“Too Little, Too Late?” Will Inhibitors of the Hepatitis C Virus P7 Ion Channel Ever Be Used in the Clinic?

References

• Pawlotsky JM , ChevaliezS, MchutchisonJG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology132 (5), 1979–1998 (2007).
   PubMed Web of Science ®Google Scholar
• 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. Gastroenterology140 (3), 746–754 (2011).
   PubMedGoogle Scholar
• Afdhal N , ReddyKR, NelsonDRet al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N. Engl. J. Med.370 (16), 1483–1493 (2014).
   PubMed Web of Science ®Google Scholar
• Afdhal N , ZeuzemS, KwoPet al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med.370 (20), 1889–1898 (2014).
   PubMed Web of Science ®Google Scholar
• Dhaliwal HS , NampoothiriRV. Daclatasvir plus sofosbuvir for HCV infection. N. Engl. J. Med.370 (16), 1560 (2014).
   PubMed Web of Science ®Google Scholar
• Kowdley KV , GordonSC, ReddyKRet al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N. Engl. J. Med.370 (20), 1879–1888 (2014).
   PubMed Web of Science ®Google Scholar
• Lawitz E , PoordadFF, PangPSet 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. Lancet383 (9916), 515–523 (2014).
   PubMed Web of Science ®Google Scholar
• Sulkowski MS , GardinerDF, Rodriguez-TorresMet al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N. Engl. J. Med.370 (3), 211–221 (2014).
   PubMed Web of Science ®Google Scholar
• Sulkowski MS , JacobsonIM, NelsonDR. Daclatasvir plus sofosbuvir for HCV infection. N. Engl. J. Med.370 (16), 1560–1561 (2014).
   PubMed Web of Science ®Google Scholar
• Aghemo A , De FrancescoR. New horizons in hepatitis C antiviral therapy with direct-acting antivirals. Hepatology58 (1), 428–438 (2013).
   PubMed Web of Science ®Google Scholar
• Sakai A , ClaireMS, FaulkKet al. The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences. Proc. Natl Acad. Sci. USA100 (20), 11646–11651 (2003).
   PubMed Web of Science ®Google Scholar
• Jones CT , MurrayCL, EastmanDK, TasselloJ, RiceCM. Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus. J. Virol.1 (16), 8374–8383 (2007).
   Google Scholar
• Steinmann E , PeninF, KallisS, PatelAH, BartenschlagerR, PietschmannT. Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog.3 (7), e103 (2007).
   PubMed Web of Science ®Google Scholar
• Griffin SD , BealesLP, ClarkeDSet al. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett.535 (1–3), 34–38 (2003).
   PubMed Web of Science ®Google Scholar
• Cook GA , DawsonLA, TianY, OpellaSJ. Three-dimensional structure and interaction studies of hepatitis C virus p7 in 1,2-dihexanoyl-sn-glycero-3-phosphocholine by solution nuclear magnetic resonance. Biochemistry52 (31), 5295–5303 (2013).
   PubMed Web of Science ®Google Scholar
• Foster TL , ThompsonGS, KalverdaAPet al. Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release. Hepatology59 (2), 408–422 (2014).
   PubMed Web of Science ®Google Scholar
• Ouyang B , XieS, BerardiMJet al. Unusual architecture of the p7 channel from hepatitis C virus. Nature498 (7455), 521–525 (2013).
   PubMed Web of Science ®Google Scholar
• Lin C , LindenbachBD, PragaiBM, MccourtDW, RiceCM. Processing in the hepatitis C virus E2-NS2 region: identification of p7 and two distinct E2-specific products with different C termini. J. Virol.68 (8), 5063–5073 (1994).
   PubMed Web of Science ®Google Scholar
• Mizushima H , HijikataM, AsabeS, HirotaM, KimuraK, ShimotohnoK. Two hepatitis C virus glycoprotein E2 products with different C termini. J. Virol.68 (10), 6215–6222 (1994).
   PubMed Web of Science ®Google Scholar
• Carrere-Kremer S , MontpellierC, LorenzoLet al. Regulation of hepatitis C virus polyprotein processing by signal peptidase involves structural determinants at the p7 sequence junctions. J. Biol. Chem.279 (40), 41384–41392 (2004).
   PubMed Web of Science ®Google Scholar
• Isherwood BJ , PatelAH. Analysis of the processing and transmembrane topology of the E2p7 protein of hepatitis C virus. J. Gen. Virol.86, 667–676 (2005).
   PubMed Web of Science ®Google Scholar
• Chandler DE , PeninF, SchultenK, ChipotC. The p7 protein of hepatitis c virus forms structurally plastic, minimalist ion channels. PLoS. Comput. Biol.8 (9), e1002702 (2012).
   PubMed Web of Science ®Google Scholar
• Carrere-Kremer S , Montpellier-PalaC, CocquerelL, WychowskiC, PeninF, DubuissonJ. Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. J. Virol.76 (8), 3720–3730 (2002).
   PubMed Web of Science ®Google Scholar
• Pavlovic D , NevilleDC, ArgaudOet al. The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc. Natl Acad. Sci. USA100 (10), 6104–6108 (2003).
   PubMed Web of Science ®Google Scholar
• Premkumar A , WilsonL, EwartGD, GagePW. Cation-selective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amiloride. FEBS Lett.557 (1–3), 99–103 (2004).
   PubMed Web of Science ®Google Scholar
• Clarke D , GriffinS, BealesLet al. Evidence for the formation of a heptameric ion channel complex by the hepatitis C virus p7 protein in vitro. J. Biol. Chem.281 (48), 37057–37068 (2006).
   PubMed Web of Science ®Google Scholar
• Gervais C , DoF, CantinAet al. Development and validation of a high-throughput screening assay for the hepatitis C virus p7 viroporin. J. Biomol. Screen16 (3), 363–369 (2011).
   PubMedGoogle Scholar
• Kurtz S , LuoG, HahnenbergerKMet al. Growth impairment resulting from expression of influenza virus M2 protein in Saccharomyces cerevisiae: identification of a novel inhibitor of influenza virus. Antimicrob. Agents Chemother. (Bethesda)39 (10), 2204–2209 (1995).
   PubMed Web of Science ®Google Scholar
• Luik P , ChewC, AittoniemiJet al. The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc. Natl Acad. Sci. USA106 (31), 12712–12716 (2009).
   PubMed Web of Science ®Google Scholar
• Steinmann E , WhitfieldT, KallisSet al. Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology46 (2), 330–338 (2007).
   PubMed Web of Science ®Google Scholar
• Lamarre D , AndersonPC, BaileyMet al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature426 (6963), 186–189 (2003).
   PubMed Web of Science ®Google Scholar
• Patargias G , ZitzmannN, DwekR, FischerWB. Protein–protein interactions: modeling the hepatitis C virus ion channel p7. J. Med. Chem.49 (2), 648–655 (2006).
   PubMed Web of Science ®Google Scholar
• Griffin SD , HarveyR, ClarkeDS, BarclayWS, HarrisM, RowlandsDJ. A conserved basic loop in hepatitis C virus p7 protein is required for amantadine-sensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. J. Gen. Virol.85 (Pt 2), 451–461 (2004).
   PubMedGoogle Scholar
• Tedbury P , WelbournS, PauseA, KingB, GriffinS, HarrisM. The subcellular localization of the hepatitis C virus non-structural protein NS2 is regulated by an ion channel-independent function of the p7 protein. J. Gen. Virol.92 (Pt 4), 819–830 (2011).
   PubMedGoogle Scholar
• Stapleford KA , LindenbachBD. Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3-NS4A enzyme complexes. J. Virol.85 (4), 1706–1717 (2011).
   PubMed Web of Science ®Google Scholar
• Popescu CI , CallensN, TrinelDet al. NS2 protein of hepatitis C virus interacts with structural and non-structural proteins towards virus assembly. PLoS Pathog.7 (2), e1001278 (2011).
   PubMed Web of Science ®Google Scholar
• Ma Y , AnantpadmaM, TimpeJMet al. Hepatitis C virus NS2 protein serves as a scaffold for virus assembly by interacting with both structural and nonstructural proteins. J. Virol.85 (1), 86–97 (2011).
   PubMed Web of Science ®Google Scholar
• Jirasko V , MontserretR, LeeJYet al. Structural and functional studies of nonstructural protein 2 of the hepatitis C virus reveal its key role as organizer of virion assembly. PLoS Pathog.6 (12), e1001233 (2010).
   PubMed Web of Science ®Google Scholar
• Jirasko V , MontserretR, AppelNet al. Structural and functional characterization of nonstructural protein 2 for its role in hepatitis C virus assembly. J. Biol. Chem.283 (42), 28546–28562 (2008).
   PubMed Web of Science ®Google Scholar
• Gentzsch J , BrohmC, SteinmannEet al. Hepatitis c virus p7 is critical for capsid assembly and envelopment. PLoS Pathog.9 (5), e1003355 (2013).
   PubMed Web of Science ®Google Scholar
• Wozniak AL , GriffinS, RowlandsDet al. Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS Pathog.6 (9), e1001087 (2010).
   PubMed Web of Science ®Google Scholar
• Atkins E , TatineniR, LiH, GretchD, HarrisM, GriffinS. The stability of secreted, acid-labile H77/JFH-1 hepatitis C virus (HCV) particles is altered by patient isolate genotype 1a p7 sequences. Virology448, 117–124 (2014).
   PubMed Web of Science ®Google Scholar
• Meredith LW , ZitzmannN, MckeatingJA. Differential effect of p7 inhibitors on hepatitis C virus cell-to-cell transmission. Antiviral Res.100 (3), 636–639 (2013).
   PubMed Web of Science ®Google Scholar
• Davies WL , GrunertRR, HaffRFet al. Antiviral activity of 1-adamantanamine (amantadine). Science144 (3620), 862–863 (1964).
   PubMedGoogle Scholar
• Sabin AB . Amantadine hydrochloride. Analysis of data related to its proposed use for prevention of A2 influenza virus disease in human beings. JAMA200 (11), 943–950 (1967).
   PubMed Web of Science ®Google Scholar
• Dawkins AT Jr , GallagerLR, TogoY, HornickRB, HarrisBA. Studies on induced influenza in man. II. Double-blind study designed to assess the prophylactic efficacy of an analogue of amantadine hydrochloride. JAMA203 (13), 1095–1099 (1968).
   PubMed Web of Science ®Google Scholar
• Togo Y , HornickRB, DawkinsATJr. Studies on induced influenza in man. I. Double-blind studies designed to assess prophylactic efficacy of amantadine hydrochloride against a2/Rockville/1/65 strain. JAMA203 (13), 1089–1094 (1968).
   PubMed Web of Science ®Google Scholar
• Wingfield WL , PollackD, GrunertRR. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. N. Engl. J. Med.281 (11), 579–584 (1969).
   PubMed Web of Science ®Google Scholar
• Hay AJ , WolstenholmeAJ, SkehelJJ, SmithMH. The molecular basis of the specific anti-influenza action of amantadine. EMBO J.4 (11), 3021–3024 (1985).
   PubMed Web of Science ®Google Scholar
• Duff KC , AshleyRH. The transmembrane domain of influenza A M2 protein forms amantadine-sensitive proton channels in planar lipid bilayers. Virology190 (1), 485–489 (1992).
   PubMed Web of Science ®Google Scholar
• Pinto LH , HolsingerLJ, LambRA. Influenza virus M2 protein has ion channel activity. Cell69 (3), 517–528 (1992).
   PubMed Web of Science ®Google Scholar
• Schnell JR , ChouJJ. Structure and mechanism of the M2 proton channel of influenza A virus. Nature451 (7178), 591–595 (2008).
   PubMed Web of Science ®Google Scholar
• Stouffer AL , AcharyaR, SalomDet al. Structural basis for the function and inhibition of an influenza virus proton channel. Nature451 (7178), 596–599 (2008).
   PubMed Web of Science ®Google Scholar
• Wang J , WuY, MaCet al. Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc. Natl Acad. Sci. USA110 (4), 1315–1320 (2013).
   PubMed Web of Science ®Google Scholar
• Balgi AD , WangJ, ChengDYet al. Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. PLoS ONE8 (2), e55271 (2013).
   PubMed Web of Science ®Google Scholar
• Griffin S , StgelaisC, OwsiankaAM, PatelAH, RowlandsD, HarrisM. Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel. Hepatology48 (6), 1779–1790 (2008).
   PubMed Web of Science ®Google Scholar
• Gottwein JM , JensenTB, MathiesenCKet al. Development and application of hepatitis C reporter viruses with genotype 1 to 7 core-nonstructural protein 2 (NS2) expressing fluorescent proteins or luciferase in modified JFH1 NS5A. J. Virol.85 (17), 8913–8928 (2011).
   PubMed Web of Science ®Google Scholar
• Foster TL , VerowM, WozniakALet al. Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel. Hepatology54 (1), 79–90 (2011).
   PubMed Web of Science ®Google Scholar
• Mihm U , GrigorianN, WelschCet al. Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C. Antivir. Ther.11 (4), 507–519 (2006).
   PubMed Web of Science ®Google Scholar
• Whitfield T , MilesAJ, ScheinostJCet al. The influence of different lipid environments on the structure and function of the hepatitis C virus p7 ion channel protein. Mol. Membr. Biol. (2011).
   PubMed Web of Science ®Google Scholar
• Stgelais C , FosterTL, VerowMet al. Determinants of hepatitis C virus p7 ion channel function and drug sensitivity identified in vitro. J. Virol.83 (16), 7970–7981 (2009).
   PubMed Web of Science ®Google Scholar
• Saint N , MontserretR, ChipotC, PeninF. Structural and functional analysis of the HCV p7 protein. Methods Mol. Biol.510, 125–143 (2009).
   PubMedGoogle Scholar
• Montserret R , SaintN, VanbelleCet al. NMR structure and ion channel activity of the p7 protein from hepatitis C virus. J. Biol. Chem.285 (41), 31446–31461 (2010).
   PubMed Web of Science ®Google Scholar
• Cook GA , OpellaSJ. Secondary structure, dynamics, and architecture of the p7 membrane protein from hepatitis C virus by NMR spectroscopy. Biochim. Biophys. Acta1808 (6), 1448–1453 (2011).
   PubMed Web of Science ®Google Scholar
• Cook GA , OpellaSJ. NMR studies of p7 protein from hepatitis C virus. Eur. Biophys. J.39 (7), 1097–1104 (2010).
   PubMed Web of Science ®Google Scholar
• Chew CF , VijayanR, ChangJ, ZitzmannN, BigginPC. Determination of pore-lining residues in the hepatitis C virus p7 protein. Biophys. J.96 (2), L10–12 (2009).
   PubMed Web of Science ®Google Scholar
• Luscombe CA , HuangZ, MurrayMG, MillerM, WilkinsonJ, EwartGD. A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-alpha-2b and nucleoside analogues. Antiviral Res.86 (2), 144–153 (2010).
   PubMed Web of Science ®Google Scholar
• Ewart GD , SutherlandT, GagePW, CoxGB. The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels. J. Virol.70 (10), 7108–7115 (1996).
   PubMed Web of Science ®Google Scholar
• Conference reports for NATAP: HepDART 2011 . www.natap.org/2011/hepDART/hepDART_19.htm
   Google Scholar
• Largo E , GladueDP, HuarteN, BorcaMV, NievaJL. Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function. Antiviral Res.101, 30–36 (2014).
   PubMed Web of Science ®Google Scholar
• Gladue DP , HolinkaLG, LargoEet al. Classical swine fever virus p7 protein is a viroporin involved in virulence in swine. J. Virol.86 (12), 6778–6791 (2012).
   PubMed Web of Science ®Google Scholar
• Khoury G , EwartG, LuscombeC, MillerM, WilkinsonJ. Antiviral efficacy of the novel compound BIT225 against HIV-1 release from human macrophages. Antimicrob. Agents Chemother. (Bethesda)54 (2), 835–845 (2010).
   Web of Science ®Google Scholar
• Gan SW , SuryaW, VararattanavechA, TorresJ. Two different conformations in hepatitis C virus p7 protein account for proton transport and dye release. PLoS ONE9 (1), e78494 (2014).
   PubMed Web of Science ®Google Scholar
• Wetherill LF , HolmesKK, VerowMet al. High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors. J. Virol.86 (9), 5341–5351 (2012).
   PubMed Web of Science ®Google Scholar
• Agirre A , BarcoA, CarrascoL, NievaJL. Viroporin-mediated membrane permeabilization. Pore formation by nonstructural poliovirus 2B protein. J. Biol. Chem.277 (43), 40434–40441 (2002).
   PubMed Web of Science ®Google Scholar
• Carter SD , DentKC, AtkinsEet al. Direct visualization of the small hydrophobic protein of human respiratory syncytial virus reveals the structural basis for membrane permeability. FEBS Lett.584 (13), 2786–2790 (2010).
   PubMed Web of Science ®Google Scholar
• Agirre A , LorizateM, NirS, NievaJL. Poliovirus 2b insertion into lipid monolayers and pore formation in vesicles modulated by anionic phospholipids. Biochim. Biophys. Acta1778 (11), 2621–2626 (2008).
   PubMed Web of Science ®Google Scholar
• Ouyang B , ChouJJ. The minimalist architectures of viroporins and their therapeutic implications. Biochim. Biophys. Acta1838 (4), 1058–1067 (2014).
   PubMed Web of Science ®Google Scholar
• Manns MP , Von HahnT. Novel therapies for hepatitis C – one pill fits all?Nat. Rev. Drug Discov.12 (8), 595–610 (2013).
   PubMed Web of Science ®Google Scholar
• Zeuzem S , DusheikoGM, SalupereRet al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N. Engl. J. Med.370 (21), 1993–2001 (2014).
   PubMed Web of Science ®Google Scholar
• Suzuki Y , IkedaK, SuzukiFet al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J. Hepatol.58 (4), 655–662 (2013).
   PubMed Web of Science ®Google Scholar
• Manns MP , VierlingJM, BaconBRet al. The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis. Gastroenterology147 (2), 366–376 (2014).
   PubMed Web of Science ®Google Scholar
• Summa V , LudmererSW, MccauleyJAet al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob. Agents Chemother.56 (8), 4161–4167 (2012).
   PubMed Web of Science ®Google Scholar
• Mccown MF , RajyaguruS, Le PogamSet al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob. Agents Chemother.52 (5), 1604–1612 (2008).
   PubMed Web of Science ®Google Scholar
• Fridell RA , WangC, SunJHet al. Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. Hepatology54 (6), 1924–1935 (2011).
   PubMed Web of Science ®Google Scholar
• Mcphee F , HernandezD, YuFet al. Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir. Hepatology58 (3), 902–911 (2013).
   PubMed Web of Science ®Google Scholar
• Ludmerer SW , GrahamDJ, BootsEet al. Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob. Agents Chemother.49 (5), 2059–2069 (2005).
   PubMed Web of Science ®Google Scholar
• Conference Reports for NATAP: EASL 48th Annual Meeting. www.natap.org/2013/EASL/EASL_15.htm
   Google Scholar
• Flisiak R , FeinmanSV, JablkowskiMet al. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology49 (5), 1460–1468 (2009).
   PubMed Web of Science ®Google Scholar
• Paeshuyse J , KaulA, De ClercqEet al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology43 (4), 761–770 (2006).
   PubMed Web of Science ®Google Scholar
• Patel H , HeathcoteEJ. Sustained virological response with 29 days of Debio 025 monotherapy in hepatitis C virus genotype 3. Gut60 (6), 879 (2011).
   PubMed Web of Science ®Google Scholar
• Zhu H , Wong-StaalF, LeeHet al. Evaluation of ITX 5061, a scavenger receptor B1 antagonist: resistance selection and activity in combination with other hepatitis C virus antivirals. J. Infect Dis.205 (4), 656–662 (2012).
   PubMed Web of Science ®Google Scholar
• Vausselin T , CallandN, BelouzardSet al. The antimalarial ferroquine is an inhibitor of hepatitis C virus. Hepatology58 (1), 86–97 (2013).
   PubMed Web of Science ®Google Scholar
• Einav S , GerberD, BrysonPDet al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat. Biotechnol.26 (9), 1019–1027 (2008).
   PubMed Web of Science ®Google Scholar
• Rai R , DevalJ. New opportunities in anti-hepatitis C virus drug discovery: targeting NS4B. Antiviral Res.90 (2), 93–101 (2011).
   PubMed Web of Science ®Google Scholar
• Esser-Nobis K , Romero-BreyI, GantenTMet al. Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology57 (3), 953–963 (2013).
   PubMed Web of Science ®Google Scholar
• Deltenre P , HenrionJ, CanvaVet al. Evaluation of amantadine in chronic hepatitis C: a meta-analysis. J. Hepatol.41 (3), 462–473 (2004).
   PubMed Web of Science ®Google Scholar
• Mangia A , LeandroG, HelblingBet al. Combination therapy with amantadine and interferon in naive patients with chronic hepatitis C: meta-analysis of individual patient data from six clinical trials. J. Hepatol.40 (3), 478–483 (2004).
   PubMed Web of Science ®Google Scholar
• Maynard M , PradatP, BaillyFet al. Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). J. Hepatol.44 (3), 484–490 (2006).
   PubMed Web of Science ®Google Scholar
• WHO issues its first hepatitis C treatment guidelines. www.who.int/mediacentre/news/releases/2014/hepatitis-guidelines/en/
   Google Scholar