na?ve HBeAg-positive patients with chronic hepatitis B,” Journal of Viral Hepatitis, vol. 16, no. 11, pp. 784–789, 2009.
[135]  D. J. Tenney, R. E. Rose, C. J. Baldick et al., “Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-na?ve patients is rare through 5 years-of therapy,” Hepatology, vol. 49, no. 5, pp. 1503–1514, 2009.
[136]  T. T. Chang, R. G. Gish, S. J. Hadziyannis et al., “A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients,” Gastroenterology, vol. 129, no. 4, pp. 1198–1209, 2005.
[137]  C. J. Baidick, D. J. Tenney, C. E. Mazzucco et al., “Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance,” Hepatology, vol. 47, no. 5, pp. 1473–1482, 2008.
[138]  D. J. Tenney, S. M. Levine, R. E. Rose et al., “Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 9, pp. 3498–3507, 2004.
[139]  C. L. Lai, N. Leung, E. K. Teo et al., “A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B,” Gastroenterology, vol. 129, no. 2, pp. 528–536, 2005.
[140]  C. L. Lai, E. Gane, Y. F. Liaw et al., “Telbivudine versus lamivudine in patients with chronic hepatitis B,” New England Journal of Medicine, vol. 357, no. 25, pp. 2576–2588, 2007.
[141]  Y. F. Liaw, E. Gane, N. Leung et al., “2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B,” Gastroenterology, vol. 136, no. 2, pp. 486–495, 2009.
[142]  H. L. Y. Chan, E. J. Heathcote, P. Marcellin et al., “Treatment of hepatitis B e antigen-positive chronic hepatitis with telbivudine or adefovir: a randomized trial,” Annals of Internal Medicine, vol. 147, no. 11, pp. 745–754, 2007.
[143]  E. J. Gane, Y. Wang, Y. F. Liaw et al., “Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B,” Liver International, vol. 31, no. 5, pp. 676–684, 2011.
[144]  W. K. Seto, C. L. Lai, J. Fung et al., “Significance of HBV DNA levels at 12 weeks of telbivudine treatment and the 3 years treatment outcome,” Journal of Hepatology, vol. 55, pp. 522–528, 2011.
[145]  S. Zeuzem, E. Gane, Y. F. Liaw et al., “Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B,” Journal of Hepatology, vol. 51, no. 1, pp. 11–20, 2009.
[146]  X. S. Zhang, R. Jin, S. B. Zhang, and M. L. Tao, “Clinical features of adverse reactions associated with telbivudine,” World Journal of Gastroenterology, vol. 14, no. 22, pp. 3549–3553, 2008.
[147]  J. Goncalves, R. Laeufle, and C. Avila, “Increased risk with combination of telbivudine and pegylated-interferon alfa-2a in study CLDT600A2406, compared to uncommon rate with telbivudine monotherapy from the Novartis global database,” Journal of Hepatology, vol. 50, pp. S329–S330, 2009.
[148]  P. Marcellin, E. J. Heathcote, M. Buti et al., “Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B,” New England Journal of Medicine, vol. 359, no. 23, pp. 2442–2455, 2008.
[149]  E. J. Heathcote, P. Marcellin, M. Buti et al., “Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B,” Gastroenterology, vol. 140, no. 1, pp. 132–143, 2011.
[150]  P. Marcellin, M. Buti, Z. Krastev, et al., “Continued efficacy and safety through 4 years of tenofovir disoproxil fumarate (TDF) treatment in HBeAg negative patients with chronic hepatitis B, (study 102): preliminary analysis,” Hepatology, vol. 52, no. 4, supplement, p. 555A, 2010.
[151]  E. J. Heathcote, E. J. Gane, R. De Man, et al., “Long term (4 years) efficacy and safety of tenofovir disoproxil fumarate (TDF) treatment in HBeAG-positive patients (HBeAg+) with chronic hepatitis B, (Study 103): preliminary analysis,” Hepatology, vol. 52, no. 4, supplement, p. 556A, 2010.
[152]  E. Gane, S. L. Lee, E. J. Heathcote, et al., “Four years efficacy and safety of tenofovir didoproxil fumarate (TDF) in Asians with HBeAg-positive and HBeAg-negative chronic hepatitis B, (CHB), preliminary analysis,” Hepatology, vol. 52, no. 4 Supplement, p. 559A, 2010.
[153]  P. Marcellin, M. Buti, E. J. Gane, et al., “Five years of treatment with Tenofovir DF, (TDF) for Chronic Hepatitis B, (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis,” Hepatology, vol. 54, p. 1011A, 2011.
[154]  D. Verhelst, M. Monge, J. L. Meynard et al., “Fanconi syndrome and renal failure induced by tenofovir: a first case report,” American Journal of Kidney Diseases, vol. 40, no. 6, pp. 1331–1333, 2002.
[155]  N. Leung, R. G. Gish, C. Wang, et al., “A randomized, double-blind comparison of 3 doses of emtricitabine in patients with chronic hepatitis B given 48 weeks of treatment,” Hepatology, vol. 34, p. 349A, 2001.
[156]  G. K. Lau and N. Leung, “Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study,” The Korean Journal of Hepatology, vol. 16, no. 3, pp. 315–320, 2010.
[157]  B. Seigneres, C. Pichoud, P. Martin, P. Furman, C. Trepo, and F. Zoulim, “Inhibitory activity of dioxolane purine analogs on wild-type and lamivudine-resistant mutants of hepadnaviruses,” Hepatology, vol. 36, no. 3, pp. 710–722, 2002.
[158]  M. F. Yuen, J. Kim, C. R. Kim et al., “A randomized placebo-controlled, dose-finding study of oral LB80380 in HBeAg-positive patients with chronic hepatitis B,” Antiviral Therapy, vol. 11, no. 8, pp. 977–983, 2006.
[159]  M. F. Yuen, K. H. Han, S. H. Um et al., “Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease,” Hepatology, vol. 51, no. 3, pp. 767–776, 2010.
[160]  G. Y. Wu, X. J. Zheng, C. C. Yin et al., “Inhibition of hepatitis B virus replication by Bay 41-4109 and its association with nucleocapsid disassembly,” Journal of Chemotherapy, vol. 20, no. 4, pp. 458–467, 2008.
[161]  S. J. Stray and A. Zlotnick, “BAY 41-4109 has multiple effects on hepatitis B virus capsid assembly,” Journal of Molecular Recognition, vol. 19, no. 6, pp. 542–548, 2006.
[162]  R. Bartenschlager, F. L. Cosset, and V. Lohmann, “Hepatitis C virus replication cycle,” Journal of Hepatology, vol. 53, no. 3, pp. 583–585, 2010.
[163]  E. Santolini, G. Migliaccio, and N. La Monica, “Biosynthesis and biochemical properties of the hepatitis C virus core protein,” Journal of Virology, vol. 68, no. 6, pp. 3631–3641, 1994.
[164]  J. McLauchlan, M. K. Lemberg, G. Hope, and B. Martoglio, “Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets,” EMBO Journal, vol. 21, no. 15, pp. 3980–3988, 2002.
[165]  V. Pène, C. Hernandez, C. Vauloup-Fellous, J. Garaud-Aunis, and A. R. Rosenberg, “Sequential processing of hepatitis C virus core protein by host cell signal peptidase and signal peptide peptidase: a reassessment,” Journal of Viral Hepatitis, vol. 16, no. 10, pp. 705–715, 2009.
[166]  J. L. Kim, K. A. Morgenstern, J. P. Griffith et al., “Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding,” Structure, vol. 6, no. 1, pp. 89–100, 1998.
[167]  V. Lohmann, F. K?rner, J. O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager, “Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line,” Science, vol. 285, no. 5424, pp. 110–113, 1999.
[168]  T. Wakita, T. Pietschmann, T. Kato et al., “Production of infectious hepatitis C virus in tissue culture from a cloned viral genome,” Nature Medicine, vol. 11, no. 7, pp. 791–796, 2005, Erratum: Nature Medicine, vol. 11, no. 8, pp. 905, 2005.
[169]  A. Merz, G. Long, M. S. Hiet et al., “Biochemical and morphological properties of hepatitis C virus particles and determination of their lipidome,” Journal of Biological Chemistry, vol. 286, no. 4, pp. 3018–3032, 2011.
[170]  E. Scarselli, H. Ansuini, R. Cerino et al., “The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus,” EMBO Journal, vol. 21, no. 19, pp. 5017–5025, 2002.
[171]  P. Pileri, Y. Uematsu, S. Campagnoli et al., “Binding of hepatitis C virus to CD81,” Science, vol. 282, no. 5390, pp. 938–941, 1998.
[172]  M. J. Evans, T. Von Hahn, D. M. Tscherne et al., “Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry,” Nature, vol. 446, no. 7137, pp. 801–805, 2007.
[173]  A. Ploss, M. J. Evans, V. A. Gaysinskaya et al., “Human occludin is a hepatitis C virus entry factor required for infection of mouse cells,” Nature, vol. 457, no. 7231, pp. 882–886, 2009.
[174]  J. Lupberger, M. B. Zeisel, F. Xiao et al., “EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy,” Nature Medicine, vol. 17, no. 5, pp. 589–595, 2011.
[175]  B. Sainz Jr., N. Barretto, D. N. Martin, et al., “Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor,” Nature Medicine, vol. 18, pp. 281–285, 2012.
[176]  L. Meertens, C. Bertaux, L. Cukierman et al., “The tight junction proteins claudin-1, -6, and -9 are entry cofactors for hepatitis C virus,” Journal of Virology, vol. 82, no. 7, pp. 3555–3560, 2008.
[177]  K. E. Coller, K. L. Berger, N. S. Heaton, J. D. Cooper, R. Yoon, and G. Randall, “RNA interference and single particle tracking analysis of hepatitis C virus endocytosis,” PLoS Pathogens, vol. 5, no. 12, Article ID e1000702, 2009.
[178]  E. Blanchard, S. Belouzard, L. Goueslain et al., “Hepatitis C virus entry depends on clathrin-mediated endocytosis,” Journal of Virology, vol. 80, no. 14, pp. 6964–6972, 2006.
[179]  J. McLauchlan, “Lipid droplets and hepatitis C virus infection,” Biochimica et Biophysica Acta, vol. 1791, no. 6, pp. 552–559, 2009.
[180]  C. I. Popescu, Y. Rouille, and J. Dubuisson, “Hepatitis C virus assembly imaging,” Viruses, vol. 3, pp. 2238–2254, 2011.
[181]  P. Gastaminza, G. Cheng, S. Wieland, J. Zhong, W. Liao, and F. V. Chisari, “Cellular determinants of hepatitis c virus assembly, maturation, degradation, and secretion,” Journal of Virology, vol. 82, no. 5, pp. 2120–2129, 2008.
[182]  C. T. Jones, C. L. Murray, D. K. Eastman, J. Tassello, and C. M. Rice, “Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus,” Journal of Virology, vol. 81, no. 16, pp. 8374–8383, 2007.
[183]  E. Steinmann, F. Penin, S. Kallis, A. H. Patel, R. Bartenschlager, and T. Pietschmann, “Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions,” PLoS pathogens, vol. 3, no. 7, article e103, 2007.
[184]  M. Yi, Y. Ma, J. Yates, and S. M. Lemon, “trans-complementation of an NS2 defect in a late step in hepatitis C virus (HCV) particle assembly and maturation,” PLoS Pathogens, vol. 5, no. 5, Article ID e1000403, 2009.
[185]  H. Huang, F. Sun, D. M. Owen et al., “Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 14, pp. 5848–5853, 2007.
[186]  K. S. Chang, J. Jiang, Z. Cai, and G. Luo, “Human apolipoprotein E is required for infectivity and production of hepatitis C virus in cell culture,” Journal of Virology, vol. 81, no. 24, pp. 13783–13793, 2007.
[187]  A. Kaul, S. Stauffer, C. Berger et al., “Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics,” PLoS Pathogens, vol. 5, no. 8, Article ID e1000546, 2009.
[188]  F. Yang, J. M. Robotham, H. B. Nelson, A. Irsigler, R. Kenworthy, and H. Tang, “Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro,” Journal of Virology, vol. 82, no. 11, pp. 5269–5278, 2008.
[189]  S. Reiss, I. Rebhan, P. Backes et al., “Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment,” Cell Host and Microbe, vol. 9, no. 1, pp. 32–45, 2011.
[190]  T. Kuntzen, J. Timm, A. Berical et al., “Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-na?ve patients,” Hepatology, vol. 48, no. 6, pp. 1769–1778, 2008.
[191]  M. P. Manns, J. G. McHutchison, S. C. Gordon et al., “Peginterferon alfa-2b plus ribavirin compared with interferonalfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial,” Lancet, vol. 358, no. 9286, pp. 958–965, 2001.
[192]  M. W. Fried, ShiffmanML, K. R. Reddy, et al., “Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection,” The New England Journal of Medicine, vol. 347, pp. 975–982, 2002.
[193]  E. Thomas, J. J. Feld, Q. Li, Z. Hu, M. W. Fried, and T. J. Liang, “Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models,” Hepatology, vol. 53, no. 1, pp. 32–41, 2011.
[194]  I. M. Jacobson, R. S. Brown, and B. Freilich, “Peginterferon a2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial,” Hepatology, vol. 46, pp. 971–981, 2007.
[195]  P. Glue, R. Rouzier-Panis, C. Raffanel et al., “A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C,” Hepatology, vol. 32, no. 3, pp. 647–653, 2000.
[196]  M. G. Swain, M. Lai, M. L. Shiffman et al., “A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon Alfa-2a and ribavirin,” Gastroenterology, vol. 139, no. 5, pp. 1593–1601, 2010.
[197]  M. G. Ghany, D. B. Strader, D. L. Thomas, and L. B. Seeff, “Diagnosis, management, and treatment of hepatitis C: an update,” Hepatology, vol. 49, no. 4, pp. 1335–1374, 2009.
[198]  C. F. Huang, J. F. Yang, C. Y. Dai et al., “Efficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C,” Journal of Infectious Diseases, vol. 201, no. 5, pp. 751–759, 2010.
[199]  I. M. Jacobson, R. S. Brown, J. McCone et al., “Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1,” Hepatology, vol. 46, no. 4, pp. 982–990, 2007.
[200]  J. G. Mchutchison, S. C. Gordon, E. R. Schiff et al., “Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C,” New England Journal of Medicine, vol. 339, no. 21, pp. 1485–1492, 1998.
[201]  J. G. McHutchison, E. J. Lawitz, M. L. Shiffman et al., “Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection,” New England Journal of Medicine, vol. 361, no. 6, pp. 580–593, 2009.
[202]  D. Ge, J. Fellay, A. J. Thompson et al., “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance,” Nature, vol. 461, no. 7262, pp. 399–401, 2009.
[203]  C. Hézode, N. Forestier, G. Dusheiko et al., “Telaprevir and peginterferon with or without ribavirin for chronic HCV infection,” New England Journal of Medicine, vol. 360, no. 18, pp. 1839–1850, 2009.
[204]  J. G. McHutchison, G. T. Everson, S. C. Gordon et al., “Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection,” New England Journal of Medicine, vol. 360, no. 18, pp. 1827–1838, 2009.
[205]  J. G. McHutchison, M. P. Manns, A. J. Muir et al., “Telaprevir for previously treated chronic HCV infection,” New England Journal of Medicine, vol. 362, no. 14, pp. 1292–1303, 2010.
[206]  S. Zeuzem, C. Hezode, P. Ferenci, et al., “Telaprevir in combination with peginterferon alfa-2a with or without ribavirin in the treatment of chronic hepatitis C. Final results of the PROVE 2 study,” Hepatology, vol. 48, supplement 1, pp. 418–419, 2008.
[207]  M. S. Sulkowski, S. Roberts, N. Afdhal, et al., “. Ribavirin dose modification in treatment-naive and previously treated patients who received telaprevir combination treatment: no impact on sustained virologic response in phase 3 studies,” Journal of Hepatology, vol. 56, supplement 2, p. A1162, 2012.
[208]  K. E. Sherman, S. Flamm, N. H. Afdhal, et al., “Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of phase 3 ILLUMINATE,” Study. Hepatology, vol. 52, supplement 4, article LB-2, 2010.
[209]  S. Zeuzem, P. Andreone, S. Pol et al., “Telaprevir for retreatment of HCV infection,” New England Journal of Medicine, vol. 364, no. 25, pp. 2417–2428, 2011.
[210]  P. Y. Kwo, E. J. Lawitz, J. McCone, et al., “SPRINT-1 investigators. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-na?ve patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial,” Lancet, vol. 376, pp. 705–716, 2010.
[211]  F. Poordad, J. McCone, B. R. Bacon et al., “Boceprevir for untreated chronic HCV genotype 1 infection,” New England Journal of Medicine, vol. 364, no. 13, pp. 1195–1206, 2011.
[212]  B. R. Bacon, S. C. Gordon, E. Lawitz et al., “Boceprevir for previously treated chronic HCV genotype 1 infection,” New England Journal of Medicine, vol. 364, no. 13, pp. 1207–1217, 2011.
[213]  T. L. Kieffer, C. Sarrazin, J. S. Miller et al., “Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients,” Hepatology, vol. 46, no. 3, pp. 631–639, 2007.
[214]  S. Susser, C. Welsch, Y. Wang et al., “Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients,” Hepatology, vol. 50, no. 6, pp. 1709–1718, 2009.
[215]  J. A. Howe, P. Qiu, R. A. Ogert, et al., “Frequencies of resistance associated amino acid variants detected by 454-sequencing during combination treatment with boceprevir plus PegIntron (peginterferon alfa-2b)/ribavirin in HCV, (GT1)-infected patients,” Journal of Hepatology, vol. 54, supplemen 1, p. 176, 2011.
[216]  S. Zeuzem, M. Sulkowski, F. Zoulim, et al., “Long-term follow up of patients with chronic hepatitis C treated with telaprevir in combination with peginterferon alfa-2A and ribavirin: interim analysis of the EXTEND study,” Hepatology, vol. 52, supplement 1, p. 436A, 2010.
[217]  H. W. Reesink, G. C. Fanning, K. A. Farha et al., “Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients,” Gastroenterology, vol. 138, no. 3, pp. 913–921, 2010.
[218]  J. M. Gottwein, T. K. Scheel, T. B. Jensen, et al., “. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses,” Gastroenterology, vol. 141, pp. 1067–1079, 2011.
[219]  Y. S. Tsantrizos, “TMC-435, an NS3/4A protease inhibitor for the treatment of HCV infection,” Current Opinion in Investigational Drugs, vol. 10, no. 8, pp. 871–881, 2009.
[220]  S. Zeuzem, T. Berg, E. Gane P, et al., “TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the aspire trial,” Journal of Hepatology, vol. 56, supplement 2, p. A2, 2012.
[221]  N. Forestier, D. Larrey, P. Marcellin et al., “Antiviral activity of danoprevir (ITMN-191/RG7227) in combination with pegylated interferon α-2a and ribavirin in patients with hepatitis C,” Journal of Infectious Diseases, vol. 204, no. 14, pp. 601–608, 2011.
[222]  E. J. Gane, R. Rouzier, C. Stedman, et al., “Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN alpha-2a/RBV in hepatitis C patients,” Journal of Hepatology, vol. 55, pp. 972–979, 2011.
[223]  S. Zeuzem, T. Asselah, P. Angus, et al., “Efficacy of the protease inhibitor BI, 201335, polymerase inhibitor BI, 207127, and ribavirin in patients with chronic HCV infection,” Gastroenterology, vol. 141, pp. 2047–2055, 2011.
[224]  F. E. Membreno and E. J. Lawitz, “The HCV NS5B nucleoside and nonnucleoside inhibitors,” Clinics in Liver Disease, vol. 15, pp. 611–626, 2011.
[225]  A. M. Lam, C. Espiritu, S. Bansal, et al., “HCV nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA,” Journal of Virology, vol. 85, pp. 12334–12342, 2011.
[226]  J. Lalezari, E. Lawitz, M. Rodriguez-Torres, et al., “Once daily PSI-7977 plus PegIFN/RBV in a phase 2B trial: rapid virologic suppression in treatment-na?ve patients with HCV GT2/GT3,” Journal of Hepatology, vol. 54, supplement 1, p. A61, 2011.
[227]  K. V. Kowdlev, E. L?witz, I. Crespo, et al., “Atomic: 97% RVR for PSI-7977 + PEG/RBV × 12 week regimen in HCV gt1: an end to response-guided therapy?” Journal of Hepatology, vol. 56, supplement 2, p. A1, 2012.
[228]  H. Wedemeyer, D. Jensen, R. Herring, et al., “Efficacy and safety of mericitabine (MCB) in combination with Peg-IFNa-2a/RBV in g1/4 treatment naive HCV patients: final analysis from the propel study,” Journal of Hepatology, vol. 56, supplement 2, p. A1213, 2012.
[229]  P. Pockros, D. Jensen, N. Tsai R, et al., “. SVR-12 among G1/4 treatment-naive patients receiving mericitabine in combination with Peg-IFNa-2a/RBV: interim analysis from the JUMP-C study,” Journal of Hepatology, vol. 56, supplement 2, p. A1205, 2012.
[230]  E. Lawitz, I. Jacobson, E. Godofsky, et al., “. A Phase 2b trial comparing 24 to 48 weeks of treatment with tegobuvir (GS-9190)/PEG/RV to 48 weeks treatment with PEG/RBV for chronic genotype 1 HCV infection,” Journal of Hepatology, vol. 54, supplemen 1, p. A445, 2011.
[231]  S. Einav, D. Gerber, P. D. Bryson et al., “Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis,” Nature Biotechnology, vol. 26, no. 9, pp. 1019–1027, 2008.
[232]  R. A. Fridell, D. Qiu, L. Valera, C. Wang, R. E. Rose, and M. Gao, “Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A Inhibitor BMS-790052,” Journal of Virology, vol. 85, no. 14, pp. 7312–7320, 2011.
[233]  P. Ferraris, E. Blanchard, and P. Roingeard, “Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes,” Journal of General Virology, vol. 91, no. 9, pp. 2230–2237, 2010.
[234]  A. Macdonald and M. Harris, “Hepatitis C virus NS5A: tales of a promiscuous protein,” Journal of General Virology, vol. 85, no. 9, pp. 2485–2502, 2004.
[235]  K. H. Lan, K. L. Lan, W. P. Lee et al., “HCV NS5A inhibits interferon-α signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines,” Journal of Hepatology, vol. 46, no. 5, pp. 759–767, 2007.
[236]  R. G. Gish and N. A. Meanwell, “The NS5A replication complex inhibitors: difference makers?” Clinics in Liver Disease, vol. 15, pp. 627–639, 2011.
[237]  S. Pol, R. H. Ghalib, V. K. Rustgi, et al., “First report of SVR12 for a NS5A replication complex inhibitor, BMS-790052 in combination with peg-IFN-alfa-2a and RBV: phase 2a trial in treatment-naive HCV-genotype 1 subjects,” Journal of Hepatology, vol. 54, supplement 1, p. A2, 2011.
[238]  G. J. Sullivan, M. Rodriques-Torres, E. Lawitz F, et al., “ABT-267 combined with pegylated interferon alpha-2a/ribavirin in genotype 1 (gt1) HCV-infected treatment-naive subjects: 12 week antiviral and safety analysis,” Journal of Hepatology, vol. 56, supplement 2, p. A1210, 2012.
[239]  S. Zeuzem, P. Buggisch, K. Agarwal, et al., “Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment naive, genotype 1 HCV subjects,” in Proceedings of the 61th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD '10), LB-1, Boston, Mass, USA, 2010.
[240]  G. R. Foster, P. Buggisch, P. Marcellin, et al., “Four-week treatment with GS-9256 and tegobuvir (GS-9190), ± RBV ± PEG, results in enhanced viral suppression on follow-up PEG/RBV therapy, in genotype 1a/1b HCV patients,” Journal of Hepatology, vol. 54, supplement 1, p. A232, 2011.
[241]  D. R. Nelson, E. J. Gane, I. M. Jacobson, et al., “VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treatment na?ve genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis,” in Proceedings of the 61th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD '11), LB-14, San Francisco, Calif, USA, 2011.
[242]  E. Z. Zhang, A. Tigges, M. Jiang, et al., “Characterization of HCV variants in genotype 1 treatment-naive patients administered the combination of TVR and VX-222 in dual arms of zenith study,” Journal of Hepatology, vol. 56, supplement 2, p. A1184, 2012.
[243]  A. Lok, D. Gardiner, E. Lawitz, et al., “Preliminary study of two antiviral agents for hepatitis C genotype 1,” The New England Journal of Medicine, vol. 366, pp. 216–224, 2012.
[244]  A. Lok, D. Gardiner, E. Lawitz, et al., “Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders,” Journal of Hepatology, vol. 54, supplement 1, p. S536, 2011.
[245]  E. Lawitz, F. Poordad, E. DeJesus, et al., “ABT-450/Ritonavir (ABT-450/R) combined with pegylated interferon alpha-2a/ribavirin after 3-day monotherapy in genotype 1 (gt1) hcv-infected treatment-naive subjects: 12-week sustained virologic response (SVR12) and safety results,” Journal of Hepatology, vol. 56, supplement 2, p. A1187, 2012.
[246]  G. Everson, C. Cooper, C. Hezode, et al., “Rapid and sustained achievement of undetectable HCV RNA during treatment with Ritonavir-boosted Danoprevir/PEG-IFNa-2A/RBV in HCV genotype 1 or 4 patients: DAUPHINE week 12 interim analysis,” Journal of Hepatology, vol. 56, supplement 2, p. A1177, 2012.
[247]  D. R. Nelson, E. Lawitz, V. Bain, et al., “High SVR12 with 16 weeks of Tegobuvir and GS-9256 with peginterferon-alfa 2a and ribavirin in treatment-naive genotype 1 HCV patients,” Journal of Hepatology, vol. 56, supplement 2, p. A12, 2012.
[248]  E. Gane, C. A. Stedman, R. H. Hyland, et al., “Once daily PSI-7977 plus RBV: pegylated interferon alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or 3,” in Proceedings of the 61th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD '11), San Francisco, Calif, USA, 2011.
[249]  F. Suzuki, K. Ikeda, J. Toyota, et al., “Dual oral therapy with the NS5A inhibitor Daclatasvir (BMS-790052) and NS3 protease inhibitor Asunaprevir (BMS-650032) in HCV genotype 1b-infected null responders or ineligible/intolerant to peginterferon/ribavirin,” Journal of Hepatology, vol. 56, supplement 2, p. A14, 2012.
[250]  M. Sulkowski, D. Gardiner, E. Lawitz, et al., “Potent viral suppression with the all oral combination of Daclatasvir and GS-7977, +/- ribavirin, in treatment na?ve patients with chronic GT1, 2, or 3,” in Proceedings of the 47th annual meeting of the European Association for the Study of the Liver (EASL '12), P1422, Barcelona, Spain, 2012.
[251]  S. Zeuzem, V. Soriano, T. Asselah, et al., “SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127, +/- ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: interim results of SOUND-C2,” Journal of Hepatology, vol. 56, supplement 2, p. A101, 2012.
[252]  V. Soriano, E. Gane, P. Angus, et al., “The efficacy and safety of the interferon-free combination of BI201335 AND BI207127 in genotype 1 HCV PATIENTS with cirrhosis—interim analysis from SOUND-C2,” Journal of Hepatology, vol. 56, supplement 2, p. A1420, 2012.
[253]  E. Lawitz, F. Poordad, K. V. Kowdley, et al., “A 12-week interferon-free regimen of ABT-450/R, ABT-072, and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-naive HCV IL28B-CC genotype-1-infected subjects,” Journal of Hepatology, vol. 56, supplement 2, p. A13, 2012.
[254]  M. Sulkowski, M. Rodriguez-Torres, E. Lawitz, et al., “High sustained virologic response rate in treatment-naive HCV genotype 1a and 1b patients treated for 12 weeks with an interferon-free all-oral quad regimen: interim results,” Journal of Hepatology, vol. 56, supplement 2, p. A1421, 2012.
[255]  X. Hanoulle, A. Badillo, J. M. Wieruszeski et al., “Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B,” Journal of Biological Chemistry, vol. 284, no. 20, pp. 13589–13601, 2009.
[256]  S. Hopkins, B. Scorneaux, Z. Huang et al., “SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of Hepatitis C virus RNA replication in vitro,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 2, pp. 660–672, 2010.
[257]  S. Hopkins, S. Mosier, R. Harris, et al., “Resistance selection following 15 days of monotherapy with SCY-635 a non-immunosuppressive cyclophilin inhibitor with potent anti-HCV activity,” Journal of Hepatology, vol. 52, supplement 1, p. A34, 2010.
[258]  L. Coelmont, X. Hanoulle, U. Chatterji et al., “Deb025 (Alisporivir) inhibits hepatitis c virus replication by preventing a cyclophilin a induced Cis-trans isomerisation in domain ii of NS5A,” PLoS One, vol. 5, no. 10, Article ID e13687, 2010.
[259]  R. Flisiak, J. M. Pawlotsky, R. Crabbe, et al., “Once daily alisporivir (DEB025) plus PegIFNalfa2A/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naive patients,” Journal of Hepatology, vol. 54, supplement 1, p. A4, 2011.
[260]  C. L. Jopling, M. Yi, A. M. Lancaster, S. M. Lemon, and P. Sarnow, “Molecular biology: modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA,” Science, vol. 309, no. 5740, pp. 1577–1581, 2005.
[261]  R. E. Lanford, E. S. Hildebrandt-Eriksen, A. Petri et al., “Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection,” Science, vol. 327, no. 5962, pp. 198–201, 2010.
[262]  A. K. Patick, A. Chen, L. J. van Doorn, et al., “Sequence analysis of hcv variants from a phase IIA trial of Miravirsen (MIR), an oligonucleotide targeting MIR-122, in treatment naive patients with chronic HCV infection,” Journal of Hepatology, vol. 56, supplement 2, A1202 pages, 2012.
[263]  H. Zhu, F. Wong-Staal, H. Lee, et al., “Evaluation of ITX, 5061, a scavenger receptor B1 antagonist: resistance selection and activity in combination with other hepatitis C virus antivirals,” The Journal of Infectious Diseases, vol. 205, pp. 656–662, 2012.
[264]  M. Rizzetto, “Hepatitis D: thirty years after,” Journal of Hepatology, vol. 50, no. 5, pp. 1043–1050, 2009.
[265]  G. Saracco, F. Rosina, M. R. Brunetto et al., “Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection,” Journal of Hepatology, vol. 5, no. 3, pp. 274–281, 1987.
[266]  G. Fattovich, S. Boscaro, and F. Noventa, “Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B,” Journal of Infectious Diseases, vol. 155, no. 5, pp. 931–935, 1987.
[267]  R. Romeo, E. Del Ninno, M. Rumi et al., “A 28-year study of the course of hepatitis Δ infection: a risk factor for cirrhosis and hepatocellular carcinoma,” Gastroenterology, vol. 136, no. 5, pp. 1629–1638, 2009.
[268]  C. Sureau, “The role of the HBV envelope proteins in the HDV replication cycle,” Current Topics in Microbiology and Immunology, vol. 307, pp. 113–131, 2006.
[269]  K. S. Wang, Q. L. Choo, and A. J. Weiner, “Structure, sequence and expression of the hepatitis delta (δ) viral genome,” Nature, vol. 323, no. 6088, pp. 508–514, 1986.
[270]  H. N. Wu, Y. J. Lin, F. P. Lin, S. Makino, M. F. Chang, and M. M. C. Lai, “Human hepatitis δ virus RNA subfragments contain an autocleavage activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 6, pp. 1831–1835, 1989.
[271]  Y. J. Li, T. Macnaughton, L. Gao, and M. M. C. Lai, “RNA-templated replication of hepatitis delta virus: genomic and antigenomic RNAs associate with different nuclear bodies,” Journal of Virology, vol. 80, no. 13, pp. 6478–6486, 2006.
[272]  J. Taylor and M. Pelchat, “Origin of hepatitis virus,” Future Microbiology, vol. 5, no. 3, pp. 393–402, 2010.
[273]  A. J. Weiner, Q. L. Choo, K. S. Wang et al., “A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24(δ) and p27(δ),” Journal of Virology, vol. 62, no. 2, pp. 594–599, 1988.
[274]  M. F. Chang, C. J. Chen, and S. C. Chang, “Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus,” Journal of Virology, vol. 68, no. 2, pp. 646–653, 1994.
[275]  S. J. Hadziyannis, “Use of α-interferon in the treatment of chronic delta hepatitis,” Journal of Hepatology, vol. 13, supplement 1, pp. S21–S26, 1991.
[276]  P. Farci, T. Roskams, L. Chessa et al., “Long-term benefit of interferon α therapy of chronic hepatitis D: regression of advanced hepatic fibrosis,” Gastroenterology, vol. 126, no. 7, pp. 1740–1749, 2004.
[277]  G. A. Niro, A. Ciancio, G. B. Gaeta et al., “Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta,” Hepatology, vol. 44, no. 3, pp. 713–720, 2006.
[278]  A. Erhardt, W. Gerlich, C. Starke et al., “Treatment of chronic hepatitis delta with pegylated interferon-α2b,” Liver International, vol. 26, no. 7, pp. 805–810, 2006.
[279]  C. Castelnau, F. Le Gal, M. P. Ripault et al., “Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up,” Hepatology, vol. 44, no. 3, pp. 728–735, 2006.
[280]  F. Gunsar, U. S. Akarca, G. Ersoz et al., “Two-year interferon therapy with or without ribavirin in chronic delta hepatitis,” Antiviral Therapy, vol. 10, no. 6, pp. 721–726, 2005.
[281]  H. Wedemeyer, C. Yurdaydìn, G. N. Dalekos et al., “Peginterferon plus adefovir versus either drug alone for hepatitis delta,” New England Journal of Medicine, vol. 364, no. 4, pp. 322–331, 2011.
[282]  C. Yurdaydin, H. Bozkaya, F. O. ?nder et al., “Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon,” Journal of Viral Hepatitis, vol. 15, no. 4, pp. 314–321, 2008.
[283]  J. S. Glenn, J. A. Watson, C. M. Havel, and J. M. White, “Identification of a prenylation site in delta virus large antigen,” Science, vol. 256, no. 5061, pp. 1331–1333, 1992.
[284]  B. B. Bordier, J. Ohkanda, P. Liu et al., “In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus,” Journal of Clinical Investigation, vol. 112, no. 3, pp. 407–414, 2003.

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