Lethal mutagenesis of hepatitis C virus induced by favipiravir

PLoS ONE

Volumn 11, Issue 10, 2016, Pages

  De Ávila, Ana I ^a   Gallego, Isabel ^a,b   Soria, Maria Eugenia ^c   Gregori, Josep ^b,c,d   Quer, Josep ^b,c,e   Ignacio Esteban, Juan ^b,c,e   Rice, Charles M ^f   Domingo, Esteban ^a,b   Perales, Celia ^a,b,c  

^a CSIC   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

^c HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^d Roche Diagnostics SL   (Spain)

^e UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^f ROCKEFELLER UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; CYSTEINE; FAVIPIRAVIR; GLYCINE; MUTAGENIC AGENT; AMIDE; ANTIVIRUS AGENT; PYRAZINE DERIVATIVE; VIRUS RNA;

AMINO ACID SUBSTITUTION; ARTICLE; CC50; CONCENTRATION RESPONSE; HEPATITIS C VIRUS; HEPATOMA CELL; HUMAN; HUMAN CELL; MUTAGENESIS; NONHUMAN; VIRAL CLEARANCE; VIRUS INFECTIVITY; VIRUS LETHAL MUTAGENESIS; VIRUS MUTATION; VIRUS REPLICATION; CELL SURVIVAL; CHEMISTRY; DRUG EFFECTS; GENETICS; HEPACIVIRUS; HIGH THROUGHPUT SEQUENCING; ISOLATION AND PURIFICATION; METABOLISM; MUTATION; PHYSIOLOGY; SEQUENCE ANALYSIS; TUMOR CELL LINE;

AMIDES; ANTIVIRAL AGENTS; CELL LINE, TUMOR; CELL SURVIVAL; HEPACIVIRUS; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; MUTATION; PYRAZINES; RNA, VIRAL; SEQUENCE ANALYSIS, RNA; VIRUS REPLICATION;

EID: 84992111855     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0164691     Document Type: Article

References (106)

1. Eigen M, Schuster P (1979) The hypercycle. A principle of natural self-organization. Berlin: Springer.
2. Loeb LA, Essigmann JM, Kazazi F, Zhang J, Rose KD, Mullins JI (1999) Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci USA 96: 1492-1497. PMID: 9990051
3. Graci JD, Cameron CE (2008) Therapeutically targeting RNA viruses via lethal mutagenesis. Future Virol 3: 553-566. doi: 10.2217/17460794.3.6.553 PMID: 19727424
4. Dapp MJ, Patterson SE, Mansky LM (2013) Back to the future: revisiting HIV-1 lethal mutagenesis. Trends Microbiol 21: 56-62. doi: 10.1016/j.tim.2012.10.006 PMID: 23195922
5. Holland JJ, Domingo E, de la Torre JC, Steinhauer DA (1990) Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis. J Virol 64: 3960-3962. PMID: 1695258
6. Domingo E, Schuster P (2016) Quasispecies: from theory to experimental systems. Current Topics in Microbiology and Immunology. Vol. 392. Springer.
7. Schuster P (2016) Quasispecies on fitness landscapes. In: E. Domingo and P. Schuster, eds. Quasispecies: From Theory to Experimental Systems. Curr Top Microbiol Immunol 392: 61-120.
8. Dietz J, Schelhorn SE, Fitting D, Mihm U, Susser S, Welker MW, et al. (2013) Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients. J Virol 87: 6172-6181. doi: 10.1128/JVI.02778-12 PMID: 23536652
9. Cuevas JM, Gonzalez-Candelas F, Moya A, Sanjuan R (2009) Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. J Virol 83: 5760-5764. doi: 10.1128/JVI.00201-09 PMID: 19321623
10. Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, et al. (2002) In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother 46: 977-981. doi: 10.1128/AAC.46.4.977-981.2002 PMID: 11897578
11. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, et al. (2005) Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 49: 981-986. doi: 10.1128/AAC.49.3.981-986.2005 PMID: 15728892
12. Sakamoto K, Ohashi S, Yamazoe R, Takahashi K, Furuta Y (2006) The inhibition of FMD virus excretion from the infected pigs by an antiviral agent, T-1105. Appendix 64 Session of the Research Group of the Standing Technical Committee of the Eu FMD.
13. Furuta Y, Takahashi K, Maekawa M, Maegawa H, Egawa H, Terashima N (2004) T-1106, a novel pyrazine nucleoside, hepatitis C virus polymerase inhibitor. In: Abstr 44th Intersci Conf Antimicrob Agents Chemother, pp 199-200, Abstr F-487.
14. Gowen BB, Wong MH, Jung KH, Sanders AB, Mendenhall M, Bailey KW, et al. (2007) In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob Agents Chemother 51: 3168-3176. doi: 10.1128/AAC.00356-07 PMID: 17606691
15. Morrey JD, Taro BS, Siddharthan V, Wang H, Smee DF, Christensen AJ, et al. (2008) Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. Antiviral Res 80: 377-379. doi: 10.1016/j.antiviral.2008.07.009 PMID: 18762216
16. Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, et al. (2009) T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res 82: 95-102. doi: 10.1016/j.antiviral.2009.02.198 PMID: 19428599
17. Smee DF, Hurst BL, Egawa H, Takahashi K, Kadota T, Furuta Y (2009) Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells. J Antimicrob Chemother 64: 741-746. doi: 10.1093/jac/dkp274 PMID: 19643775
18. Julander JG, Shafer K, Smee DF, Morrey JD, Furuta Y (2009) Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob Agents Chemother 53: 202-209. doi: 10.1128/AAC.01074-08 PMID: 18955536
19. Gowen BB, Wong MH, Jung KH, Smee DF, Morrey JD, Furuta Y (2010) Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models. Antiviral Res 86: 121-127. doi: 10. 1016/j.antiviral.2009.10.015 PMID: 19874853
20. Kiso M, Takahashi K, Sakai-Tagawa Y, Shinya K, Sakabe S, Le QM, et al. (2010) T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc Natl Acad Sci U S A 107: 882-887. doi: 10. 1073/pnas.0909603107 PMID: 20080770
21. Mendenhall M, Russell A, Smee DF, Hall JO, Skirpstunas R, Furuta Y, et al. (2011) Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever. PLoS Negl Trop Dis 5: e1342. doi: 10.1371/journal.pntd.0001342 PMID: 22022624
22. Gowen BB, Juelich TL, Sefing EJ, Brasel T, Smith JK, Zhang L, et al. (2013) Favipiravir (T-705) inhibits Junin virus infection and reduces mortality in a guinea pig model of Argentine hemorrhagic fever. PLoS Negl Trop Dis 7: e2614. doi: 10.1371/journal.pntd.0002614 PMID: 24386500
23. Safronetz D, Falzarano D, Scott DP, Furuta Y, Feldmann H, Gowen BB (2013) Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Antimicrob Agents Chemother 57: 4673-4680. doi: 10.1128/AAC.00886-13 PMID: 23856782
24. Smee DF, Tarbet EB, Furuta Y, Morrey JD, Barnard DL (2013) Synergistic combinations of favipiravir and oseltamivir against wild-type pandemic and oseltamivir-resistant influenza A virus infections in mice. Future Virol 8: 1085-1094. doi: 10.2217/fvl.13.98 PMID: 24563658
25. Caroline AL, Powell DS, Bethel LM, Oury TD, Reed DS, Hartman AL (2014) Broad spectrum antiviral activity of favipiravir (T-705): protection from highly lethal inhalational Rift Valley Fever. PLoS Negl Trop Dis 8: e2790. doi: 10.1371/journal.pntd.0002790 PMID: 24722586
26. Scharton D, Bailey KW, Vest Z, Westover JB, Kumaki Y, Van Wettere A, et al. (2014) Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antiviral Res 104: 84-92. doi: 10.1016/j.antiviral.2014.01. 016 PMID: 24486952
27. Yamada K, Noguchi K, Komeno T, Furuta Y, Nishizono A (2016) Efficacy of Favipiravir (T-705) in Rabies Postexposure Prophylaxis. J Infect Dis 213: 1253-1261. doi: 10.1093/infdis/jiv586 PMID: 26655300
28. Safronetz D, Rosenke K, Westover JB, Martellaro C, Okumura A, Furuta Y, et al. (2015) The broadspectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset. Sci Rep 5: 14775. doi: 10.1038/srep14775 PMID: 26456301
29. Westover JB, Sefing EJ, Bailey KW, Van Wettere AJ, Jung KH, Dagley A, et al. (2016) Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res 126: 62-68. doi: 10.1016/j.antiviral.2015.12.006 PMID: 26711718
30. Oestereich L, Rieger T, Ludtke A, Ruibal P, Wurr S, Pallasch E, et al. (2016) Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. J Infect Dis 213: 934-938. doi: 10.1093/infdis/jiv522 PMID: 26531247
31. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (2013) Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 100: 446-454. doi: 10.1016/j.antiviral.2013.09. 015 PMID: 24084488
32. Sangawa H, Komeno T, Nishikawa H, Yoshida A, Takahashi K, Nomura N, et al. (2013) Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob Agents Chemother 57: 5202-5208. doi: 10.1128/AAC.00649-13 PMID: 23917318
33. Jin Z, Smith LK, Rajwanshi VK, Kim B, Deval J (2013) The ambiguous base-pairing and high substrate efficiency of T-705 (Favipiravir) Ribofuranosyl 5'-triphosphate towards influenza A virus polymerase. PLoS ONE 8: e68347. doi: 10.1371/journal.pone.0068347 PMID: 23874596
34. Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, et al. (2013) T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol 87: 3741-3751. doi:10. 1128/JVI.02346-12 PMID: 23325689
35. Arias A, Thorne L, Goodfellow I (2014) Favipiravir elicits antiviral mutagenesis during virus replication in vivo. Elife 3: e03679. doi: 10.7554/eLife.03679 PMID: 25333492
36. Blight KJ, McKeating JA, Rice CM (2002) Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol 76: 13001-13014. doi: 10.1128/JVI.76.24.13001-13014. 2002 PMID: 12438626
37. Jones CT, Catanese MT, Law LM, Khetani SR, Syder AJ, Ploss A, et al. (2010) Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nat Biotechnol 28: 167-171. doi: 10.1038/nbt.1604 PMID: 20118917
38. Vandamme A, Witvrouw M, Pannecouque C, Balzarini J, Van Laethem K, Schmit J, et al. (2000) Evaluating Clinical Isolates for Their Phenotypic and Genotypic Resistance Against Anti-HIV Drugs; Kinchington D, Schinazi R, editors. Totowa, NJ: Humana Press Inc.
39. Perales C, Beach NM, Gallego I, Soria ME, Quer J, Esteban JI, et al. (2013) Response of hepatitis C virus to long-term passage in the presence of alpha interferon. Multiple mutations and a common phenotype. J Virol 87: 7593-7607. doi: 10.1128/JVI.02824-12 PMID: 23637397
40. Lindenbach BD, Rice CM (2003) Evasive maneuvers by hepatitis C virus. Hepatology 38: 769-771. doi: 10.1002/hep.510380327 PMID: 12939603
41. Perales C, Beach NM, Gallego I, Soria ME, Quer J, Esteban JI, et al. (2013) Response of hepatitis C virus to long-term passage in the presence of alpha interferon: multiple mutations and a common phenotype. J Virol 87: 7593-7607. doi: 10.1128/JVI.02824-12 PMID: 23637397
42. Ortega-Prieto AM, Sheldon J, Grande-Perez A, Tejero H, Gregori J, Quer J, et al. (2013) Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis. PLoS One 8: e71039. doi: 10.1371/journal.pone.0071039 PMID: 23976977
43. Airaksinen A, Pariente N, Menendez-Arias L, Domingo E (2003) Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis. Virology 311: 339-349. PMID: 12842623
44. Sanchez G, Bosch A, Gomez-Mariano G, Domingo E, Pinto RM (2003) Evidence for quasispecies distributions in the human hepatitis A virus genome. Virology 315: 34-42. PMID: 14592757
45. Gregori J, Esteban JI, Cubero M, Garcia-Cehic D, Perales C, Casillas R, et al. (2013) Ultra-Deep Pyrosequencing (UDPS) Data Treatment to Study Amplicon HCV Minor Variants. PLoS ONE 8: e83361. doi: 10.1371/journal.pone.0083361 PMID: 24391758
46. Ramirez C, Gregori J, Buti M, Tabernero D, Camos S, Casillas R, et al. (2013) A comparative study of ultra-deep pyrosequencing and cloning to quantitatively analyze the viral quasispecies using hepatitis B virus infection as a model. Antiviral Res 98: 273-283. doi: 10.1016/j.antiviral.2013.03.007 PMID: 23523552
47. Gregori J, Perales C, Rodriguez-Frias F, Esteban JI, Quer J, Domingo E (2016) Viral quasispecies complexity measures. Virology 493: 227-237. doi: 10.1016/j.virol.2016.03.017 PMID: 27060566
48. Gregori J, Salicru M, Domingo E, Sanchez A, Esteban JI, Rodriguez-Frias F, et al. (2014) Inference with viral quasispecies diversity indices: clonal and NGS approaches. Bioinformatics 30:1104-1111.
49. Efron B, Tibshirani R (1994) An introduction to the bootstrap, Chapman & Hall/CRC, Boca Raton.
50. Davidson AC, Hinkley DV (1997) Bootstrap Methods and their applications, Cambridge University Press, Cambridge.
51. Dudoit S, van der Laan MJ (2008) Multiple testing procedures with applications to genomics. Springer, New York.
52. Lindenbach BD (2009) Measuring HCV infectivity produced in cell culture and in vivo. Methods Mol Biol 510: 329-336. doi: 10.1007/978-1-59745-394-3-24 PMID: 19009272
53. Grande-Perez A, Gomez-Mariano G, Lowenstein PR, Domingo E (2005) Mutagenesis-induced, large fitness variations with an invariant arenavirus consensus genomic nucleotide sequence. J Virol 79: 10451-10459. doi: 10.1128/JVI.79.16.10451-10459.2005 PMID: 16051837
54. Gonzalez-Lopez C, Gomez-Mariano G, Escarmos C, Domingo E (2005) Invariant aphthovirus consensus nucleotide sequence in the transition to error catastrophe. Infection Genetics and Evolution 5: 366-374.
55. Sheldon J, Beach NM, Moreno E, Gallego I, Pineiro D, Martinez-Salas E, et al. (2014) Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus. J Virol 88: 12098-12111. doi: 10.1128/JVI.01860-14 PMID: 25122776
56. Rocha-Pereira J, Jochmans D, Dallmeier K, Leyssen P, Nascimento MS, Neyts J (2012) Favipiravir (T-705) inhibits in vitro norovirus replication. Biochem Biophys Res Commun 424: 777-780. doi: 10. 1016/j.bbrc.2012.07.034 PMID: 22809499
57. Gallego I, Sheldon J, Moreno E, Gregori J, Quer J, Esteban JI, et al. (2016) Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus. Antimicrob Agents Chemother 60: 3786-3793. doi: 10.1128/AAC.00581-16 PMID: 27067341
58. Domingo E (2016) Virus as Populations. Academic Press, Elsevier, Amsterdam.
59. Domingo E, Sheldon J, Perales C (2012) Viral quasispecies evolution. Microbiol Mol Biol Rev 76: 159-216. doi: 10.1128/MMBR.05023-11 PMID: 22688811
60. Perales C, Henry M, Domingo E, Wain-Hobson S, Vartanian JP (2011) Lethal mutagenesis of footand-mouth disease virus involves shifts in sequence space. J Virol 85: 12227-12240. doi: 10.1128/JVI.00716-11 PMID: 21917974
61. Sierra M, Airaksinen A, Gonzalez-Lopez C, Agudo R, Arias A, Domingo E (2007) Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe. J Virol 81: 2012-2024. doi: 10.1128/JVI.01606-06 PMID: 17151116
62. Grande-Perez A, Lazaro E, Lowenstein P, Domingo E, Manrubia SC (2005) Suppression of viral infectivity through lethal defection. Proc Natl Acad Sci USA 102: 4448-4452. doi: 10.1073/pnas. 0408871102 PMID: 15767582
63. Agudo R, Ferrer-Orta C, Arias A, de la Higuera I, Perales C, Perez-Luque R, et al. (2010) A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape. PLoS Pathog 6: e1001072. doi: 10.1371/journal.ppat.1001072 PMID: 20865120
64. Agudo R, de la Higuera I, Arias A, Grande-Perez A, Domingo E (2016) Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism. Virology 494: 257-266. doi: 10.1016/j.virol.2016.04.023 PMID: 27136067
65. Agudo R, Arias A, Pariente N, Perales C, Escarmis C, Jorge A, et al. (2008) Molecular characterization of a dual inhibitory and mutagenic activity of 5-fluorouridine triphosphate on viral RNA synthesis. Implications for lethal mutagenesis. J Mol Biol 382: 652-666. doi: 10.1016/j.jmb.2008.07.033 PMID: 18662697
66. Keating GM (2014) Sofosbuvir: A review of its use in patients with chronic hepatitis C. Drugs 74: 1127-1146. doi: 10.1007/s40265-014-0247-z PMID: 24958336
67. Koff RS (2014) Review article: The efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther 39: 478-487. doi: 10.1111/apt.12601 PMID: 24387618
68. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. (2013) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368: 34-44. doi: 10.1056/NEJMoa1208953 PMID: 23281974
69. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. (2013) Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 368: 1867-1877. doi: 10.1056/NEJMoa1214854 PMID: 23607593
70. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, et al. (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: 2100-2107. doi: 10.1016/S0140-6736(13)60247-0 PMID: 23499440
71. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. (2014) Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 370: 1879-1888. doi: 10.1056/NEJMoa1402355 PMID: 24720702
72. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. (2013) Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 368: 1878-1887. doi: 10.1056/NEJMoa1214853 PMID: 23607594
73. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. (2013) 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 13: 401-408. doi: 10.1016/S1473-3099(13)70033-1 PMID: 23499158
74. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. (2014) Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 370: 1483-1493. doi: 10.1056/NEJMoa1316366 PMID: 24725238
75. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. (2014) Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370: 1889-1898. doi: 10.1056/NEJMoa1402454 PMID: 24725239
76. Asselah T (2014) Daclatasvir plus sofosbuvir for HCV infection: an oral combination therapy with high antiviral efficacy. J Hepatol 61: 435-438. doi: 10.1016/j.jhep.2014.04.042 PMID: 24816173
77. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, et al. (2014) 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 383: 515-523. doi: 10.1016/S0140-6736(13)62121-2 PMID: 24209977
78. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, et al. (2014) Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: The COSMOS randomised study. Lancet 384: 1756-1765. doi: 10.1016/S0140-6736(14)61036-9 PMID: 25078309
79. Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. (2014) Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 370: 1993-2001. doi: 10.1056/NEJMoa1316145 PMID: 24795201
80. Asselah T, Boyer N, Saadoun D, Martinot-Peignoux M, Marcellin P (2016) Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives. Liver Int 36 Suppl 1: 47-57.
81. Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. (2015) Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 373: 2599-2607. doi: 10.1056/NEJMoa1512610 PMID: 26571066
82. Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, et al. (2015) Ledipasvir and sofosbuvir for hepatitis C genotype 4: A proof-of-concept, single-centre, open-label phase 2a cohort study. Lancet Infect Dis 15: 1049-1054. doi: 10.1016/S1473-3099(15)00157-7 PMID: 26187031
83. Buti M, Esteban R (2015) Hepatitis C virus genotype 3: A genotype that is not 'easy-to-treat'. Expert Rev Gastroenterol Hepatol 9: 375-385. doi: 10.1586/17474124.2015.960396 PMID: 25222289
84. Buti M, Llaneras J, Riveiro-Barciela M, Esteban R (2015) Therapy for hepatitis C genotype 3: moving forward. J Viral Hepat 22: 683-690. doi: 10.1111/jvh.12419 PMID: 25967352
85. Ferenci P (2015) Treatment of hepatitis C in difficult-to-treat patients. Nat Rev Gastroenterol Hepatol 12: 284-292. doi: 10.1038/nrgastro.2015.53 PMID: 25895822
86. Sato M, Maekawa S, Komatsu N, Tatsumi A, Miura M, Muraoka M, et al. (2015) Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. J Virol 89: 6105-6116. doi: 10.1128/JVI. 03127-14 PMID: 25810555
87. Svarovskaia ES, Dvory-Sobol H, Parkin N, Hebner C, Gontcharova V, Martin R, et al. (2014) Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 59: 1666-1674. doi: 10.1093/cid/ciu697 PMID: 25266287
88. Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang EZ, Spanks J, et al. (2013) Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. Clin Infect Dis 57: 221-229. doi: 10.1093/cid/cit226 PMID: 23575197
89. Foster GR, Pianko S, Brown A, Forton D, Nahass RG, George J, et al. (2015) Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 149: 1462-1470. doi: 10.1053/j.gastro.2015.07.043 PMID: 26248087
90. Reig M, Marino Z, Perello C, Inarrairaegui M, Ribeiro A, Lens S, et al. (2016) Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferonfree therapy: A note of caution. J Hepatol In press.
91. Hultgren C, Milich DR, Weiland O, Sallberg M (1998) The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol 79 (Pt 10): 2381-2391. doi: 10.1099/0022-1317-79-10-2381 PMID: 9780043
92. Ning Q, Brown D, Parodo J, Cattral M, Gorczynski R, Cole E, et al. (1998) Ribavirin inhibits viralinduced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J Immunol 160: 3487-3493. PMID: 9531310
93. Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, et al. (2007) Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 46: 1548-1563. doi: 10.1002/hep.21853 PMID: 17929300
94. Zhang Y, Jamaluddin M, Wang S, Tian B, Garofalo RP, Casola A, et al. (2003) Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol 77: 5933-5947. doi: 10.1128/JVI.77.10.5933-5947. 2003 PMID: 12719586
95. Eriksson B, Helgstrand E, Johansson NG, Larsson A, Misiorny A, Noren JO, et al. (1977) Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate. Antimicrob Agents Chemother 11: 946-951. PMID: 879760
96. Bougie I, Bisaillon M (2003) Initial binding of the broad spectrum antiviral nucleoside ribavirin to the hepatitis C virus RNA polymerase. J Biol Chem 278: 52471-52478. doi: 10.1074/jbc.M308917200 PMID: 14563844
97. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, et al. (1973) Mechanism of action of 1-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci USA 70: 1174-1178. PMID: 4197928
98. Goswami BB, Borek E, Sharma OK, Fujitaki J, Smith RA (1979) The broad spectrum antiviral agent ribavirin inhibits capping of mRNA. Biochem Biophys Res Commun 89: 830-836. PMID: 226095
99. Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, et al. (2015) Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatmentexperienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): A randomised, open-label trial. Lancet 385: 2502-2509. doi: 10.1016/S0140-6736(15)60159-3 PMID: 25837829
100. Wyles D, Pockros P, Morelli G, Younes Z, Svarovskaia E, Yang JC, et al. (2015) Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens. Hepatology 61: 1793-1797. doi: 10.1002/hep.27814 PMID: 25846014
101. Sarrazin C (2016) The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 64: 486-504. doi: 10.1016/j.jhep.2015.09.011 PMID: 26409317
102. Wyles DL, Gutierrez JA (2014) Importance of HCV genotype 1 subtypes for drug resistance and response to therapy. J Viral Hepat 21: 229-240. doi: 10.1111/jvh.12230 PMID: 24597691
103. Farci P, Purcell RH (2000) Clinical significance of hepatitis C virus genotypes and quasispecies. Semin Liver Dis 20: 103-126. PMID: 10895435
104. Farci P (2011) New insights into the HCV quasispecies and compartmentalization. Semin Liver Dis 31: 356-374. doi: 10.1055/s-0031-1297925 PMID: 22189976
105. Harouaka D, Engle RE, Wollenberg K, Diaz G, Tice AB, Zamboni F, et al. (2016) Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci U S A 113: 1375-1380. doi: 10.1073/pnas.1516879113 PMID: 26787866
106. Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. (2016) Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med 13: e1001967. doi: 10.1371/journal.pmed. 1001967 PMID: 26930627