Download PDF
Semin Liver Dis 2014; 34(01): 037-046
DOI: 10.1055/s-0034-1371009
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Interferon-Free Strategies with a Nucleoside/Nucleotide Analogue

Jordan J. Feld
1   Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
29 April 2014 (online)

   Permissions and Reprints

Abstract

A key to effective interferon- (IFN-) free therapy for hepatitis C virus (HCV) infection is a direct-acting antiviral (DAA) with a high barrier to resistance that can act as the backbone to any regimen. Ideally, this agent should also be active against all HCV genotypes, be well tolerated and have few drug interactions. Nucleoside/nucleotide analogues (NAs) that inhibit the function of the HCV RNA-dependent-RNA polymerase fit these requirements and thus hold promise as a cornerstone for new IFN-free regimens. To date, the issue with this class of agents has been toxicity. Numerous NAs in early clinical development have led to significant toxicity leading to their abandonment. However, sofosbuvir, a prodrug of a uridine NA, has moved through development with a clean-safety profile leading to its recent approval. When combined with ribavirin (RBV) alone, sofosbuvir is effective against genotype 2 and even genotype 3 if duration is extended. There are currently limited data with this combination in genotype 1; however, when sofosbuvir is combined with other DAAs of different classes, it is highly effective in almost all patients. To date, sofosbuvir has been studied with protease, NS5A, and nonnucleoside HCV polymerase inhibitors, including as part of a fixed-dose combination single tablet with the NS5A inhibitor ledipasvir, with very high rates of SVR with as little as 8 weeks of therapy. Combining two DAAs to sofosbuvir may shorten therapy even further. Because of the poor replicative fitness of the S282T sofosbuvir-resistant variant, resistance to sofosbuvir has not been a significant clinical issue in trials thus far. In addition to sofosbuvir, other NAs are in early-stage development. Provided unanticipated toxicity does not emerge, NAs are likely to play a major role as a backbone for future HCV therapy. The rationale for using this class of agents and the clinical data available to date are reviewed.

Keywords

hepatitis C virus - interferon - nucleoside inhibitors - direct-acting antivirals - sofosbuvir
 

  • References

  • 1 Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19 (7) 837-849
    CrossrefPubMedGoogle Scholar
  • 2 Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56 (Suppl. 01) S88-S100
    PubMedGoogle Scholar
  • 3 Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2010; 2 (30) 30ra32
    CrossrefPubMedGoogle Scholar
  • 4 Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138 (2) 447-462
    CrossrefPubMedGoogle Scholar
  • 5 Pawlotsky JM. The results of Phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: a new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterology 2011; 140 (3) 746-754
    CrossrefPubMedGoogle Scholar
  • 6 Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005; 436 (7053) 967-972
    CrossrefPubMedGoogle Scholar
  • 7 Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology 2011; 53 (5) 1742-1751
    CrossrefPubMedGoogle Scholar
  • 8 Feld JJ. Is there a role for ribavirin in the era of hepatitis C virus direct-acting antivirals?. Gastroenterology 2012; 142 (6) 1356-1359
    CrossrefPubMedGoogle Scholar
  • 9 Feld JJ, Nanda S, Huang Y , et al. Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 2007; 46 (5) 1548-1563
    CrossrefPubMedGoogle Scholar
  • 10 Sarasin-Filipowicz M, Oakeley EJ, Duong FH , et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 2008; 105 (19) 7034-7039
    CrossrefPubMedGoogle Scholar
  • 11 Migliaccio G, Tomassini JE, Carroll SS , et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem 2003; 278 (49) 49164-49170
    CrossrefPubMedGoogle Scholar
  • 12 Le Pogam S, Jiang WR, Leveque V , et al. In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology 2006; 351 (2) 349-359
    CrossrefPubMedGoogle Scholar
  • 13 Pawlotsky JM, Najera I, Jacobson I. Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase. Antivir Ther 2012; 17 (3) 411-423
    CrossrefPubMedGoogle Scholar
  • 14 Le Pogam S, Seshaadri A, Ewing A , et al. RG7128 alone or in combination with pegylated interferon-α2a and ribavirin prevents hepatitis C virus (HCV) Replication and selection of resistant variants in HCV-infected patients. J Infect Dis 2010; 202 (10) 1510-1519
    CrossrefPubMedGoogle Scholar
  • 15 Mariño Z, van Bömmel F, Forns X, Berg T. New concepts of sofosbuvir-based treatment regimens in patients with hepatitis C. Gut 2014; 63 (2) 207-215
    PubMedGoogle Scholar
  • 16 Summa V, Ludmerer SW, McCauley JA , et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56 (8) 4161-4167
    CrossrefPubMedGoogle Scholar
  • 17 Kowdley K , et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT 267, ABT-333, and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype 1 infection. Hepatology 2012; 56: S1
    PubMedGoogle Scholar
  • 18 Janssen HL, Reesink HW, Lawitz EJ , et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013; 368 (18) 1685-1694
    CrossrefPubMedGoogle Scholar
  • 19 Garcia-Rivera JA, Bobardt M, Chatterji U , et al. Multiple mutations in hepatitis C virus NS5A domain II are required to confer a significant level of resistance to alisporivir. Antimicrob Agents Chemother 2012; 56 (10) 5113-5121
    CrossrefPubMedGoogle Scholar
  • 20 Legrand-Abravanel F, Nicot F, Izopet J. New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs 2010; 19 (8) 963-975
    CrossrefPubMedGoogle Scholar
  • 21 Lewis W, Levine ES, Griniuviene B , et al. Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proc Natl Acad Sci U S A 1996; 93 (8) 3592-3597
    CrossrefPubMedGoogle Scholar
  • 22 Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov 2003; 2 (10) 812-822
    CrossrefPubMedGoogle Scholar
  • 23 Toniutto P, Fabris C, Bitetto D, Fornasiere E, Rapetti R, Pirisi M. Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus. Curr Opin Investig Drugs 2007; 8 (2) 150-158
    PubMedGoogle Scholar
  • 24 Bristol-Myers Squibb. Bristol-Myers Squibb discontinues development of BMS-986094, an investigational NS5B nucleotide for the treatment of hepatitis C. Available at: http://bms.newshq.businesswire.com/press-release/financial-news/bristol-myers-squibb-discontinues-development-bms-986094-investigationa2012 . Accessed December 30, 2013
    PubMedGoogle Scholar
  • 25 Pockros PJ. Lessons learned from failed clinical trials in hepatitis C drug development. Available at: http://www.ihlpress.com/pdf%20files/hepdart09_presentations/clinical_trial_design/6_MAC_Pockros_HEPDART09.pdf . Accessed February 10, 2014
    PubMedGoogle Scholar
  • 26 Vertex. Vertex provides update on ongoing all-oral studies of VX-135 in hepatitis C. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=7804562013 . Accessed December 30, 2013
    PubMedGoogle Scholar
  • 27 Jacobson IM, Gordon SC, Kowdley KV , et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368 (20) 1867-1877
    CrossrefPubMedGoogle Scholar
  • 28 Charlton M , et al. Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation: Preliminary Results of a Prospective, Multicenter Study. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 29 Sofia MJ, Bao D, Chang W , et al. Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010; 53 (19) 7202-7218
    CrossrefPubMedGoogle Scholar
  • 30 Gane EJ, Stedman CA, Hyland RH , et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368 (1) 34-44
    CrossrefPubMedGoogle Scholar
  • 31 Lalezari L, Nelson D, Hyland R , et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. J Hepatol 2013; 59: S1
    CrossrefPubMedGoogle Scholar
  • 32 Osinusi A, Meissner EG, Lee YJ , et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013; 310 (8) 804-811
    CrossrefPubMedGoogle Scholar
  • 33 Sovaldi. Highlights of prescribing information. Available at: http://www.gilead.com/∼/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf . Accessed December 30, 2013
    PubMedGoogle Scholar
  • 34 Jacobson I , et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: The COSMOS study. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 35 Palanisamy N, Danielsson A, Kokkula C , et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 2013; 99 (1) 12-17
    CrossrefPubMedGoogle Scholar
  • 36 Bae A, Sun SC, Qi X , et al. Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 2010; 54 (12) 5288-5297
    CrossrefPubMedGoogle Scholar
  • 37 Sulkowski MS, , GD, Rodriguez-Torres M. , et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCG GT 1, 2, or 3. Hepatology 2012; 56: S1
    PubMedGoogle Scholar
  • 38 A SPECIAL MEETING REVIEW EDITION: Advances in the Treatment of Hepatitis C Virus Infection From EASL 2013. Gastroenterol Hepatol (N Y). 2013; 9(6 Suppl 3): 1–18
    PubMedGoogle Scholar
  • 39 Lawitz E, Poordad FF, Pang PS , et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2013;
    PubMedGoogle Scholar
  • 40 Gilead. Gilead announces SVR12 rates from three phase 3 studies evaluating a once-daily fixed-dose combination of sofosbuvir and ledipasvir for Genotype 1 hepatitis c patients. Available at: http://www.gilead.com/news/press-releases/2013/12/gilead-announces-svr12-rates-from-three-phase-3-studies-evaluating-a-oncedaily-fixeddose-combination-of-sofosbuvir-and-ledipasvir-for-genotype-1-hepatitis-c-patients?mode=print-sthash.B2jn6Vun.dpuf . Accessed December 30, 2013
    PubMedGoogle Scholar
  • 41 Kohli A , et al. Combination oral, ribavirin free, antiviral therapy to optimize treatment outcomes for hepatitis C GT-1 treatment naive patients: interim results from the NIAID SYNERGY trial. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 42 Lawitz E, Mangia A, Wyles D , et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368 (20) 1878-1887
    CrossrefPubMedGoogle Scholar
  • 43 Zeuzem S , et al. Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 44 Lawitz E , et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 45 Goossens N, Negro F. Is the genotype 3 of the hepatitis C virus the new villain?. Hepatology 2013;
    PubMedGoogle Scholar
  • 46 Elfiky AA, Elshemey WM, Gawad WA, Desoky OS. Molecular modeling comparison of the performance of NS5b polymerase inhibitor (PSI-7977) on prevalent HCV genotypes. Protein J 2013; 32 (1) 75-80
    CrossrefPubMedGoogle Scholar
  • 47 Ruane PJ , et al. Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in patients of Egyptian ancestry. Hepatology 2013; 58: S1 Abstract 1090
    PubMedGoogle Scholar
  • 48 Tong X, Le Pogam S, Li L , et al. In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir. J Infect Dis 2013;
    PubMedGoogle Scholar
  • 49 Pawlotsky JM, Dahari H, Neumann AU , et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 2004; 126 (3) 703-714
    CrossrefPubMedGoogle Scholar
  • 50 Wedemeyer H, Jensen D, Herring Jr R , et al; PROPEL Investigators. PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naïve HCV genotype 1/4 patients. Hepatology 2013; 58 (2) 524-537
    CrossrefPubMedGoogle Scholar
  • 51 Feld JJ , et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine and ribavirin with or without peginterferon alfa-2a (40KD) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study. Hepatology 2012; 56 (4, Suppl): 81A
    PubMedGoogle Scholar
  • 52 Fry J , et al. VX-135, a once-daily nucleotide HCV polymerase inhibitor, was well tolerated and demonstrated potent antiviral activity when given with ribavirin in treatment-naive patients with genotype 1 HCV. Hepatology 2013; 58: S1 Abstract 1104
    PubMedGoogle Scholar
  • 53 Standring DN , et al. A Novel Uridine Nucleotide Prodrug, IDX20963, and Its Potential for Use in a Low-Dose Direct-Acting Antiviral Regimen for HCV. Hepatology 2013; 58: S1
    PubMedGoogle Scholar
  • 54 Idenix. Idenix Pharmaceuticals announces update on development program for its lead HCV nucleotide prodrug candidate, IDX20963. Available at: http://ir.idenix.com/releasedetail.cfm?ReleaseID=7728222013 . Accessed December 30, 2013
    PubMedGoogle Scholar