Advances in newly developing therapy for chronic hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. Increased understanding of the HCV has allowed further development of new direct-acting antiviral (DAA) agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. In late 2013 the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG-IFN+RBV for genotypes 1, 4 was approved for use in the US. A number of promising new DAA regimens which are IFN-free are in phase 3 development and the first will likely be approved for use in the US in 2014. The currently approved regimens are discussed in detail and currently available data on future regimens are reviewed herein.

Keywords

direct-acting antiviral (DAA) / nucleotide polymerase inhibitors / protease inhibitors

References

[1] Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012; 19(7): 449−464

[2] Pockros PJ. New direct-acting antivirals in the development for hepatitis C virus infection. Therap Adv Gastroenterol 2010; 3(3): 191−202

[3] US Food and Drug Administration. Approval of Victrelis (boceprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV).

[4] US Food and Drug Administration. Approval of Incivek (telaprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV).

[5] Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13): 1195−1206

[6] Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364(25): 2405−2416

[7] McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM; PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362(14): 1292−1303

[8] Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13): 1207−1217

[9] FDA Drug Safety Communication. Serious skin reactions after combination treatment with the hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin.

[10] Suzuki F, Sezaki H, Akuta N, Suzuki Y, Seko Y, Kawamura Y, Hosaka T, Kobayashi M, Saito S, Arase Y, Ikeda K, Kobayashi M, Mineta R, Watahiki S, Miyakawa Y, Kumada H. Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b. J Clin Virol 2012; 54(4): 352−354

[11] Ali A, Aydin C, Gildemeister R, Romano KP, Cao H, Ozen A, Soumana D, Newton A, Petropoulos CJ, Huang W, Schiffer CA. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 2013; 8(7): 1469−1478

[12] Hunt D, Pockros P. What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr Gastroenterol Rep 2013; 15(1): 303

[13] Prescribing Information for OLYSIO TM (simeprevir): Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued 2013-November

[14] Evans MJ, Rice CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci USA 2004; 101(35): 13038−13043

[15] Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4(3): e1000032

[16] Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465(7294): 96−100

[17] Gilead Sciences Inc. Solvadi^TM (sofosbuvir) tablets, for oral use: US prescribing information. 2013.

[18] Svarovskaia ES, Dvory HS, Hebner C, . No resistance detected in four phase 3 clinical studies in HCV genotype 1−6 of sofosbuvir+ ribavirin with or without peginterferon. Hepatology 2013; 58(4 Suppl): 1091A−1092A (abstract No. 1843)

[19] Svarovskaia ES, Dvory-Sobol H, Gontcharova V, . Comprehensive resistance testing in patients who relapsed after treatment with sofosbuvir (GS-7977)-containing regimens in phase 2 studies. Hepatology 2012; 56(4 Suppl): 551A (abstract No. 753)

[20] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, Afdhal N, Vierling JM, Gordon SC, Anderson JK, Hyland RH, Dvory-Sobol H, An D, Hindes RG, Albanis E, Symonds WT, Berrey MM, Nelson DR, Jacobson IM. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381(9883): 2100−2107

[21] Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13(5): 401−408

[22] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368(1): 34−44

[23] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR, Jacobson IM, Kowdley KV, Nyberg L, Subramanian GM, Hyland RH, Arterburn S, Jiang D, McNally J, Brainard D, Symonds WT, McHutchison JG, Sheikh AM, Younossi Z, Gane EJ. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368(20): 1878−1887

[24] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, Schiff E, Al-Assi MT, Subramanian GM, An D, Lin M, McNally J, Brainard D, Symonds WT, McHutchison JG, Patel K, Feld J, Pianko S, Nelson DR; 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

[25] Zeuzem S, Dusheiko GM, Salupere R, . Sofosbuvir+ ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58(4 Suppl): 733A−734A (abstract No. 1085)

[26] Sulkowski MS, Rodriguez-Torres M, Lalezari JP, . All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology 2013; 58(4 Suppl): 313A−314A (abstract No. 212)

[27] Curry MP, Forns X, Chung RT, . Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58(4 Suppl): 314A−315A (abstract No. 213)

[28] Charlton MR, Gane EJ, Manns MP, . 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(6 Suppl): 1378A (abstract No. LB-2)

[29] Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosgurin P, Nicolas-Métral V, Dumont JM, Porchet H, Crabbé R, Scalfaro P. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008; 47(3): 817−826

[30] Flisiak R, Feinman SV, Jablkowski M, Horban A, Kryczka W, Pawlowska M, Heathcote JE, Mazzella G, Vandelli C, Nicolas-Métral V, Grosgurin P, Liz JS, Scalfaro P, Porchet H, Crabbé R. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology 2009; 49(5): 1460−1468

[31] Pawlotsky JM, Sarin SK, Foster G, . Alisporivir plus ribavirin is highly effective as interferon-free or interferon add- on regimen in previously untreated HCV-GT2 or GT3 patients: SVR12 results from VITAL-1 phase 2b study[abstract No. LB 11]. 47th Annual 791 Meeting of the European Association for the Study of the Liver; 2012-Apr; Barcelona

[32] Au J, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014; 95(1): 78−88

[33] Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. 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 2014; 383(9916): 515−523

[34] Gane EJ, Stedman CA, Hyland RH, . Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: data from the ELECTRON trial. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 73

[35] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 2013; 368(1): 45−53

[36] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, Everson GT, Kwo P, Foster GR, Sulkowski MS, Xie W, Pilot-Matias T, Liossis G, Larsen L, Khatri A, Podsadecki T, Bernstein B. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014; 370(3): 222−232

[37] Cohen DE, Xie W, Larsen L, . Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects with Ribavirin Dose Reductions 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 1118

[38] Everson GT, Sims KD, Thuluvath PJ, . Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve patients with chronic HCV genotype 1 infection. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB1

[39] Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366(3): 216−224

[40] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370(3): 211−221

[41] Jacobson IM, Asselah T, Ferenci P, . STARTVerso3: A randomized, double-blind, placebo-controlled Phase III trial of faldaprevir in combination with pegylated interferon alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 1100

[42] Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Müllhaupt B, Schuchmann M, Bourlière M, Buti M, Roberts SK, Gane EJ, Stern JO, Vinisko R, Kukolj G, Gallivan JP, Böcher WO, Mensa FJ. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369(7): 630−639

[43] Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB20

[44] Lawitz E, Vierling JM, Murillo A, . High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742+/ RBV for 12 weeks in HCV genotype 1 infected patients: the C-WORTHY Study. 64th Annual Meeting of the American Association for the Study of Liver diseases, November-1−5, 2013, Washington; abstract 76

[45] Jacobson IM, Ghalib RH, Rodriguez-Torres M, . 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-naïve and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB3

[46] Younossi ZM, Singer ME, Mir HM, Henry L, Hunt S. Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients. J Hepatol 2014; 60(3): 530−537

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