Ledipasvir/Sofosbuvir: A Review of Its Use in Chronic Hepatitis C
The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni®) was recently approved in the US and the EU. The phase III ION trials included treatment-naive (ION-1 and -3) or treatment-experienced (ION-2) patients with chronic HCV genotype 1 infection (≈20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 had cirrhosis). A sustained virological response 12 weeks’ post-treatment (SVR12) was seen in 99 % of treatment-naive patients receiving ledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. Moreover, in ION-3, an 8-week regimen achieved an SVR12 rate of 94 % overall and 97 % in the subgroup of patients with a baseline HCV RNA level of <6 million IU/mL. SVR12 rates of 94 and 99 % were seen in treatment-experienced patients who received ledipasvir/sofosbuvir for 12 and 24 weeks in ION-2. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated. In conclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that represents a significant advance in the treatment of chronic hepatitis C.
KeywordsSofosbuvir SVR12 Rate Virological Relapse NS5A RAVs High SVR12 Rate
The preparation of this review was not supported by any external funding. Gillian Keating is a salaried employee of Adis/Springer. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.
- 1.Gilead Sciences Inc. Harvoni® (ledipasvir and sofosbuvir) tablets for oral use: US prescribing information. 2015. http://www.harvoni.com/. Accessed 30 Mar 2015.
- 2.European Medicines Agency. Harvoni (ledipasvir/sofosbuvir) film-coated tablets: EU summary of product characteristics. 2014. http://www.ema.europa.eu/. Accessed 2 Mar 2015.
- 3.Hebner C, Lee Y-J, Han B, et al. In vitro pan-genotypic and combination activity of sofosbuvir (GS-7977) in stable replicon cell lines [abstract no. 1875]. Hepatology. 2012;56(4 Suppl):1066A.Google Scholar
- 7.Sarrazin C, Dvory-Sobol H, Svarovskaia ES, et al. Baseline and post-baseline resistance analyses of phase 2/3 studies of ledipasvir/sofosbuvir ± RBV [abstract no. 1926 plus poster]. Hepatology. 2014;60(4 Suppl):1128A.Google Scholar
- 8.Mizokami M, Takehara T, Yokosuka O, et al. 100 % SVR12 in Japanese patients with chronic genotype 1 hepatitis C virus infection receiving ledipasvir/sofosbuvir fixed dose combination for 12 weeks: results from a multicenter phase 3 study [abstract no. 1929 plus poster]. Hepatology. 2014;60(4 Suppl):1130A.Google Scholar
- 9.German P, Mathias A, Yang JC, et al. The pharmacokinetics of ledipasvir, an HCV specific NS5A inhibitor in HCV-uninfected subjects with moderate and severe hepatic impairment [abstract no. 467 plus poster]. Hepatology. 2013;58(4 Suppl 1):432A.Google Scholar
- 10.Mogalian E, Mathias A, Yang JC, et al. The pharmacokinetics of ledipasvir, an HCV specific NS5A inhibitor, in HCV-uninfected subjects with severe renal impairment [abstract no. 1952]. Hepatology. 2014;60(4 Suppl):1145A–6A.Google Scholar
- 11.Kirby B, German P, Shen G, et al. No differences in the pharmacokinetics of sofosbuvir (GS-7977) and sofosbuvir/ledipasvir (GS-7977/GS-5885) fixed dose combination between Japanese and Caucasians [abstract no. 954]. Hepatol Int. 2013;7(Suppl 1):S375–6.Google Scholar
- 12.German P, Pang PS, Fang L, et al. Drug-drug interaction profile of the fixed-dose combination tablet ledipasvir/sofosbuvir [abstract no. 1976 plus poster]. Hepatology. 2014;60(4 Suppl):1162A.Google Scholar
- 13.German P, Garrison K, Pang PS, et al. Drug–drug interactions between anti-HCV regimen ledipasvir/sofosbuvir and antiretrovirals [abstract no. 82]. In: 2015 Conference on Retroviruses and Opportunistic Infections. 2015.Google Scholar
- 15.Mathias A, Cornpropst M, Clemons D, et al. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants, cyclosporine A or tacrolimus in healthy volunteers [abstract no. 1869 plus poster]. Hepatology. 2012;56(4 Suppl):1063A–4A.Google Scholar
- 16.Flamm SL, Everson GT, Charlton M, et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective multicenter study [abstract no. 239 plus slide presentation]. Hepatology. 2014;60(4 Suppl):320A–1A.Google Scholar
- 17.Reddy KR, Everson GT, Flamm SL, et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post-transplant recurrence: preliminary results of a prospective, multicenter study [abstract no. 8 plus slide presentation]. Hepatology. 2014;60(4 Suppl):200A–1A.Google Scholar
- 19.Lawitz E, Poordad FF, Pang PS, et 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. Lancet. 2014;383(9916):515–23.CrossRefPubMedGoogle Scholar
- 20.Naggie S, Cooper C, Saag MS, et al. Ledipasvir/sofosbuvir for 12 weeks in patients coinfected with HCV and HIV-1 [abstract no. 152LB]. In: 2015 Conference on Retroviruses and Opportunistic Infections. 2015.Google Scholar
- 21.Bernstein DE, Mangia A, Brau N, et al. Concordance between SVR4, SVR12 and SVR24 in genotype 1 HCV-infected patients who received all oral fixed-dose combination ledipasvir/sofosbuvir with or without ribavirin in phase 3 clinical trials [abstract no. 1947 plus slide presentation]. Hepatology. 2014;60(4 Suppl):1142A–3A.Google Scholar
- 22.Jacobson IM, Kwo PY, Kowdley KV, et al. Virologic response rates to all oral fixed-dose combination ledipasvir/sofosbuvir regimens are similar in patients with and without traditional negative predictive factors in phase 3 clinical trials [abstract no. 1945 plus poster]. Hepatology. 2014;60 (4 Suppl):1141A–2A.Google Scholar
- 23.Gordon SC, Fried MW, Kwo PY, et al. No differences in the efficacy of fixed-dose combination ledipasvir/sofosbuvir in patients according to fibrosis stage determined by liver biopsy or laboratory biomarker in phase 3 clinical trials [abstract no. 1958 plus poster]. Hepatology. 2014;60(4 Suppl):1149A–50A.Google Scholar
- 24.Younossi Z, Stepanova M, Marcellin P, et al. Sustained virologic response with ledipasvir (LDV) and sofosbuvir (SOF) regimens lead to substantial improvement in patient-reported outcomes (PROs) among chronic hepatitis C (CHC) patients with early hepatic fibrosis as well as those with advanced hepatic fibrosis [abstract no. 1445 plus poster]. Hepatology. 2014;60(4 Suppl):892A–3A.Google Scholar
- 25.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. Hepatology. 2015. doi: 10.1002/hep.27724.
- 26.Osinusi A, Townsend K, Kohli A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015. doi: 10.1001/jama.2015.1373.
- 27.Gane E, Hyland RH, Pang P, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in HCV infected populations including decompensated patients and patients with prior sofosbuvir treatment experience [abstract no. 238 plus slide presentation]. Gastroenterology. 2014;146(5 Suppl 1):S904–S5.Google Scholar
- 28.Kapoor R, Kohil A, Sidharthan S, et al. All oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from the NIAID SYNERGY trial [abstract no. 240 plus slide presentation]. Hepatology. 2014;60(4 Suppl):321A.Google Scholar
- 29.Gane EJ, Hyland RH, An D, et al. High efficacy of LDV/SOF regimens for 12 weeks for patients with HCV genotype 3 or 6 infection [abstract no. LB-11 plus poster]. Hepatology. 2014;60(1 Suppl).Google Scholar
- 30.Alqahtani S, Afdhal NH, Zeuzem S, et al. Safety of ledipasvir/sofosbuvir with and without ribavirin for the treatment of patients with chronic HCV genotype 1 infection: an analysis of the phase 3 ION trials [abstract no. 1944 plus poster]. Hepatology. 2014;60 (4 Suppl):1140A–1A.Google Scholar
- 31.Bourlière M, Sulkowski MS, Omata M, et al. An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin [abstract no. 82 plus slide presentation]. Hepatology. 2014;60(4 Suppl):239A.Google Scholar
- 32.American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C (December 19). 2014. http://www.hcvguidelines.org/full-report-view. Accessed 2 Mar 2015.
- 33.Petersen T, Gordon LA, Townsend K, et al. Pill burden and treatment length reduce adherence to IFN-free hepatitis C therapy in an urban cohort [abstract no. 667]. Top Antivir Med. 2014;22(e-1):331–2.Google Scholar
- 34.Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015. doi: 10.1016/S0140-6736(14)61228-9.
- 35.Lawitz E, Poordad F, Hyland RH, et al. High rates of SVR in patients with genotype 1 HCV infection and cirrhosis after treatment with ledipasvir/sofosbuvir + ribavirin or ledipasvir/sofosbuvir + GS-9669 for 8 weeks [abstract no. 1948]. Hepatology. 2014;60(4 Suppl):1143A.Google Scholar
- 37.Wyles DL, Pockros PJ, Yang JC, et al. Retreatment of patients who failed prior sofosbuvir-based regimens with all oral fixed-dose combination ledipasvir/sofosbuvir plus ribavirin for 12 weeks [abstract no. 235 plus slide presentation]. Hepatology. 2014;60(4 Suppl):317A–8A.Google Scholar