Skip to main content

Ledipasvir/Sofosbuvir: A Review in Chronic Hepatitis C

Drugs volume 78, pages 245–256 (2018)Cite this article

Abstract

Oral once-daily, fixed-dose, ledipasvir/sofosbuvir (Harvoni®) [± ribavirin] is approved in several countries for the treatment of chronic hepatitis C (CHC) in adults and adolescents aged 12 to < 18 years, with direct-acting antiviral (DAA) regimens resulting in a paradigm shift in the treatment of the disease. In the clinical trial and/or clinical practice setting, ledipasvir/sofosbuvir (± ribavirin) was associated with high sustained virological response rates 12 weeks post-treatment (SVR12) in treatment-naive and -experienced adults and adolescents with chronic hepatitis C virus (HCV) genotype (GT) 1 infection, including in those with compensated cirrhosis or who were co-infected with HIV. SVR12 rates in real-world studies were consistent with those in trials. In other trials, ledipasvir/sofosbuvir (± ribavirin) was associated with high SVR12 rates in various CHC populations, including patients with HCV GT2, 3, 4, 5 or 6 infection, cirrhosis, pre and/or post liver or renal transplantation, inherited blood disorders or failure after prior DAA and/or interferon therapy. Thus, ledipasvir/sofosbuvir (± ribavirin) is a valuable effective and generally well tolerated option for adolescent and adult patients with HCV GT1, 4, 5 or 6 infection, including those with HIV co-infection or cirrhosis, with evidence also supporting its use in patients with chronic HCV GT2 or 3 infection.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

  1. Younossi Z, Birerdinc A, Henry L. Hepatitis C infection: a multi-faceted systemic disease with clinical, patient-reported and economic consequences. J Hepatol. 2016;65:S109–19.

    Article  PubMed  Google Scholar 

  2. Asselah T, Boyer N, Saadoun D, et al. Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives. Liver Int. 2016;36(Suppl S1):47–7.

  3. Majumdar A, Kitson MT, Roberts SK. Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy. Drugs. 2015;75:823–34.

    Article  CAS  PubMed  Google Scholar 

  4. European Medicines Agency. Harvoni 90 mg/400 mg film-coated tablets: summary of product characteristics. 2017. http://www.ema.europa.eu. Accessed 2 Nov 2017.

  5. German P, Mathias A, Brainard D, et al. Clinical pharmacokinetics and pharmacodynamics of ledipasvir/sofosbuvir, a fixed-dose combination tablet for the treatment of hepatitis C. Clin Pharmacokinet. 2016;55(11):1337–51.

    Article  CAS  PubMed  Google Scholar 

  6. Keating GM. Ledipasvir/sofosbuvir: a review of its use in chronic hepatitis C. Drugs. 2015;75(6):675–85.

    Article  CAS  PubMed  Google Scholar 

  7. Cheng G, Tian Y, Doehle B, et al. In vitro antiviral activity and resistance profile characterization of the hepatitis C virus NS5A inhibitor ledipasvir. Antimicrob Agents Chemother. 2016;60(3):1847–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889–98.

    Article  PubMed  Google Scholar 

  9. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483–93.

    Article  CAS  PubMed  Google Scholar 

  10. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879–88.

    Article  PubMed  Google Scholar 

  11. Mizokami M, Dvory-Sobol H, Izumi N, et al. Resistance analyses of Japanese hepatitis co-infected patients receiving sofosbuvir or ledipasvir/sofosbuvir containing regimens in phase 3 studies. J Viral Hepat. 2016;23(10):780–8.

    Article  CAS  PubMed  Google Scholar 

  12. Wyles D, Dvory-Sobol H, Svarovskaia ES, et al. Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir. J Hepatol. 2017;66(4):703–10.

    Article  CAS  PubMed  Google Scholar 

  13. Sarrazin C, Dvory-Sobol H, Svarovskaia ES, et al. Prevalence of resistance-associated substitutions in HCV NS5A, NS5B, or NS3 and outcomes of treatment with ledipasvir and sofosbuvir. Gastroenterology. 2016;151(3):501-12.e1.

  14. Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome. J Hepatol. 2017;66:910–8.

    Article  CAS  PubMed  Google Scholar 

  15. Kan H, Imamura M, Kawakami Y, et al. Emergence of drug resistance-associated variants and changes in serum lipid profiles in sofosbuvir plus ledipasvir-treated chronic hepatitis C patients. J Med Virol. 2017;89(11):1963–72.

    Article  CAS  PubMed  Google Scholar 

  16. Kirby BJ, Symonds WT, Kearney BP, et al. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet. 2015;54:677–90.

    Article  CAS  PubMed  Google Scholar 

  17. Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixed-dose combination with or without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis. 2015;15(6):645–53.

    Article  CAS  PubMed  Google Scholar 

  18. Kowdley KV, An D, Pang PS, et al. Analysis of subgroup differences in the ION-3 trial of ledipasvir-sofosbuvir in chronic hepatitis C infection. Open Forum Infect Dis. 2015;2(2):1–2.

    Article  Google Scholar 

  19. Wilder JM, Jeffers LJ, Ravendhran N, et al. Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: a retrospective analysis of phase 3 data. Hepatology. 2016;63(2):437–44.

    Article  CAS  PubMed  Google Scholar 

  20. Saab S, Park SH, Mizokami M, et al. Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older. Hepatology. 2016;63(4):1112–9.

    Article  CAS  PubMed  Google Scholar 

  21. Reddy KR, Bourliere M, Sulkowski M, et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: an integrated safety and efficacy analysis. Hepatology. 2015;62(1):79–86.

    Article  CAS  PubMed  Google Scholar 

  22. Younossi ZM, Stepanova M, Marcellin P, et al. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, -2, and -3 clinical trials. Hepatol. 2015;61(6):1798–808.

    Article  CAS  Google Scholar 

  23. Wyles D, Pockros P, Morelli G, et al. Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens. Hepatology. 2015;61(6):1793–7.

    Article  CAS  PubMed  Google Scholar 

  24. Lawitz E, Pockros P, Yang JC, et al. Ledipasvir/sofosbuvir regimens for the retreatment of patients who failed sofosbuvir-based regimens [abstract no. O-011]. Hepatol Int. 2016;10(Suppl 1):S9.

  25. Tam E, Luetkeymer AF, Mantry PS, et al. Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naive patients: findings from two randomized trials. Liver Int. 2017. https://doi.org/10.1111/liv.13616.

    PubMed  Google Scholar 

  26. Akuta N, Sezaki H, Suzuki F, et al. Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. J Med Virol. 2017;89(7):1248–54.

    Article  CAS  PubMed  Google Scholar 

  27. Kowdley KV, Sundaram V, Jeon CY, et al. Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection. Hepatology. 2017;65(4):1094–103.

    Article  CAS  PubMed  Google Scholar 

  28. Butt AA, Yan P, Shaikh OS, et al. Treatment adherence and virological response rates in hepatitis C virus infected persons treated with sofosbuvir-based regimens: results from ERCHIVES. Liver Int. 2016;36(9):1275–83.

    Article  CAS  PubMed  Google Scholar 

  29. Terrault NA, Zeuzem S, Di Bisceglie AM, et al. Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology. 2016;151(6):1131-40.e5.

  30. Tapper EB, Bacon BR, Curry MP, et al. Real-world effectiveness for 12 weeks of ledipasvir-sofosbuvir for genotype 1 hepatitis C: the Trio Health study. J Viral Hepat. 2017;24(1):22–7.

    Article  CAS  PubMed  Google Scholar 

  31. Tapper EB, Bacon BR, Curry MP, et al. Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study. Hepatology. 2016;64(6):1893–9.

    Article  CAS  PubMed  Google Scholar 

  32. Curry MP, Tapper EB, Bacon B, et al. Effectiveness of 8- or 12-weeks of ledipasvir and sofosbuvir in real-world treatment-naive, genotype 1 hepatitis C infected patients. Aliment Pharmacol Ther. 2017:1–9.

  33. Backus LI, Belperio PS, Shahoumian TA, et al. Real-world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment-naive, genotype 1 hepatitis C-infected patients. Hepatology. 2016;64(2):405–14.

    Article  CAS  PubMed  Google Scholar 

  34. Backus LI, Belperio PS, Shahoumian TA, et al. Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine clinical practice. Aliment Pharmacol Ther. 2016;44:400–10.

    Article  CAS  PubMed  Google Scholar 

  35. Backus LI, Belperio PS, Shahoumian TA, et al. Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients. Antivir Ther. 2017. https://doi.org/10.3851/IMP3117.

    PubMed  Google Scholar 

  36. Balistreri WF, Murray KF, Rosenthal P, et al. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2017;66(2):371–8.

    Article  CAS  PubMed  Google Scholar 

  37. Younossi ZM, Stepanova M, Balistreri W, et al. Health-related quality of life in adolescent patients with hepatitis C genotype 1 treated with sofosbuvir and ledipasvir. J Ped Gastroenterol Nutr. 2018;66(1):1112–6.

    Article  Google Scholar 

  38. Gane EJ, Hyland RH, Yang Y, et al. Efficacy of ledipasvir plus sofosbuvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2 infection. Gastroenterology. 2017;152(6):1366–71.

    Article  CAS  PubMed  Google Scholar 

  39. Feld JJ, Ramji A, Shafran SD, et al. Ledipasvir-sofosbuvir plus ribavirin in treatment-naive patients with hepatitis C virus genotype 3 infection: an open-label study. Clin Infect Dis. 2017;65(1):13–9.

    Article  PubMed  Google Scholar 

  40. Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology. 2015;149(6):1454–61.

    Article  CAS  PubMed  Google Scholar 

  41. Abergel A, Metivier S, Samuel D, et al. Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology. 2016;64(4):1049–56.

    Article  CAS  PubMed  Google Scholar 

  42. Kohli A, Kapoor R, Sims Z, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept phase 2a cohort study. Lancet Infect Dis. 2015;15(9):1049–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis. 2016;16(4):459–64.

    Article  CAS  PubMed  Google Scholar 

  44. Nguyen MH, Trinh H, Do S, et al. Open label study of 8 vs. 12 weeks of ledipasvir/sofosbuvir in genotype 6 treatment naive or experienced patients. Am J Gastroenterol. 2017;112(12):1824–31.

    Article  CAS  PubMed  Google Scholar 

  45. Asahina Y, Itoh Y, Ueno Y, et al. Ledipasvir/sofosbuvir in the treatment of Japanese patients with chronic HCV genotype 2 infection [abstract no. 1184]. Hepatology. 2017;66(1 Suppl):638A.

  46. Pol S, ANRS/AFEF HEPATHER study group. Safety and efficacy of the combination sofosbuvir-ledipasvir in HCV mono-infected patients from the French Cohort ANRS CO22 HEPATHER [abstract no. 1087]. Hepatology. 2017;66(1 Suppl):582A.

  47. Cornberg M, Petersen J, Schober A, et al. Real-world use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection. Aliment Pharmacol Ther. 2017;45(5):688–700.

    Article  CAS  PubMed  Google Scholar 

  48. Tsertsvadze T, Chkhartishvilli N, Abutidze A, et al. Real-world effectiveness of sofosbuvir and ledipasvir/sofosbuvir based regimens in hepatitis C virus genotype 3 infection within national hepatitis C elimination program in the country of Georgia [abstract no.1167]. Hepatology. 2017;66(1 Suppl):627-8A.

  49. Manns M, Samuel D, Gane EJ, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016;16(6):685–97.

    Article  CAS  PubMed  Google Scholar 

  50. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015;149(3):649–59.

    Article  CAS  PubMed  Google Scholar 

  51. Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):705–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cooper CL, Naggie S, Saag MS, et al. Successful retreatment of HCV/HIV-coinfected patients who failed 12 weeks of LDV/SOF. Clin Infect Dis. 2016;63:528–31.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Younossi ZM, Stepanova M, Sulkowski M, et al. Sofosbuvir and ledipasvir improve patient-reported outcomes in patients co-infected with hepatitis C and human immunodeficiency virus. J Viral Hepat. 2016;23(11):857–65.

    Article  CAS  PubMed  Google Scholar 

  54. Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015;15(4):397–404.

    Article  CAS  PubMed  Google Scholar 

  55. Hagiwara S, Nishida N, Watanabe T, et al. Outcome of combination therapy with sofosbuvir and ledipasvir for chronic type C liver disease. Oncology. 2017;92(Suppl 1):3–9.

    Article  PubMed  Google Scholar 

  56. Barone M, Iannone A, Shahini E, et al. A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: the ital-c network. J Viral Hepatitis. 2017. https://doi.org/10.1111/jvh.12765.

    Google Scholar 

  57. Ferreira VL, Assis Jarek NA, Tonin FS, et al. Ledipasvir/sofosbuvir with or without ribavirin for the treatment of chronic hepatitis C genotype 1: a pairwise meta-analysis. J Gastroenterol Hepatol. 2017;32(4):749–55.

    Article  CAS  PubMed  Google Scholar 

  58. Younossi ZM, Stepanova M, Pol S, et al. The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. Liver Int. 2016;36(1):42–8.

    Article  CAS  PubMed  Google Scholar 

  59. Abbalkhail F, Elsiesy H, Elbeshbeshy H, et al. Treatment of patients with hepatitis C virus infection (genotype 4) with ledipasvir-sofosbuvir in the liver transplant setting. Transplant Proc. 2017. https://doi.org/10.1097/TP.0000000000001907.

    Google Scholar 

  60. Kwok RM, Ahn J, Schiano TD, et al. Sofosbuvir plus ledispasvir for recurrent hepatitis C in liver transplant recipients. Liver Transpl. 2016;22(11):1536–43.

    Article  PubMed  Google Scholar 

  61. Saxena V, Khungar V, Verna EC, et al. Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: results from the HCV-TARGET study. Hepatology. 2017;66(4):1090–101.

    Article  CAS  PubMed  Google Scholar 

  62. Colombo M, Aghemo A, Liu H, et al. Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial. Ann Intern Med. 2017;166(2):109–17.

    Article  PubMed  Google Scholar 

  63. Stedman CAM, Hyland RH, Ding X, et al. Once daily ledipasvir/sofosbuvir fixed-dose combination with ribavirin in patients with inherited bleeding disorders and hepatitis C genotype 1 infection. Haemophilia. 2016;22(2):214–7.

    Article  CAS  Google Scholar 

  64. Walsh CE, Workowski K, Terrault NA, et al. Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders. Haemophilia. 2017;23(2):198–206.

    Article  CAS  PubMed  Google Scholar 

  65. Mangia A, Sarli R, Gamberini R, et al. Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection. Aliment Pharmacol Ther. 2017;46(4):424–31.

    Article  CAS  PubMed  Google Scholar 

  66. Alqahtani SA, Afdhal N, Zeuzem S, et al. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of phase III ION trials. Hepatology. 2015;62(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  67. Gilead Sciences. HARVONI® (ledipasvir and sofosbuvir): US prescribing information. 2017. http://www.gilead.com. Accessed 1 Nov 2017

  68. Rosenblatt R, Kumar S, Mehta A, et al. Baseline creatinine clearance is a predictor of worsening renal function while on treatment with sofosbuvir-ledipasvir [abstract no. Su1464]. Gastroenterology. 2016;150(4 Suppl. 1):S1107.

  69. German P, Mathias A, Brainard D, et al. A thorough QT study to evaluate the effects of supratherapeutic doses of ledipasvir on the QTc interval in healthy subjects. Clin Pharmacol Drug Dev. 2017. https://doi.org/10.1002/cpdd.390.

    PubMed  Google Scholar 

  70. WHO. Global hepatitis report 2017. 2017. http://www.who.int/hepatitis/. Accessed 30 Nov 2017.

  71. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol. 2016;61(1):153–94.

    Google Scholar 

  72. European Medicines Agency. Vosevi (sofosbuvir, velpatasvir and voxilaprevir) 400 mg/100 mg/10 mg film coated tablets: summary of product characteristics. 2017. http://www.ema.europa.eu. Accessed 4 Nov 2017.

  73. Carter W, Connelly S, Struble K. Reinventing HCV treatment: past and future perspectives. J Clin Pharmacol. 2017;57(3):287–96.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

During the peer review process, the manufacturer of tocilizumab was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    Lesley J. Scott

Authors
  1. Lesley J. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lesley J. Scott.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

Lesley Scott is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information about this Adis Drug Review can be found at http://www.medengine.com/Redeem/F3DCF0600DB0B722.

Additional information

The manuscript was reviewed by: A. Ascione, Fatebefratelli Hospital, Centre for Liver Disease, Napoli, Italy; S. Karatapanis, General Hospital of Rhodes, First Department of Internal Medicine, Rhodes, Greece; R. Pisapia, Epidemiology of Emerging and Re-emerging Infections and AIDs Reference Center, Istituto Nazionale per la Malattie Infettive “L. Spallanzani”, Rome, Italy; R. E. Stauber, Medical University of Graz, Department of Internal Medicine, Graz, Austria.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scott, L.J. Ledipasvir/Sofosbuvir: A Review in Chronic Hepatitis C. Drugs 78, 245–256 (2018). https://doi.org/10.1007/s40265-018-0864-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-018-0864-z