The Clinical Development of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®)
- 21 Downloads
The fixed-dose combination tablet of ledipasvir (LDV), an HCV NS5A inhibitor, and sofosbuvir (SOF), an HCV nucleotide analog NS5B polymerase inhibitor, was the first all-oral (one-pill once daily), interferon-free and ribavirin-free regimen approved for the treatment of patients with chronic hepatitis C. With over 5,900 HCV-infected patients enrolled in LDV/SOF clinical trials through late 2017, the accelerated clinical development program was able to generate safety and efficacy data across a broad range of patient populations. The initial registration trials demonstrated that 12 weeks of treatment with LDV/SOF resulted in high cure rates of over 95% in HCV genotype 1 patients regardless of historical negative treatment predictors including cirrhosis or prior treatment history. The program subsequently expanded to include other HCV genotypes and special populations with significant unmet medical need including but not limited to decompensated liver disease, HIV/HCV coinfection, posttransplantation, and children. With favorable pharmacokinetic properties, good safety profile, and high efficacy rates, the approval of LDV/SOF (Harvoni®) ushered in a new era of treatment and management for the millions of HCV-infected patients globally.
KeywordsDirect-acting antivirals HCV genotype 1 infection Hepatitis C virus NS5A inhibitors NS5B nucleotide inhibitors
Hepatitis C virus
Human immunodeficiency virus type 1
Sustained virologic response
The authors would like to thank the patients and their families as well as study site staff who participated in the clinical trials of Sovaldi and Harvoni.
Compliance with Ethical Standards
Conflict of Interest Anu Osinusi and John G. McHutchison are employees of Gilead Sciences, Inc.
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 1.Gower E et al (2014) Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 61(1 Suppl):S45–S57Google Scholar
- 6.Sovaldi (sofosbuvir) tablets: US prescribing information (2013) Gilead Sciences, Foster City. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf
- 8.German P, Yang J, West S et al (2014) Effect of food and acid reducing agents on the relative bioavailability and pharmacokinetics of ledipasvir/sofosbuvir fixed-dose combination tablet. Presentation at the 15th international workshop on clinical pharmacology of HIV and hepatitis therapy, Washington, 19–21 May 2014Google Scholar
- 9.Lawitz E, Rodríguez-Torres M, Cornpropst MT et al (2012) The effect of hepatic impairment on the pharmacokinetics and antiviral activity of PSI-7977 in hepatitis C infected subjects treated for seven days. J Hepatol 56(suppl 2):S445–S446Google Scholar
- 10.Cornpropst M, Denning J, Clemons D et al (2012) The effect of renal impairment and end stage renal disease on the single-dose pharmacokinetics of GS-7977. Presented at 47th annual meeting of the European Association for the Study of the Liver, BarcelonaGoogle Scholar
- 11.Gane E, Robson RA, Bonacini M et al (2014) Safety, antiviral efficacy, and pharmacokinetics of sofosbuvir in patients with severe renal impairment. Presented at 65th annual meeting of the American Association for the Study of Liver Diseases, BostonGoogle Scholar
- 14.Harvoni (ledipasvir/sofosbuvir) tablets: US prescribing information (2014) Gilead Sciences, Foster City. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf
- 16.Lawitz E, Lalezari J, Rodriguez-Torres M et al (2010) High rapid virologic response (RVR) with PSI-7977 QD plus PEG-IFN/RBV in a 28-day phase 2a trial. Hepatology 52(suppl):706Google Scholar
- 18.Lawitz EJ et al (2012) A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol 57(1):24–31Google Scholar
- 29.Bourliere M et al (2015) 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 15(4):397–404PubMedPubMedCentralGoogle Scholar
- 71.Lawitz E, Landis CS, Maliakkal BJ et al (2017) Safety and efficacy of treatment with once-daily ledipasvir/sofosbuvir (90/400 mg) for 12 weeks in genotype 1 HCV-infected patients with severe renal impairment [Abstract 1587]. In: The Liver Meeting® 2017 – the 68th annual meeting of the American Association for the Study of Liver Diseases (AASLD), Washington, 20–24 Oct 2017Google Scholar
- 75.Wei L, Xie Q, Hou JL et al (2017) Safety and efficacy of ledipasvir/sofosbuvir in a genotype 1 HCV infected Chinese population: results from a phase 3 clinical trial. In: The Liver Meeting® 2017 – the 68th annual meeting of the American Association for the Study of Liver Diseases (AASLD), Washington, 20–24 Oct 2017Google Scholar
- 76.Shiha G, Waked I, Soliman R et al (2017) Ledipasvir/sofosbuvir for 8 or 12 weeks with or without ribavirin in HCV genotype 4 patients in Egypt [Abstract OP158]. In: Asian Pacific Association for the Study of the Liver (APASL), Shanghai, 15–19 Feb 2017Google Scholar