Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection
Author(s): ,
Stefan Zeuzem
Affiliations:
Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
,
Ira M. Jacobson
Affiliations:
Hepatology Section, Division of Gastroenterology, Department of Medicine, New York University School of Medicine and NYU Langone Health, New York, USA
,
James S. Park
Affiliations:
Hepatology Section, Division of Gastroenterology, Department of Medicine, New York University School of Medicine and NYU Langone Health, New York, USA
Johannes Vermehren
Affiliations:
Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
Corresponding author. Address: Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Tel.: +49 69 6301 5122; fax: +49 69 6301 83112.
EASL LiverTree™. Vermehren J. Nov 1, 2018; 256715
Dr. Johannes Vermehren
Dr. Johannes Vermehren

Access to this content is an EASL members and LiverTree™ Privileged Users benefit.

Journal Abstract
References
Discussion Forum (0)
Rate & Comment (0)
Summary

Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12-week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

Keyword(s)
Direct-acting antivirals, Hepatitis C Virus infection, Glecaprevir, Pibrentasvir, Voxilaprevir, Velpatasvir, Sofosbuviri
[1]. World Health Organization Hepatitis C Factsheet; available online at: ; last accessed on July 1, 2018.
[2]. AASLD. Recommendations for Testing, Managing, and Treating Hepatitis C; available online at: ; last accessed on July 1, 2018.
[4]. M.P. Manns - Hepatitis C virus infection
[5]. P. Golabi - Patient-reported outcomes and fatigue in patients with chronic hepatitis C infection
[6]. E. Gane - Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment
[7]. D. Roth - 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
[8]. M.P. Curry - Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis
[9]. J.L. Calleja - Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort
[10]. P. Buggisch - Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C
[11]. L.I. Backus - Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients
[12]. J.M. Pascasio - Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation
[13]. M.C.M. Cheung - Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis
[14]. K. Kozbial - Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment
[15]. Z. Younossi - Systematic review: patient-reported outcomes in chronic hepatitis C – the impact of liver disease and new treatment regimens
[16]. Charlotte Hedskog - Identification of novel HCV genotype and subtypes in patients treated with sofosbuvir based regimens
[17]. D.B. Smith - Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource
[18]. E. Gower - Global epidemiology and genotype distribution of the hepatitis C virus infection
[19]. W. Sievert - A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt
[20]. A. Probst - Role of hepatitis C virus genotype 3 in liver fibrosis progression–a systematic review and meta-analysis
[21]. A.J. van der Meer - Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis
[22]. A. Kau - Treatment predictors of a sustained virologic response in hepatitis B and C
[23]. C. Welsch - Clinical relevance of HCV antiviral drug resistance
[24]. C. Hezode - Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis
[25]. C. Sarrazin - SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon α-2b for genotype 1 nonresponders
[26]. C. Sarrazin - Dynamic hepatitis c virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir
[27]. J. Vermehren - New hepatitis C therapies in clinical development
[28]. M.J. Sofia - Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus
[29]. S. Zeuzem - Sofosbuvir and ribavirin in HCV genotypes 2 and 3
[30]. Simone Susser - Origin, prevalence and response to therapy of hepatitis C virus genotype 2k/1b chimeras
[31]. J.M. Vierling - Efficacy of an eight-week regimen of grazoprevir plus elbasvir with and without ribavirin in treatment-naive, noncirrhotic HCV genotype 1B infection
[32]. Tania Mara Welzel - Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial
[33]. K.V. Kowdley - Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis
[34]. B.K. Kutala - Efficacy and safety of sofosbuvir-based therapies in patients with advanced liver disease in a real-life cohort
[35]. B.E. Yee - Lower response to simeprevir and sofosbuvir in HCV genotype 1 in routine practice compared with clinical trials
[36]. S. Zeuzem - Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and non-cirrhotic patients with chronic hepatitis C virus genotype 1, 4 or 6 infection: a randomized trial
[37]. F. da Silva - Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries
[38]. J. Dietz - HCV resistance-associated substitutions in patients with HCV genotype 4 and failure to DAA combination therapies and implications for a retreatment
[39]. F. Tacke - Treatment of HCV genotype 2 with sofosbuvir and ribavirin results in lower sustained virological response rates in real life than expected from clinical trials
[40]. G. Cheng - GS-5816, a second-generation HCV NS5A inhibitor with potent antiviral activity, broad genotypic coverage, and a high resistance barrier
[41]. G.R. Foster - Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection
[42]. N. Goossens - Is genotype 3 of the hepatitis C virus the new villain?
[43]. C. Wang - In vitro activity of daclatasvir on hepatitis C virus genotype 3 NS5A
[44]. M.S. Sulkowski - Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection
[45]. D.R. Nelson - All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study
[46]. R. Fissell - Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS
[47]. Gilead Sciences. Sovaldi package insert; available online at: ; last accessed July 1, 2018.
[48]. P.J. Pockros - Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease
[49]. T.M. Welzel - Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort
[50]. P. Ingiliz - HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe
[51]. E.F. Donaldson - Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir
[52]. Julia Dietz - Patterns of resistance-associated substitutions in patients with chronic HCV infection following treatment with direct-acting antivirals
[53]. A. Osinusi - Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study
[54]. D. Wyles - Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens
[55]. M. Bourlière - Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection
[56]. C. Sarrazin - The importance of resistance to direct antiviral drugs in HCV infection in clinical practice
[57]. P. Krishnan - Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir/r-, ombitasvir- and dasabuvir-based regimens
[58]. O. Lenz - Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies
[59]. T. Kanda - Real-world experiences with the combination treatment of ledipasvir plus sofosbuvir for 12 weeks in HCV genotype 1-infected japanese patients: achievement of a sustained virological response in previous users of peginterferon plus ribavirin with HCV NS3/4
[60]. E.J. Gane - Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen
[61]. E. Lawitz - Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks
[62]. T. Ng - In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor pibrentasvir
[63]. S. Zeuzem - Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection
[64]. T. Asselah - Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis
[65]. D. Wyles - Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial
[66]. X. Forns - 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
[67]. F. Poordad - Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment
[68]. F. Poordad - Glecaprevir/Pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure
[69]. N. Reau - Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus infection
[70]. I.M. Jacobson - Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials
[71]. T. Asselah - Eliminating hepatitis C within low-income countries – The need to cure genotypes 4, 5, 6
[72]. M. Puoti - High SVR rates with eight and twelve weeks of pangenotypic glecaprevir/pibrentasvir: integrated efficacy and safety analysis of genotype 1–6 patients without cirrhosis
[73]. G.T. Everson - Sofosbuvir with velpatasvir in treatment-naive noncirrhotic patients with genotype 1 to 6 hepatitis c virus infection
[74]. Gilead Sciences. Vosevi package insert; available online at: ; last accessed on July 1, 2018.
[75]. P. Krishnan - Pooled resistance analysis in HCV genotype 1–6 infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials
[76]. Gilead Sciences. Epclusa package insert; available online at ; last accessed on July 1, 2018.
[77]. J. von Felden - High efficacy of sofosbuvir/velpatasvir and impact of baseline resistance-associated substitutions in hepatitis C genotype 3 infection
[78]. D. Wyles - Retreatment of hepatitis C virus infection in patients who failed glecaprevir/pibrentasvir
Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.


Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.



Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.


Save Settings