1887

Chapter 13 : Anti–Hepatitis Virus Agents

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in
Zoomout

Anti–Hepatitis Virus Agents, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch13-1.gif /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch13-2.gif

Abstract:

Antiviral therapy for hepatitis viruses, in particular hepatitis C virus (HCV), has evolved dramatically over the past 5 to 10 years. This chapter reviews agents that have been, or are being, developed to treat hepatitis B virus (HBV) (Chapter 32) and HCV (Chapter 54) infections. Detailed information is provided for approved agents and those in advanced stages of clinical development. Agents in earlier stages of development are described more briefly. Agents approved but rarely if ever used for a specific pathogen have been removed from this edition (e.g., interferon-α and HBV). The reader is referred to the respective disease-specific chapters for full discussions of the viral agents and the diseases they cause.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Chemical structures of agents with activity against hepatitis B virus.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Timeline of key historical events in the development of anti-HCV direct-acting agents.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3a
FIGURE 3a

Chemical structures of HCV NS5B inhibitors.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3b
FIGURE 3b

Chemical structures of HCV NS3/4A inhibitors.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3c
FIGURE 3c

Chemical structures of HCV NS5A inhibitors.

Citation: Scherer M, Sammons C, Nelson B, Hammer S, Verna E. 2017. Anti–Hepatitis Virus Agents, p 239-270. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555819439.ch13
1. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF Asia Hepatitis Lamivudine Study Group. 1998. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 339:61–.[PubMed]
2. Schiff E, Cianciara J, Karayalcin S, Kowdley K, Woessner M, McMullen S, Pearce M, Brown N. 2000. Durable HBeAg and HBsAg seroconversion after lamivudine for chronic hepatitis B. J Hepatol 32:99.
3. Naoumov NV, Lopes AR, Burra P, Caccamo L, Iemmolo RM, de Man RA, Bassendine M, O'Grady JG, Portmann BC, Anschuetz G, Barrett CA, Williams R, Atkins M. 2001. Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation. J Hepatol 34:888894.[PubMed]
4. Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, de Man RA, Goodman Z, Condreay LD, Crowther LM, Woessner MA, McPhillips PJ, Brown NA International Lamivudine Investigator Group. 2003. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol 38:818826.[PubMed]
5. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. 2005. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 352:26822695.[PubMed]
6. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Button P, Pluck N Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. 2004. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 351:12061217.[PubMed]
7. Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, Han S, Poynard T, Myers M, Chao G, Lloyd D, Brown NA Telbivudine Phase II Investigator Group. 2005. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 129:528536.[PubMed]
8. Sung JJ, Lai JY, Zeuzem S, Chow WC, Heathcote EJ, Perrillo RP, Brosgart CL, Woessner MA, Scott SA, Gray DF, Gardner SD. 2008. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol 48:728735.[PubMed]
9. Das K, Xiong X, Yang H, Westland CE, Gibbs CS, Sarafianos SG, Arnold E. 2001. Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J Virol 75:47714779.[PubMed]
10. Ono SK, Kato N, Shiratori Y, Kato J, Goto T, Schinazi RF, Carrilho FJ, Omata M. 2001. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Invest 107:449455.[PubMed]
11. Lau DT, Khokhar MF, Doo E, Ghany MG, Herion D, Park Y, Kleiner DE, Schmid P, Condreay LD, Gauthier J, Kuhns MC, Liang TJ, Hoofnagle JH. 2000. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 32:828834.[PubMed]
12. Lim SG, Ng TM, Kung N, Krastev Z, Volfova M, Husa P, Lee SS, Chan S, Shiffman ML, Washington MK, Rigney A, Anderson J, Mondou E, Snow A, Sorbel J, Guan R, Rousseau F Emtricitabine FTCB-301 Study Group. 2006. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med 166:4956.[PubMed]
13. Ying C, De Clercq E, Neyts J. 2000. Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis B virus activity in cell culture. J Viral Hepat 7:7983.[PubMed]
14. Cherrington JM, Mulato AS, Fuller MD, Chen MS. 1996. Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonomethoxy)ethyl]adenine in vitro. Antimicrob Agents Chemother 40:22122216.[PubMed]
15. Noble S, Goa KL. 1999. Adefovir dipivoxil. Drugs 58:479487; discussion 488–479.
16. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Arterburn S, Xiong S, Currie G, Brosgart CL Adefovir Dipivoxil 438 Study Group. 2005. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 352:26732681.[PubMed]
17. Fung SK, Andreone P, Han SH, Rajender Reddy K, Regev A, Keeffe EB, Hussain M, Cursaro C, Richtmyer P, Marrero JA, Lok AS. 2005. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol 43:937943.[PubMed]
18. Chang TT, Lai CL. 2006. Hepatitis B virus with primary resistance to adefovir. N Engl J Med 355:322323, author reply 323.[PubMed]
19. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL Adefovir Dipivoxil 437 Study Group. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348:808816.[PubMed]
20. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL Adefovir Dipivoxil 438 Study Group. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 348:800807.[PubMed]
21. Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, Hussain M, Lok AS. 2006. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 44:283290.[PubMed]
22. Innaimo SF, Seifer M, Bisacchi GS, Standring DN, Zahler R, Colonno RJ. 1997. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother 41:14441448.[PubMed]
23. McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL. 2007. The HBV drug entecavir—effects on HIV-1 replication and resistance. N Engl J Med 356:26142621.[PubMed]
24. Seifer M, Hamatake RK, Colonno RJ, Standring DN. 1998. In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir. Antimicrob Agents Chemother 42:32003208.[PubMed]
25. Hadziyannis SJ. 2006. New developments in the treatment of chronic hepatitis B. Expert Opin Biol Ther 6:913921.[PubMed]
26. Bifano M, Yan JH, Smith RA, Zhang D, Grasela DM, LaCreta F. 2007. Absence of a pharmacokinetic interaction between entecavir and adefovir. J Clin Pharmacol 47:13271334.[PubMed]
27. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D BEHoLD AI463022 Study Group. 2006. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 354:10011010.[PubMed]
28. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L BEHoLD AI463027 Study Group. 2006. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 354:10111020.[PubMed]
29. Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ. 2007. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother 51:902911.[PubMed]
30. Leung N, Peng CY, Hann HW, Sollano J, Lao-Tan J, Hsu CW, Lesmana L, Yuen MF, Jeffers L, Sherman M, Min A, Mencarini K, Diva U, Cross A, Wilber R, Lopez-Talavera J. 2009. 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 49:7279.[PubMed]
31. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, Boron-Kaczmarska A, Martin P, Goodman Z, Colonno R, Cross A, Denisky G, Kreter B, Hindes R AI463026 BEHoLD Study Group. 2006. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 130:20392049.[PubMed]
32. European Association for the Study of the Liver. 2012. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 57:167185.[PubMed]
33. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z, Chi YC, Zhang H, Hindes R, Iloeje U, Beebe S, Kreter B. 2010. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52:886893.[PubMed]
34. Brinkman K, Smeitink JA, Romijn JA, Reiss P. 1999. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354:11121115.[PubMed]
35. Seifer M, Patty A, Duldlan DGG, Imbach JL, Sommadossi JP, Bryant M, Standring D. 2005. Telbivudine (LdT) preferentially inhibits second (+) strand HBV DNA synthesis. J Hepatol 42:151.
36. Lai CL, Lim SG, Brown NA, Zhou XJ, Lloyd DM, Lee YM, Yuen MF, Chao GC, Myers MW. 2004. A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 40:719726.[PubMed]
37. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, Di Bisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA Globe Study Group. 2007. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357:25762588.[PubMed]
38. Standring D, Seifer M, Patty A, Chapron C, Van Doorn LJ, Chao G, Brown N, Lai CL. 2006. HBV resistance determination from the telbivudine GLOBE registration trial. J Hepatol 44:S191.
39. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, Heathcote EJ, Manns M, Bzowej N, Niu J, Han SH, Hwang SG, Cakaloglu Y, Tong MJ, Papatheodoridis G, Chen Y, Brown NA, Albanis E, Galil K, Naoumov NV GLOBE Study Group. 2009. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 136:486495.[PubMed]
40. Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, Chao YC, Myers RP, Minuk GY, Jeffers L, Sievert W, Bzowej N, Harb G, Kaiser R, Qiao XJ, Brown NA 018 Study Group. 2007. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med 147:745754.[PubMed]
41. Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B ACTG Protocol A5127 Team. 2006. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 44:11101116.[PubMed]
42. van Bömmel F, Zöllner B, Sarrazin C, Spengler U, Hüppe D, Möller B, Feucht HH, Wiedenmann B, Berg T. 2006. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 44:318325.[PubMed]
43. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. 2008. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 359:24422455.[PubMed]
44. van Bömmel F, de Man RA, Wedemeyer H, Deterding K, Petersen J, Buggisch P, Erhardt A, Hüppe D, Stein K, Trojan J, Sarrazin C, Böcher WO, Spengler U, Wasmuth HE, Reinders JG, Möller B, Rhode P, Feucht HH, Wiedenmann B, Berg T. 2010. Long-term efficacy of tenofovir monotherapy for hepatitis B virus–monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology 51:7380.[PubMed]
45. Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Dinh P, Corsa A, Subramanian GM, McHutchison JG, Husa P, Gane E. 2014. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 146:980988.[PubMed]
46. Berg T, Zoulim F, Moeller B, Trinh H, Marcellin P, Chan S, Kitrinos KM, Dinh P, Flaherty JF Jr, McHutchison JG, Manns M. 2014. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol 60:715722.[PubMed]
47. Chan HL, Chan CK, Hui AJ, Chan S, Poordad F, Chang TT, Mathurin P, Flaherty JF, Lin L, Corsa A, Gaggar A, Subramanian GM, McHutchison JG, Lau G, Lee S, Gane EJ. 2014. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology 146:12401248.[PubMed]
48. Lavocat F, Dény P, Pichoud C, Al Hawajri N, Kitrinos K, Borroto-Esoda K, Zoulim F. 2013. Similar evolution of hepatitis B virus quasispecies in patients with incomplete adefovir response receiving tenofovir/emtricitabine combination or tenofovir monotherapy. J Hepatol 59:684695.[PubMed]
49. Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, Borroto-Esoda K, Miller MD. 2014. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology 59:434442.[PubMed]
50. Gallant J, Brunetta J, Crofoot G, Benson P, Mills A, Brison C, Cheng A, Garner W, Fordyce M, Das M, McCallister S. 2015. Efficacy and safety of switching to simpler single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B coinfected adults in North America and Japan (NCT02071082): week 48 results. IAS (Supplement):387388. (abstract 13.)
51. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. 2002. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975982.[PubMed]
52. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. 2001. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958965.[PubMed]
53. Lohmann V, Körner F, Koch J, Herian U, Theilmann L, Bartenschlager R. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110113.[PubMed]
54. Farrar MA, Schreiber RD. 1993. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 11:571611.[PubMed]
55. Darnell JE Jr, Kerr IM, Stark GR. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:14151421.[PubMed]
56. Sen GC, Ransohoff RM. 1993. Interferon-induced antiviral actions and their regulation. Adv Virus Res 42:57102.[PubMed]
57. Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG. 1990. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379390.[PubMed]
58. Pavlovic J, Zürcher T, Haller O, Staeheli P. 1990. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64:33703375.[PubMed]
59. Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD. 1993. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261:14451448.[PubMed]
60. Dal Pero F, Tang KH, Gerotto M, Bortoletto G, Paulon E, Herrmann E, Zeuzem S, Alberti A, Naoumov NV. 2007. Impact of NS5A sequences of Hepatitis C virus genotype 1a on early viral kinetics during treatment with peginterferon- alpha 2a plus ribavirin. J Infect Dis 196:9981005.[PubMed]
61. Hazari S, Taylor L, Haque S, Garry RF, Florman S, Luftig R, Regenstein F, Dash S. 2007. Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in hepatitis C virus replicon. Virol J 4:89.[PubMed]
62. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. 2009. Genetic variation in IL28B predicts hepatitis C treatment–induced viral clearance. Nature 461:399401.[PubMed]
63. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M. 2009. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461:798801.[PubMed]
64. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, Carosi G, Sasadeusz J, Katlama C, Montaner J, Sette H Jr, Passe S, De Pamphilis J, Duff F, Schrenk UM, Dieterich DT APRICOT Study Group. 2004. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 351:438450.[PubMed]
65. Gish RG. 2006. Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother 57:813.[PubMed]
66. Aweeka FT, Kang M, Yu JY, Lizak P, Alston B, Chung RT AIDS Clinical Trials Group 5092s Study Team. 2007. Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team. HIV Med 8:288294.[PubMed]
67. Butt AA. 2003. Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. AIDS Read 13:344348.[PubMed]
68. Pfeiffer JK, Kirkegaard K. 2005. Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA. J Virol 79:23462355.[PubMed]
69. Simmonds P. 2004. Genetic diversity and evolution of hepatitis C virus—15 years on. J Gen Virol 85:31733188.[PubMed]
70. Stedman C. 2014. Sofosbuvir, a NS5B polymerase inhibitor in the treatment of hepatitis C: a review of its clinical potential. Therap Adv Gastroenterol 7:131140.[PubMed]
71. Gilead Sciences Inc. 2015. Sovaldi® (sofosbuvir) tablets for oral use. U.S. prescribing information. Gilead Sciences Inc, Foster City, CA.
72. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA. 2010. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem 285:3433734347.[PubMed]
73. Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA. 2010. 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 53:72027218.[PubMed]
74. 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. 2013. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 368:18671877.[PubMed]
75. 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. 2013. 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 381:21002107.[PubMed]
76. Lawitz E, Gane EJ. 2013. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 369:678679.[PubMed]
77. Brainard DM, McHutchison JG. 2015. Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med 373:1888.[PubMed]
78. 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. 2013. 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 381:21002107.[PubMed]
79. 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. 2013. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 368:18781887.[PubMed]
80. 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. 2013. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 368:18671877.[PubMed]
81. Kati W, Koev G, Irvin M, Beyer J, Liu Y, Krishnan P, Reisch T, Mondal R, Wagner R, Molla A, Maring C, Collins C. 2015. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob Agents Chemother 59:15051511.[PubMed]
82. Lu L, Dekhtyar T, Masse S, Pithawalla R, Krishnan P, He W, Ng T, Koev G, Stewart K, Larson D, Bosse T, Wagner R, Pilot-Matias T, Mo H, Molla A. 2007. Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro. Antiviral Res 76:9397.[PubMed]
83. Mo H, Lu L, Pilot-Matias T, Pithawalla R, Mondal R, Masse S, Dekhtyar T, Ng T, Koev G, Stoll V, Stewart KD, Pratt J, Donner P, Rockway T, Maring C, Molla A. 2005. Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro. Antimicrob Agents Chemother 49:43054314.[PubMed]
84. Zhou Y, Webber SE, Murphy DE, Li LS, Dragovich PS, Tran CV, Sun Z, Ruebsam F, Shah AM, Tsan M, Showalter RE, Patel R, Li B, Zhao Q, Han Q, Hermann T, Kissinger CR, Lebrun L, Sergeeva MV, Kirkovsky L. 2008. Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1‘lambda6-benzo[1’,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: exploration of 7′-substitution of benzothiadiazine. Bioorg Med Chem Lett 18:14131418.[PubMed]
85. Khatri A, Menon RM, Marbury TC, Lawitz EJ, Podsadecki TJ, Mullally VM, Ding B, Awni WM, Bernstein BM, Dutta S. 2015. Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment. J Hepatol 63:805812.[PubMed]
86. AbbVie, Inc. 2016. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), co-packaged for oral use. U.S. Prescribing Information. AbbVie, Inc, North Chicago, IL.
87. Hézode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, Marcellin P, Hall C, Schnell G, Pilot-Matias T, Mobashery N, Redman R, Vilchez RA, Pol S. 2015. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 385:25022509.[PubMed]
88. Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, Wang H, Hu B, Coakley EP, Podsadecki TJ, Awni WM, Dutta S. 2015. Drug-drug interaction profile of the all-oral anti–hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 63:2029.[PubMed]
89. Krishnan P, Tripathi R, Schnell G, Reisch T, Beyer J, Irvin M, Xie W, Larsen L, Cohen D, Podsadecki T, Pilot-Matias T, Collins C. 2015. Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. Antimicrob Agents Chemother 59:54455454.[PubMed]
90. Rigat KL, Lu H, Wang YK, Argyrou A, Fanslau C, Beno B, Wang Y, Marcinkeviciene J, Ding M, Gentles RG, Gao M, Abell LM, Roberts SB. 2014. Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase. J Biol Chem 289:3345633468.[PubMed]
91. Lemm JA, Liu M, Gentles RG, Ding M, Voss S, Pelosi LA, Wang YK, Rigat KL, Mosure KW, Bender JA, Knipe JO, Colonno R, Meanwell NA, Kadow JF, Santone KS, Roberts SB, Gao M. 2014. Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase. Antimicrob Agents Chemother 58:34853495.[PubMed]
92. He B, Sims K, Chung E, Luo WL, Pursley J, Wind-Rotolo M, LaCreta F, Bertz R, AbuTarif M. 2015. The pharmacokinetics of beclabuvir (BMS-791325) when administered in combination with daclatasvir and asunaprevir in treatment-naïve patients with or without cirrhosis infected with HCV genotype 1. J Hepatol 62(EASL Suppl.):S633S634. abstract P0799.
93. Sims KD, Lemm J, Eley T, Liu M, Berglind A, Sherman D, Lawitz E, Vutikullird AB, Tebas P, Gao M, Pasquinelli C, Grasela DM. 2014. Randomized, placebo-controlled, single-ascending-dose study of BMS-791325, a hepatitis C virus (HCV) NS5B polymerase inhibitor, in HCV genotype 1 infection. Antimicrob Agents Chemother 58:34963503.[PubMed]
94. AbuTarif M, He B, Ding Y, Sims K, Zhu K, Rege B, Pursley J, Wind-Rotolo M, Li W, Bertz RJ. 2014. The effect of steady-state BMS-791-325, a non-nucleoside HCV NS5B inhibitor, on the pharmacokinetics of midazolam in healthy Japanese and Caucasian males. [abstract P_22]. Rev Antiviral Ther Inf Dis (Supplement, 15th International Workshop in Clinical Pharmacology of HIV & Hepatitis Therapy):4849.
95. Tao X, Sims K, Hesney M, Stonier M, Pursley J, Griffies A, Bhatnagar R, Smith C, Huang J, AbuTarif M. 2015. The effect of daclatasvir, asunaprevir, and beclabuvir on the pharmacokinetics of selective serotonin reuptake inhibitors in healthy subjects. [abstract 81]. Rev Antiviral Ther Inf Dis (Supplement, 16th International Workshop in Clinical Pharmacology of HIV & Hepatitis Therapy):83.
96. Everson GT, Sims KD, Rodriguez-Torres M, Hézode C, Lawitz E, Bourlière M, Loustaud-Ratti V, Rustgi V, Schwartz H, Tatum H, Marcellin P, Pol S, Thuluvath PJ, Eley T, Wang X, Huang SP, McPhee F, Wind-Rotolo M, Chung E, Pasquinelli C, Grasela DM, Gardiner DF. 2014. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 146:420429.[PubMed]
97. Poordad F, Sievert W, Mollison L, Bennett M, Tse E, Bräu N, Levin J, Sepe T, Lee SS, Angus P, Conway B, Pol S, Boyer N, Bronowicki JP, Jacobson I, Muir AJ, Reddy KR, Tam E, Ortiz-Lasanta G, de Lédinghen V, Sulkowski M, Boparai N, McPhee F, Hughes E, Swenson ES, Yin PD UNITY-1 Study Group. 2015. Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection. JAMA 313:17281735.[PubMed]
98. Muir AJ, Poordad F, Lalezari J, Everson G, Dore GJ, Herring R, Sheikh A, Kwo P, Hézode C, Pockros PJ, Tran A, Yozviak J, Reau N, Ramji A, Stuart K, Thompson AJ, Vierling J, Freilich B, Cooper J, Ghesquiere W, Yang R, McPhee F, Hughes EA, Swenson ES, Yin PD. 2015. Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. JAMA 313:17361744.[PubMed]
99. Hassanein T, Sims KD, Bennett M, Gitlin N, Lawitz E, Nguyen T, Webster L, Younossi Z, Schwartz H, Thuluvath PJ, Zhou H, Rege B, McPhee F, Zhou N, Wind-Rotolo M, Chung E, Griffies A, Grasela DM, Gardiner DF. 2015. A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection. J Hepatol 62:12041206.[PubMed]
100. Gentile I, Buonomo AR, Zappulo E, Coppola N, Borgia G. 2014. GS-9669: a novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 12:11791186.[PubMed]
101. Kohli A, Osinusi A, Sims Z, Nelson A, Meissner EG, Barrett LL, Bon D, Marti MM, Silk R, Kotb C, Gross C, Jolley TA, Sidharthan S, Petersen T, Townsend K, Egerson D, Kapoor R, Spurlin E, Sneller M, Proschan M, Herrmann E, Kwan R, Teferi G, Talwani R, Diaz G, Kleiner DE, Wood BJ, Chavez J, Abbott S, Symonds WT, Subramanian GM, Pang PS, McHutchison J, Polis MA, Fauci AS, Masur H, Kottilil S. 2015. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 385:11071113.[PubMed]