Abstract
Purpose of the Review
Hepatitis C virus (HCV) therapy has improved dramatically in recent years; however, small clinical gaps remained. The recent approval of the final two antiviral regimens likely to come to clinical use addresses most unmet medical needs. The clinical trial data supporting the approval of these regimens is reviewed, highlighting how they address outstanding clinical needs and noting the very few gaps that still remain.
Recent Findings
The approval of sofosbuvir/velpatasvir/voxilaprevir provides an excellent salvage regimen for patients who have failed prior treatment with direct antiviral agents. A 12-week course of therapy leads to sustained virological response in almost all retreatment settings. In addition, the approval of glecaprevir/pibrentasvir offers an 8-week treatment option for all non-cirrhotic treatment-naïve patients and also provides a much needed therapy for patients with chronic kidney disease and HCV genotypes other than 1 and 4.
Summary
Two newly approved regimens have been approved for HCV patients who previously failed direct antiviral therapy and patients with chronic kidney disease with genotypes other than 1 and 4.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Pawlotsky JM, Feld JJ, Zeuzem S, Hoofnagle JH. From non-A, non-B hepatitis to hepatitis C virus cure. J Hepatol. 2015;62(1 Suppl):S87–99.
Feld JJ, Foster GR. Second generation direct-acting antivirals—do we expect major improvements? J Hepatol. 2016;65(1 Suppl):S130–42.
Feld JJ, Maan R, Zeuzem S, Kuo A, Nelson DR, Di Bisceglie AM, et al. Effectiveness and safety of sofosbuvir-based regimens for chronic HCV genotype 3 infection: results of the HCV-TARGET study. Clin Infect Dis. 2016;63(6):776–83.
• Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, 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):1131–1140 e1135. Key study showing real-world data with highly effective HCV regimens
Lim JK, Liapakis AM, Shiffman ML, Lok AS, Zeuzem S, Terrault NA, Park JS, Landis CS, Hassan M, Gallant J et al Safety and effectiveness of ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with genotype 1 hepatitis C virus infection and cirrhosis. Clin Gastroenterol Hepatol 2018.
Cacoub P, Desbois AC, Isnard-Bagnis C, Rocatello D, Ferri C. Hepatitis C virus infection and chronic kidney disease: time for reappraisal. J Hepatol. 2016;65(1 Suppl):S82–94.
Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537–45.
Sise ME, Backman E, Ortiz GA, Hundemer GL, Ufere NN, Chute DF, et al. Effect of sofosbuvir-based hepatitis C virus therapy on kidney function in patients with CKD. Clin J Am Soc Nephrol CJASN. 2017;12(10):1615–23.
Li T, Qu Y, Guo Y, Wang Y, Wang L. Efficacy and safety of direct-acting antivirals-based antiviral therapies for hepatitis C virus patients with stage 4-5 chronic kidney disease: a meta-analysis. Liver Int. 2017;37(7):974–81.
Maan R, Al Marzooqi SH, Klair JS, Karkada J, Cerocchi O, Kowgier M, et al. The frequency of acute kidney injury in patients with chronic hepatitis C virus infection treated with sofosbuvir-based regimens. Aliment Pharmacol Ther. 2017;46(1):46–55.
Nazario HE, Ndungu M, Modi AA. Sofosbuvir and simeprevir in hepatitis C genotype 1-patients with end-stage renal disease on haemodialysis or GFR <30 ml/min. Liver Int. 2016;36(6):798–801.
Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2(3):161–76.
van der Meer AJ, Feld JJ, Hofer H, Almasio PL, Calvaruso V, Fernandez-Rodriguez CM, et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. J Hepatol. 2017;66(3):485–93.
Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61(4):1127–35.
Leroy V, Angus P, Bronowicki JP, Dore GJ, Hezode C, Pianko S, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology. 2016;63(5):1430–41.
Hezode C, Lebray P, De Ledinghen V, Zoulim F, Di Martino V, Boyer N, et al. Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme. Liver Int. 2017;37(9):1314–24.
•• Foster GR, Afdhal N, Roberts SK, Brau N, Gane EJ, Pianko S, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608–17. Pivotal trial demonstrating the very high efficacy of sofosobvuir and velpatasvir for the more ‘difficult-to-cure’ genotype 3 infection
• Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618–28. Key study demonstrating the importance of ribavirin in treating patients with decompensated cirrhosis
AASLD/IDSA: Recommendations for Testing, Managing, and Treating Hepatitis C. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Diseases Society of America. http://www.hcvguidelines.org/ (Accessed 11 Dec 2017) 2017.
Kondili LA, Gaeta GB, Brunetto MR, Di Leo A, Iannone A, Santantonio TA, et al. Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: interim evaluations from the PITER network. PLoS One. 2017;12(10):e0185728.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879–88.
•• Bourliere M, Gordon SC, Flamm SL, Cooper CL, Ramji A, Tong M, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2134–46. Critical study highlighting the efficacy of sofosbuvir/velpatasvir/voxilaprevir as a salvage regimen for people who have not responded to first-line DAA therapy
Struble K, Chan-Tack K, Qi K, Naeger LK, Birnkrant D Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration’s evaluation. Hepatology 2017.
Zeuzem S, Mizokami M, Pianko S, Mangia A, Han KH, Martin R, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome. J Hepatol. 2017;66(5):910–8.
• Jacobson IM, Lawitz E, Gane EJ, Willems BE, Ruane PJ, Nahass RG, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153(1):113–22. Important study showing that this triple combination can be used effectively for 8 weeks in some but not all genotypes. The fact that it was not as effective as 12 weeks for genotype 1a led to its approval primarily as a salvage regimen in North America
•• Zeuzem S, Foster GR, Wang S, Asatryan A, Gane E, Feld JJ, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378(4):354–69. Important demonstration of the efficacy of glecaprevir/pibrentasvir when given for only 8 weeks in patients with genotype 1 and 3 infection without cirrhosis, providing the first 8-week regimen without restrictions for non-cirrhotic patients
Asselah T, Kowdley KV, Zadeikis N, Wang S, Hassanein T, Horsmans Y, Colombo M, Calinas F, Aguilar H, de Ledinghen V et al Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 2017.
• Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis. 2017;17(10):1062–8. Key study demonstrating the efficacy and safety of glecaprevir/pibrentasvir in patients with compenstaed cirrhosis
Wyles D, Poordad F, Wang S, Alric L, Felizarta F, Kwo PY, Maliakkal B, Agarwal K, Hassanein T, Weilert F et al Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial. Hepatology 2017.
Wyles D, Poordad F, Wang S, Alric L, F F, Kwo P, Maliakkal B, Agarwal K, Hassanein T, Weilert F et al SURVEYOR-II, Part 3: efficacy and safety of glecaprevir/pibrentasvir (ABT-493/ABT-530) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or cirrhosis Hepatology 2016, AASLD The Liver Meeting 2016.
•• Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Brau N, Brown A, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med. 2017;377(15):1448–55. Critical study highlighting that this combination is safe and effective in patients with advanced kidney disease, offering a regimen for patients with genotypes other than 1 and 4 HCV
Poordad F, Pol S, Asatryan A, Buti M, Shaw D, Hezode C, et al. Glecaprevir/pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology. 2017;
Vosevi Product Insert. 2017.
Mavyret Product Insert. 2017.
https:// http://www.hep-druginteractions.org/. 2017.
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Marwa Ismail declares no conflicts of interest.
Jordan J. Feld reports grants and personal fees from AbbVie, Gilead, Merck, Janssen, personal fees from Contravir, and grants from Abbott, outside the submitted work.
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Ismail, M., Feld, J.J. The Newest Direct-Acting Antiviral Agents: the Final Chapter in DAA Development. Curr Hepatology Rep 17, 97–104 (2018). https://doi.org/10.1007/s11901-018-0392-z
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DOI: https://doi.org/10.1007/s11901-018-0392-z