v
Search
Advanced Search

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Direct-acting Antiviral Agents for the Treatment of Chronic Hepatitis C Virus Infection

  • Tatsuo Kanda,
  • Shingo Nakamoto,
  • Masato Nakamura,
  • Xia Jiang,
  • Tatsuo Miyamura,
  • Shuang Wu and
  • Osamu Yokosuka
 Author information
Journal of Clinical and Translational Hepatology   2014;2(1):1-6

doi: 10.14218/JCTH.2013.00025

Abstract

Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan. Therefore, eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals. In 2011, the use of first-generation HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV. Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients. However, this treatment regimen also led to severe adverse events. Second-generation direct-acting antiviral agents (DAAs) for HCV, such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates, with similar adverse events to other peg-interferon and ribavirin treatments. Higher SVR rates in HCV genotype 1- and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin, respectively. For “difficult-to-treat” HCV-infected patients, more therapeutic options are needed. Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.

Keywords

Daclatasvir, Interferon-free, Protease inhibitors, Simeprevir, Sofosbuvir

Introduction

Hepatitis C virus (HCV) causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).1,2 Eradication of HCV by (peg-)interferon with or without ribavirin prevents chronic HCV patients from progressing to hepatic fibrosis, HCC, and hepatic failure, and improves survival rates.3–7 Even in HCV-infected patients with histologically proven cirrhosis, achievement of sustained virological response (SVR) after treatment was associated with a reduction of liver-related mortality and HCC development,8 although the risk of occurrence was not completely eliminated.8,9

HCV is an enveloped positive-stranded RNA virus belonging to the genus Hepacivirus, a member of the Flaviviridae family. The HCV genome is ~9,600 nt in length and contains a 5′ nontranslated region (5′NTR), a single open reading flame, and a 3′NTR. A single polyprotein translated from the HCV genome is processed by HCV proteases, including HCV NS2 cysteine protease, HCV NS3 serine protease, and host proteases, into structural (core, E1, E2 and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins.10 The HCV RNA replication complex forms in the endoplasmic reticulum, and a phosphoprotein HCV NS5A and an RNA-dependent RNA polymerase HCV NS5B, make a positive-stranded RNA from negative-stranded RNA as a template. Subsequently, HCV virions are produced and egress from hepatocytes into human blood. Direct-acting antiviral agents (DAAs) against HCV specifically target one of these proteins and strongly inhibit HCV replication, and interferon and/or ribavirin could non-specifically inhibit HCV replication in addition to other viral replications. Fig. 1 shows HCV-coding proteins and their representative DAAs.10

HCV-coding proteins and their representative direct-acting antiviral agents (DAAs). Structural and non-structural (NS) proteins are core, E1, E2, and p7, and NS2, NS3, NS4A (4A), NS4B (4B), NS5A, and NS5B, respectively.
Fig. 1  HCV-coding proteins and their representative direct-acting antiviral agents (DAAs). Structural and non-structural (NS) proteins are core, E1, E2, and p7, and NS2, NS3, NS4A (4A), NS4B (4B), NS5A, and NS5B, respectively.10

Peg-interferon with ribavirin has been the standard of care (SOC) treatment for HCV-infected individuals.10 Although this treatment led to ~80% SVR in patients infected with HCV genotype 2 or 3, it only led to ~50% SVR in patients infected with HCV genotype 1 and those with high viral loads.10,11 In 2011, protease inhibitors such as boceprevir and telaprevir were available for HCV genotype 1-infected individuals in US, Japan, and other countries. Although protease inhibitor-including regimens for patients infected with HCV genotype 1 always received simultaneous peg-interferon with ribavirin treatments, these regimens have achieved 70~80% SVR in treatment-naïve patients or previously treated relapsers.12–18 Protease inhibitor-including regimens are now considered the SOC treatment for HCV genotype 1-infected patients, although peg-interferon with ribavirin treatment is considered the SOC for HCV genotype 2 or 3 infection. However, interferon therapy is beset by well-known adverse events, including influenza-like symptoms, cytopenia, and depression, and the lack of response in some patients to interferon therapy has been disappointing. These adverse events prevent “difficult-to-treat” patients from eradicating this virus.19 In the near future, the use of interferon-free treatment strategies will likely play a central role in the treatment of chronic HCV infection. In this review article, we focus on protease inhibitor containing regimens and interferon-free regimens against chronic HCV infection.

First-generation protease inhibitors: telaprevir and boceprevir

Telaprevir and boceprevir are two of the first generation oral HCV NS3/4A protease inhibitors.16 SVR rates in telaprevir-based triple therapy in HCV genotype 1-infected treatment-naïve and treatment-experienced patients were 69–75% and 51–52%, respectively.12,20 SVR rates in boceprevir-based triple therapy in HCV genotype 1-infected treatment-naïve and treatment-experienced patients were 63–66% and 59–66%, respectively.15,16 Telaprevir and boceprevir must be used in combination with peg-interferon with ribavirin for optimal efficacy, and although occasionally this combination is associated with serious adverse events, it markedly improved SVR rates in HCV genotype 1-infected patients.17,21–23 D’Ambrosio and Colombo reported that the rates of treatment discontinuation due to adverse events were as high as 14%.24 Since it is possible that telaprevir and boceprevir induce drug-resistance mutations, peg-interferon with ribavirin or their combination with other class DAAs is absolutely necessary with their use.

Second-generation protease inhibitors: simeprevir, faldaprevir, and vaniprevir

Simeprevir (TMC435) is an oral, once-daily (QD), HCV NS3/4A macrocyclic protease inhibitor with potent antiviral activity in HCV genotype 1-infected patients as well as HCV genotypes 2, 4, 5 and 6.25 Protease Inhibitor TMC435 trial assessing the optimal dose and duration as once daily anti-viral regimen (PILLAR) is an ongoing study in 13 countries in North America, Europe and Asia-Pacific regions, and showed that simeprevir administered QD with peg-interferon-alpha-2a and ribavirin in treatment-naïve patients infected with HCV genotype 1 for 24–48 weeks resulted in 75–86% SVR (versus 65% in placebo with peg-interferon-alpha-2a and ribavirin-treated group).25 Simeprevir QD in combination with peg-interferon and ribavirin significantly improved SVR rates, and the majority of patients shortened their treatment duration to 24 weeks. Of importance, the adverse event profile of simeprevir was generally similar to that of control, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormality.25 A Japanese study also showed that simeprevir administered QD with peg-interferon-alpha-2a and ribavirin in treatment-naïve patients infected with HCV genotype 1, aged 20–70 years, for 24 weeks resulted in 77–92% SVR (versus 46% in placebo with peg-interferon-alpha-2a and ribavirin-treated group).26 Unlike telaprevir or boceprevir, simeprevir appeared generally safe and well tolerated.25,26 V36A/M/L/G, T54A/S, V55A, Q80K/R/H/G, R155K/T/I/M/G/L/S/Q, A156V/T/S/I/G, D168A/V/E/G/N/T/Y/H/I, and V170A have been identified as amino acid substitutions resistant to NS3/4A protease inhibitors, including linear ketoamides (telaprevir, boceprevir, and faldaprevir) and macrocyclic compounds (vaniprevir and simeprevir).27–29 Among simeprevir-treated patients, resistance mutations such as R155K or D168V alone or a combination of Q80K/R, R155K, and/or D168E mutations have emerged.30 R155K and D168V were observed primarily in HCV subgenotypes 1a and 1b isolates, respectively.30

Faldaprevir (BI 201335) is a HCV NS3/4A protease inhibitor with pharmacokinetic properties supportive of QD dosing, with potent antiviral activity in HCV genotype 1-infected patients as well as HCV genotypes 4, 5, and 6.31 Faldaprevir 240 mg, dosed QD in combination with peg-interferon and ribavirin, increased SVR rates of treatment-naïve HCV genotype 1 patients from 56% in the placebo group to as high as 84%.31 Faldaprevir selected NS3 mutants predominantly encoded for R155K and D168V in HCV subgenotypes 1a and 1b, respectively.31 Faldaprevir 240 mg QD, in combination with peg-interferon and ribavirin, led to SVR in ~35% or 50% of HCV genotype 1 patients with strictly defined prior null or partial response to peg-interferon and ribavirin treatment, respectively.32 A preliminary Japanese study also showed that faldaprevir with peg-interferon and ribavirin was efficacious and well tolerated.33

Vaniprevir, a HCV NS3/4A protease inhibitor, with peg-interferon and ribavirin, significantly increased SVR rates among treatment-experienced patients with chronic HCV genotype 1 infection, compared to retreatment with peg-interferon and ribavirin alone.34

Interferon-including regimens

The presently approved HCV NS3/4A protease inhibitors such as telaprevir- and boceprevir-containing regimens must be combined with peg-interferon and ribavirin for their use against HCV genotype 1 to prevent generation of resistant mutants during the treatment.12–16,20 Without combining with other DAAs, second-generation HCV NS3/4A protease inhibitors should be used together with peg-interferon plus ribavirin for HCV genotype 1-infected patients.35 Genome-wide association studies showed a potent association between single nucleotide polymorphisms (SNPs) near the IL28B gene and the treatment response of peg-interferon plus ribavirin therapy.36–38 Although the IL28B SNPs still have an impact on the treatment response against 24-week telaprevir-based triple combination therapy for patients with HCV genotype 1,39 boceprevir and telaprevir attenuated the association between IL28B SNPs and treatment response.40 Due to the adverse events of peg-interferon plus ribavirin, patients with contra-indications to peg-interferon plus ribavirin treatment are also not candidates for boceprevir- or telaprevir-based triple therapy.19 The benefits of the addition of one DAA to peg-interferon plus ribavirin treatment would be limited by the underlying issues of safety and tolerability.41

Interferon-free regimens

The oral combination of different DAAs holds promise as an interferon-free treatment for chronic HCV infection.41 In the near future, the use of all-oral DAAs and interferon-free regimens for the treatment of HCV-infected patients with a potent antiviral effect against HCV and with less adverse events may be a viable therapeutic option.18 Of course, IL28B SNPs do not have an impact on the treatment response of interferon-free regimens, and interferon-free regimens seem to improve the SVR rates in HCV genotype 1-infected patients with IL28B minor genotypes.

Sofosbuvir

Sofosbuvir (GS-7977; formerly PSI-7977) is a pyrimidine nucleoside analog inhibitor of HCV pangenotype NS5B polymerase.42 The addition of sofosbuvir to peg-interferon plus ribavirin treatment could lead to an SVR of 90–91% and 92% in HCV genotype 1 patients treated for 24–48 weeks, and HCV genotype 2 patients treated for 12 weeks, respectively.43 In HCV genotype 1-infected patients receiving sofosbuvir 400 mg plus peg-interferon and ribavirin for 12 weeks, for 24 weeks, or 12 weeks of sofosbuvir plus peg-interferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin, SVRs of 89%, 89%, or 87% were achieved, respectively.44 In HCV genotype 4- and 6-infected patients who received sofosbuvir 400 mg plus peg-interferon and ribavirin for 24 weeks achieved SVRs of 82% and 100% were achieved, respectively.44 These results suggest that simple and short sofosbuvir-based regimens may be effective for HCV-infected individuals.43,44

Among HCV genotype 2- or 3-infected patients for whom treatment with peg-interferon was not an option, the SVR rate was 78% with 12 weeks of sofosbuvir and ribavirin, as compared to 0% with placebo.45 Among previously treated patients, the SVR rate was 50% with sofosbuvir and ribavirin for 12 weeks and 73% for 16 weeks. SVR rates were lower among HCV genotype 3-infected patients than among those with HCV genotype 2.45 Twenty-four weeks of treatment with sofosbuvir and ribavirin for HCV genotype 1-infected patients with unfavorable treatment characteristics resulted in 40–68% SVR rates.46 Twelve weeks of sofosbuvir and ribavirin treatment seemed excellent for HCV genotype 2 infection, but even 24 weeks of sofosbuvir and ribavirin treatment was insufficient against HCV genotype 1 infection.

An interferon-free regimen-at-fixed-dose combination of sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin, led to 95–100% SVR rates in patients with HCV genotype 1 infection who were treatment-naïve or previously treated with protease-inhibitor regimen, irrespective of treatment history or the presence of compensated cirrhosis.47 The results of sofosbuvir-based treatments are shown in Table 1. In HCV genotype 1 infection, SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin were 79–96% and 96–100%, in staging fibrosis of the liver of F0–F2 and F3–F4, respectively.48 In an in vitro study, NS5B, S282T, and M289L were identified as resistance-associated mutations.49

Table 1

Sustained virological response (SVR) rates in hepatitis C patients treated with sofosbuvir-including regimens

ReferencesGNumber of patientsNaiveTherapy formulaSVR (%)
Lawitz et al.43148Yes12 wk of sofosbuvir (200 mg)/peginterferon/ribavirin and 12/36 wk of peginterferon/ribavirin85
147Yes12 wk of sofosbuvir (400 mg)/peginterferon/ribavirin and 12/36 wk of peginterferon/ribavirin89
126Yes12 wk of placebo/peginterferon/ribavirin and 12/36 wk of peginterferon/ribavirin58
2/325Yes12 wk of sofosbuvir (400 mg)/peginterferon/ribavirin and 12/36 wk of peginterferon/ribavirin92
Kowdley et al.44152Yes12 wk of sofosbuvir (400 mg)/peginterferon/ribavirin89 (ITT)
1/4/6125Yes24 wk of sofosbuvir (400 mg)/peginterferon/ribavirin89 (ITT)
1155Yes12 wk of sofosbuvir (400 mg)/peginterferon/ribavirin and 12 wk of either sofosbuvir monotherapy or sofosbuvir plus ribavirin87 (ITT)
Jacobson et al.452/3207Almost12 wk of sofosbuvir/ribavirin78 (SVR12)
2/371AlmostPlacebo0 (SVR12)
1/2/3103No12 wk of sofosbuvir/ribavirin50 (SVR12)
1/2/398No16 wk of sofosbuvir/ribavirin73 (SVR12)
Lawitz et al.421/4/5/6327Yes12 wk of sofosbuvir/peginterferon/ribavirin90 (SVR12)
1/2/3256Yes12 wk of sofosbuvir/ribavirin67 (SVR12)
2/3243Yes24 wk of peginterferon/ribavirin67 (SVR12)
Osinusi et al.46110Yes24 wk of sofosbuvir/weight-based ribavirin90
125Yes24 wk of sofosbuvir/weight-based ribavirin68
125Yes24 wk of sofosbuvir/low-dose ribavirin48
Lawitz et al.47120Yes8 wk of sofosbuvir/ledipasvir95 (SVR12)
121Yes8 wk of sofosbuvir/ledipasvir/ribavirin100 (SVR12)
119Yes12 wk of sofosbuvir/ledipasvir/ribavirin95 (SVR12)
119No12 wk of sofosbuvir/ledipasvir95 (SVR12)
121No12 wk of sofosbuvir/ledipasvir/ribavirin100 (SVR12)

G, genotype; Naïve, treatment-naïve; SVR, sustained virological response; wk, weeks

Daclatasvir

Daclatasvir, an NS5A inhibitor identified by chemical genetics strategy, has been shown to have a potent clinical effect.50 Dual therapy with daclatasvir and asunaprevir, NS3 protease inhibitor, led to SVR in certain HCV genotype 1-infected patients who had not a responded previously to therapy. A high rate of SVR was achieved when these two DAAs were combined with peg-interferon and ribavirin.51,52 Results of daclatasvir-based treatments are shown in Table 2. It has been reported that there is a potent association between a pre-existing NS5A-Y93H mutation and virological failure on daclatasvir/asunaprevir combination treatment.53 Suzuki et al.54 reported that the NS5A-Y93H variant pre-existed in 23% of HCV genotype 1b-infected patients treated with dual oral therapy of daclatasvir and asunaprevir; where 50% experienced virological failure, and 50% achieved SVR. Future studies are necessary to further elucidate the clinical efficacy of daclatasvir for HCV.

Table 2

Sustained virological response (SVR) rates in hepatitis C patients treated with daclatasvir-including regimens

ReferencesGNumber of patientsNaiveTherapy formulaSVR (%)
Chayama et al.511b10No (Null)24 wk of daclatasvir (60 mg)/asunaprevir (600 mg)90 (SVR12)
Lok et al.521a/1b11No (Null)24 wk of daclatasvir (60 mg)/asunaprevir (600 mg)36 (SVR12)
1a/1b10No (Null)24 wk of daclatasvir (60 mg)/asunaprevir (600 mg)/peginterferon/ribavirin100 (SVR12)

G, genotype; Naïve, treatment-naïve; SVR, sustained virological response; Null, null response; wk, weeks

Conclusions

To prevent the occurrence of HCC in chronic hepatitis C patients, it follows that HCV needs to be eradicated from these patients. For “difficult-to-treat” HCV-infected patients, more therapeutic options are needed. To date, sofosbuvir containing interferon-free regimens may be more efficacious, safer, and better tolerated with less adverse events than peg-interferon-based triple therapy with telaprevir and boceprevir. Further studies are needed to more fully understand efficacy and safety of new drugs, including assessment of clinical drug-drug interactions.

Abbreviations

DAA: 

direct-acting antiviral agent

HCC: 

hepatocellular carcinoma

HCV: 

hepatitis C virus

NS: 

non-structural protein

SNP: 

single nucleotide polymorphism

SOC: 

standard of care

SVR: 

sustained virological response

Declarations

Acknowledgement

This work was supported by grants for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (Dr. Kanda and Dr. Nakamoto), and grants from the Ministry of Health, Labour and Welfare of Japan (Dr. Kanda and Prof. Yokosuka).

Conflict of interest

Dr. Kanda reports receiving lecture fees from Chugai Pharmaceutical, MSD, Tanabe-Mitsubishi, Ajinomoto, Bristol-Myers Squibb, and GlaxoSmithKline, and Prof. Yokosuka reports receiving grant support from Chugai Pharmaceutical, Bayer, MSD, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, and Bristol-Myers Squibb.

Authors’ contributions

Drafting the manuscript (TK), discussion and approval of the manuscript (TK, SN, MN, XJ, TM, SW, OY).

References

  1. Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26:34S-38S
  2. Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A 1990;87:6547-6549
  3. Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012;6:409-435
  4. Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132:517-524
  5. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:174-181
  6. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142:105-114
  7. Yoshida H, Arakawa Y, Sata M, Nishiguchi S, Yano M, Fujiyama S. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 2002;123:483-491
  8. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnù L, Mazzella G. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007;45:579-587
  9. Kanda T, Imazeki F, Mikami S, Kato K, Shimada N, Yonemitsu Y. Occurrence of hepatocellular carcinoma was not a rare event during and immediately after antiviral treatment in Japanese HCV-positive patients. Oncology 2011;80:366-372
  10. Kanda T, Imazeki F, Yokosuka O. New antiviral therapies for chronic hepatitis C. Hepatol Int 2010;4:548-561
  11. Lagging M, Rembeck K, Rauning Buhl M, Christensen P, Dalgard O, Farkkila M. Retreatment with peg-interferon and ribavirin in patients with chronic hepatitis C virus genotype 2 or 3 interferon with prior relapse. Scand J Gastroenterol 2013;48:839-847
  12. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-2416
  13. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417-2428
  14. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011;365:1014-1024
  15. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206
  16. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-1217
  17. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naïve patients chronically infected with HCV of genotype 1 in Japan. J Hepatol 2012;56:78-84
  18. Kanda T, Omata M, Yokosuka O. Treatment of hepatitis C virus infection in the future. Clin Transl Med 2013;2:9
  19. Kanda T, Omata M, Yokosuka O. Antiviral therapy for “difficult-to-treat” hepatitis C virus-infected patients. Chin Med J (Engl) 2013;126:4568-4574
  20. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292-1303
  21. Burger D, Beck D, Buggisch P, Buti M, Craxi A, Foster G. Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 2013;58:792-800
  22. Hezode C. Management of anemia and other treatment complications. Dig Liver Dis 2013;45:S337-S342
  23. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther 2014;39:93-103
  24. D’Ambrosio R, Colombo M. Safety and direct antiviral agents in real life. Dig Liver Dis 2013;45:S363-S366
  25. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: The randomized PILLAR study. Hepatology 2013;58:1918-1929
  26. Hayashi N, Seto C, Kato M, Komoda Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol 2014;49:138-147
  27. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011;55:192-206
  28. Romano KP, Ali A, Royer WE, Schiffer CA. Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. Proc Natl Acad Sci U S A 2010;107:20986-20991
  29. Suzuki F, Sezaki H, Akuta N, Suzuki Y, Seko Y, Kawamura Y. 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;54:352-354
  30. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a Phase IIb Trial. Gastroenterology 2014;146:430-441
  31. Sulkowski MS, Asselah T, Lalezari J, Ferenci P, Fainboim H, Leggett B. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 2013;57:2143-2154
  32. Sulkowski MS, Bourliere M, Bronowicki JP, Asselah T, Pawlotsky JM, Shafran SD. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013;57:2155-2163
  33. Nishiguchi S, Sakai Y, Kuboki M, Tsunematsu S, Urano Y, Sakamoto W. Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection. Liver Int 2013;34:78-88
  34. Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Lawitz E, Zhou A. Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of sustained viral response in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis. Clin Gastroenterol Hepatol 2013
  35. Palanisamy N, Danielsson A, Kokkula C, Yin H, Bondeson K, Wesslen L. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 2013;99:12-17
  36. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399-401
  37. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100-1104
  38. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105-1109
  39. Tsubota A, Shimada N, Atsukawa M, Abe H, Kato K, Ika M. Impact of IL28B polymorphisms on 24-week telaprevir-based combination therapy for Asian chronic hepatitis C patients with HCV genotype 1b. J Gastroenterol Hepatol 2014;29:144-150
  40. Muir AJ. IL28B in the era of direct-acting antivirals for hepatitis C. J Clin Gastroenterol 2013;47:222-227
  41. Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R. Oral combination therapy with a nucleotide polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010;376:1467-1475
  42. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887
  43. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naïve patients with genotypes 1, 2, and 3 hepatitis C infection: a randomized, double-blind, phase 2 trial. Lancet Infect Dis 2013;13:401-408
  44. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naïve patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomized, multicentre phase 2 trial. Lancet 2013;381:2100-2107
  45. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867-1877
  46. Osinusi A, Meissner EG, Lee YJ, Bon D, Heytes L, Nelson A. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013;310:804-811
  47. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. Lancet 2014;383:515-523
  48. Jacobson IM, Ghalib RH, Rodriguez-Torres M, Younossi ZM, Corregidor A, Sulkowski MS. 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. Hepatology 2013;58:1379
  49. Lam AM, Espiritu C, Bansal S, Micolochick Streuer HM, Zennou V, Otto MJ. Hepatitis C virus nucleoside inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J Virol 2011;85:12334-12342
  50. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effects. Nature 2010;465:96-100
  51. Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012;55:742-748
  52. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012;366:216-224
  53. Karino Y, Toyota J, Ikeda K, Suzuki F, Chayama K, Kawakami Y. Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir. J Hepatol 2013;58:646-654
  54. Suzuki Y, Ikeda K, Suzuki F, Toyoda J, Karino Y, Chayama K. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol 2013;58:655-662
  55. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-221
  56. Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014;370:222-232
Copyright © 2014 The Second Affiliated Hospital of Chongqing Medical University. Published by XIA & HE Publishing Ltd. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 1942976
  • Visits today : 4274
Back to Top

Direct-acting Antiviral Agents for the Treatment of Chronic Hepatitis C Virus Infection

Tatsuo Kanda, Shingo Nakamoto, Masato Nakamura, Xia Jiang, Tatsuo Miyamura, Shuang Wu, Osamu Yokosuka
  • Reset Zoom
  • Download TIFF