Showing posts with label geno2. Show all posts
Showing posts with label geno2. Show all posts

Saturday, August 6, 2016

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection

Journal of Viral Hepatitis

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection
A Randomized, Double-blind, Dose-ranging Phase 1 Study

M. Rodriguez-Torres; S. Glass; J. Hill; B. Freilich; D. Hassman; A. M. Di Bisceglie; J. G. Taylor; B. J. Kirby; H. Dvory-Sobol; J. C. Yang; D. An; L. M. Stamm; D. M. Brainard; S. Kim; D. Krefetz; W. Smith; T. Marbury; E. Lawitz Disclosures J Viral Hepat. 2016;23(8):614-622.


  • Abstract and Introduction
  • Methods
  • Results 
  • Discussion


  • Discussion Only
    In this randomized, phase 1b study, the safety, antiviral efficacy and PK of GS-9857 at doses ranging from 50 to 300 mg were assessed in patients with chronic genotype 1–4 HCV infection. GS-9857 was generally well tolerated by patients with chronic HCV infection when administered once daily for 3 days. All AEs were of mild or moderate severity, with diarrhoea and headache occurring most commonly during this study. Although increased incidence of rash, pruritus, nausea and anaemia have been commonly reported with the use of certain protease inhibitor-based regimens,[7–10] no such events were observed during this study. Grade 3 or Grade 4 laboratory abnormalities occurred in 16.9% of patients receiving GS-9857 and were not associated with GS-9857 dose or AEs. Notably, assessments of ALT, AST and alkaline phosphatase levels did not reveal any Grade 3 or Grade 4 abnormalities, indicating that GS-9857 administration was not associated with significant changes in liver function. Physical examination and ECG evaluation did not reveal clinically significant findings.

    Treatment with GS-9857 at doses of 100 mg or 300 mg resulted in >3 log10 IU/mL median maximal reduction in viral load from baseline across all genotypes, including genotype 3, indicating that GS-9857 exhibited potent antiviral activity in HCV-infected patients. This observation is consistent with in vitro data showing that GS-9857 has pan-genotypic activity against genotype 1 to 6 replicons, with the half-maximal effective concentration ranging from 1.5 to 6.6 nm.[5] With the exception of patients with genotype 3a infection who received GS-9857 doses of <100 mg, a rapid and consistent reduction in HCV RNA was achieved and maintained through day 10. For patients with genotype 3a infection who received GS-9857 50 mg, HCV RNA reductions occurred more slowly.

    This study characterized substitutions at positions 36, 41, 43, 54, 55, 80, 122, 155, 156, 168 and 170, which have been reported to be associated with resistance to NS3/4A protease inhibitors.[11–17] Prior to the start of GS-9857 treatment, 22.4% of patients who were sequenced harboured NS3 RAVs. Treatment with GS-9857 resulted in similar mean maximal viral load reductions in patients with and without NS3 RAVs, indicating that the antiviral efficacy of GS-9857 was maintained in the presence of mutations commonly associated with resistance to treatment. The majority of patients (73.6%) who were sequenced after 3 days of GS-9857 treatment did not have emergent NS3 RAVs, and there were no emergent NS3 RAVs in patients with genotype 2 or 4 infection. A156V or A156T were the most prevalent substitutions to emerge in patients with genotype 1a or 1b infection. In vitro data indicate that GS-9857 has potent activity against the most common genotype 1 RAVs except A156T;[5] this substitution is associated with high levels of resistance (>100-fold) but low viral fitness (1.5% compared to wild-type genotype 1a replicon).[12] The overall low frequency of emergent NS3 RAVs suggests that GS-9857 has a relatively high barrier to resistance as compared with other first-generation protease inhibitors, which may be a substantial benefit in the context of retreatment of patients who have failed a prior treatment with a DAA-based regimen.

    Administration of GS-9857 at doses ranging from 50 to 300 mg under fasting conditions resulted in dose-proportional increases in exposure. The median half-life across cohorts ranged from approximately 29–42 h, supporting once-daily dosing. Consistent with its long median half-life, significant accumulation of GS-9857 exposure was observed. GS-9857 plasma PK was similar among patients with genotype 1a, 1b, 2, 3 or 4 HCV infection.

    Patients with cirrhosis or chronic liver disease were excluded from this preliminary investigational study. As such, the lack of significant safety concerns observed may be the result of selection for a study population less prone to AEs. Further evaluations of GS-9857 in patients with more advanced disease or additional complications will be necessary to confirm the findings of this study.
    In summary, administration of multiple doses of GS-9857 was well tolerated and resulted in a robust decline of HCV RNA levels in patients with genotype 1–4 HCV infection. Notably, the potent antiviral activity of GS-9857 was preserved in the presence of commonly observed NS3 mutations associated with resistance to protease inhibitors. GS-9857 demonstrated linear PK when administered at doses ranging from 50 to 300 mg under fasting conditions. The median half-life of GS-9857 ranged from 29 to 42 h, conducive to once-daily dosing. Lastly, GS-9857 has demonstrated additive antiviral activity when evaluated in vitro in combination with sofosbuvir or velpatasvir.[5] Together, these data support the further development of once-daily GS-9857 in combination with other DAAs for the treatment of patients with chronic HCV infection.

    Full Article -  GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection
    This phase 1b study of the investigational drug GS-9857 showed positive results on its efficacy and tolerability in chronic HCV infection, supporting its further evaluation.

    Sunday, July 31, 2016

    Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 Genotype 1, 2,3,4 or 6 / Phase 2 Trial

    Articles In Press

    This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

    Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with HCV Genotype 2, 3, 4, or 6 Infections in an Open-label, Phase 2 Trial
    Edward Gane, Kris V. Kowdley, David Pound, Catherine A.M. Stedman, Mitchell Davis, Kyle Etzkorn, Stuart C. Gordon, David Bernstein, Gregory Everson, Maribel Rodriguez-Torres, Naoky Tsai, Omer Khalid, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Myron Tong, Raymond T. Chung, Kimberly Beavers, John E. Poulos, Paul Y. Kwo, Mindie H. Nguyen
    DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.038
    Publication stage: In Press Accepted Manuscript
    Published online: July 30, 2016
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    Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients.

    DISCUSSION ONLY
    With the recent approval of DAAs, safe and effective combination regimens are now available for the majority of patients chronically infected with HCV. SVR rates exceeding 90% can be achieved in most patient populations regardless of genotype, treatment experience, or presence of cirrhosis. Although the proportion of patients who do not achieve SVR with currently approved DAA regimens is small, the absolute number of DAA failures will steadily increase in parallel with the rate of treatment uptake. DAA failures represent an unmet medical need without, at this time, any approved retreatment options. In this open-label, phase 2 study, the combination of sofosbuvir velpatasvir plus GS-9857 for 12 weeks was safe and highly effective for the treatment of patients with genotypes 2, 3, 4, or 6 HCV infection with or without compensated cirrhosis who were treatment-experienced, including those who had failed previous DAA regimens. The high SVR12 rate among treatment-experienced patients with genotype 3 HCV infection and cirrhosis is noteworthy, given the lower SVR12 rates generally experienced by patients this patient population.

    Currently approved regimens for non-genotype 1 HCV have durations of 12 to 24 weeks, depending on choice of regimen and patient’s baseline characteristics, such as HCV genotype, treatment history and presence or absence of cirrhosis. The feasibility of further shortening the duration of treatment has been a goal of research, especially for non-ribavirin containing regimens. Several trials have evaluated various combinations of DAAs for four weeks, but with uniformly disappointing 0utcomes—SVR12 rates of 20% to 40%

    In this trial, 6 weeks of sofosbuvir-velpatasvir plus GS-9857 achieved suboptimal results (<90% SVR12 rate) in a historically easy-to-treat population of treatment-naïve patients without cirrhosis. Eight weeks of sofosbuvir-velpatasvir plus GS-9857 was safe and effective for treatment-naïve patients with cirrhosis, including those with HCV genotype 3. Thus, the 8-week regimen may serve as a shorter-duration option for treatment-naïve patients with or without cirrhosis and is currently being evaluated in Phase 3 clinical trials.

    Additionally, the high SVR12 rates across genotypes suggests the pangenotypic treatment potential of sofosbuvir-velpatasvir plus GS-9857. While genotype 1 patients were not treated in this study, a parallel open-label, phase 2 study of patients infected with HCV genotype 1 was also conducted,where patients received treatment for 6 to 12 weeks.

    This study was limited by its small sample size and open-label design. Although the first Phase 2 clinical trial to evaluate retreatment of non-genotype 1 HCV infected patients previously treated with DAA-regimens that included NS5A inhibitors, only six patients in this subgroup were enrolled. Also, no patients with genotype 5 HCV and only 3 patients with genotype 6 HCV were enrolled, reflecting the low prevalence of these infections in North America and New Zealand.

    In conclusion, sofosbuvir-velpatasvir plus GS-9857 is a safe and effective treatment in patients with HCV genotypes 2, 3, 4, and 6, with and without compensated cirrhosis. High SVR rates were achieved in treatment-experienced patients, including those with DAA-experience, after12 weeks of sofosbuvir-velpatasvir plus GS-9857 and in treatment-naïve patients with compensated cirrhosis after 8 weeks of this regimen. These three potent pangenotypic DAAs have been coformulated into afixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination in patients for eight weeks treatment-naïve patients of all genotypes and for twelve weeks in patients of all genotypes who had received previous treatment with a DAA.

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    Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
    Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
    DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
    Publication stage: In Press Accepted Manuscript

    The best regimen to retreat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus (HCV) genotype 1 infection.

    Published online: July 30, 2016
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    DISCUSSION ONLY
    The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).

    In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16

    In this open-label, phase 2 study, 12 weeks of treatment with sofosbuvir-velpatasvir plus GS9857 was safe and highly effective in patients with HCV genotype 1, with and without cirrhosis, who did not achieve SVR after prior treatment with DAA, including those who had previously received an NS5A inhibitor. In treatment-naive patients, the 8-week regimen was safe and effective, regardless of cirrhosis status. Among the treatment-naïve patients who relapsed, the presence of baseline RASs appeared to have no impact on treatment outcome. Treatment emergent RASs by deep sequencing with a 1% cutoff were rare (3/17, 18%) and no treatment emergent RASs among relapsers were detected with the 15% cutoff. This is consistent with the anticipated high barrier of resistance of the combination therapy based on in vitro data (Lawitz et al: Hepatology XXX Abstract 2015).

    Treatment-naïve patients without cirrhosis treated for 8 weeks achieved a SVR12 rate of 100%,which is higher than results reported in other recent studies of combining 3 or 4 DAAs for treatment for the same population and treatment duration.20,21 Treatment-naïve patients with cirrhosis treated for 8 weeks had lower SVR12 rates of 81-94% than patients without cirrhosis. Larger studies will determine whether this short duration is adequate for this patient population. One unexpected result in our trial was the apparent lack of benefit of the addition of ribavirin to sofosbuvir-velpatasvir plus GS-9857 for treatment-naïve patients with cirrhosis. Although patients in this group receiving ribavirin had a numerically lower rate of SVR12 than treatment naïve patients with cirrhosis who received sofosbuvir-velpatasvir plus GS-9857 without ribavirin (81% vs 94%), the confidence intervals overlap and it is likely that this reflects the small sample sizes. 

    Factors limiting the interpretation of these results of this trial include its small size and uncontrolled, open-label design. Although the trial enrolled only patients with genotype 1 HCV, another trial of similar design has been conducted to assess this combination regimen in patients with non-genotype 1 HCV.

    In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12 weeks provided a high rate of SVR12 (100%) and was well-tolerated in a group of patients currently without treatment options—those with and without compensated cirrhosis who have not achieved SVR after previous treatment with a NS5A inhibitor-containing regimen. The addition of GS-9857 to sofosbuvir-velpatasvir was also safe in the treatment-naïve population where it was effective in reducing the treatment duration to 8 weeks while preserving a high rate of SVR12. These three potent pangenotypic DAAs have been coformulated into a fixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination for eight weeks in treatment-naïve patients and for twelve weeks in DAA-experienced patients, including those who have previously received an NS5A inhibitor.

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    Friday, March 18, 2016

    Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

    Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

    Corresponding authors: Raoel Maan , Adriaan J. van der Meer
    How to cite: Maan R and van der Meer AJ. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease [version 1; referees: 3 approved]. F1000Research 2016, 5(F1000 Faculty Rev):367 (doi: 10.12688/f1000research.7399.1)

    Copyright: © 2016 Maan R and van der Meer AJ. This is an open access article distributed under the terms of the
    Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Competing interests:
    Raoel Maan received financial compensation for consultancy from AbbVie. Adriaan J. van der Meer received financial compensation for lecture activities for MSD and Gilead.


    First published: 17 Mar 2016, 5(F1000 Faculty Rev):367 (doi:
    10.12688/f1000research.7399.1) Latest published: 17 Mar 2016, 5(F1000 Faculty Rev):367 (doi: 10.12688/f1000research.7399.1)

    Get PDF

    Abstract
    Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population

    Natural history
    Chronic hepatitis C virus (HCV) infection continues to be a major global public health problem, with recent estimates suggesting that 64–103 million people are infected worldwide1. Chronic infection leads to slowly progressive hepatic fibrosis, which may eventually lead to cirrhosis2,3. Once cirrhosis is established, patients have an increased risk of developing complications such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding, and hepatocellular carcinoma (HCC). Although the incidence of HCV infection is declining in the West, it has been estimated that the incidence of patients with HCV-induced cirrhosis will not peak until 20304. At the moment, chronic HCV infection is already the leading indication for liver transplantation in many Western countries5. Not to be forgotten, however, is that the natural history of chronic HCV infection extends beyond the liver as well. Before the stage of cirrhosis, there may already be extrahepatic manifestations that impair the patient’s health-related quality of life (HRQoL), of which fatigue is most frequently reported (approximately 50% of patients)68. In terms of solid clinical endpoints, patients are at increased risk of diabetes mellitus, renal failure, cardiovascular events, and malignant lymphoma9. The impaired overall survival among those with chronic HCV infection is thus the result of an increase in both liver-related as well as non-liver-related deaths, as was recently highlighted in an unique natural history study from Taiwan which included 19,636 participants who were followed for a mean duration of 16.2 years10.
    Antiviral therapy
    Before 2011, treatment for chronic HCV infection depended on the administration of pegylated interferon alpha (PegIFN) and ribavirin (RBV), which was accompanied by the occurrence of many side effects such as flu-like symptoms, depression, and cytopenias. These side effects were bothersome, especially because the IFN-based regimens had a limited chance of attaining a sustained virological response (SVR [HCV RNA negativity in the circulation 12–24 weeks after cessation of antiviral therapy]). If physicians were not already reluctant to treat out of fear for severe adverse events in the specific population of patients with advanced liver disease, PegIFN and RBV were often unsuccessful. In patients with compensated cirrhosis, SVR rates ranged from 10 to 44% for HCV genotypes 1 and 4 and 33 to 72% for HCV genotypes 2 and 3. When patients were known to have decompensated cirrhosis, SVR rates even dropped to 0–16% for HCV genotypes 1 and 4 and 44–57% for HCV genotypes 2 and 311. However, because of safety issues, IFN therapy, in case of unstable liver disease, was mostly restricted to specialized centers. As a result, many patients were unable to attain an SVR, which is considered to be the marker for viral clearance based on its long-term durability12.

    The successful development of protease inhibitors for the treatment of the human immunodeficiency virus initiated the development of the first direct-acting antivirals (DAAs) for the treatment of HCV infection. In 2011, the protease inhibitors telaprevir and boceprevir were the first DAAs to be introduced. When added to PegIFN and RBV, the duration of therapy could be halved to 24–28 weeks in about 50% of patients, while SVR rates improved substantially in both treatment-naïve and treatment-experienced patients with HCV genotype 11317. Unfortunately, among those with cirrhosis, the treatment duration could not be easily reduced and the improvement in the rate of SVR was only limited with an increase to approximately 50%. The downsides include the following: these first two DAAs were not very effective against HCV genotypes other than genotype 1; treatment became more complex with various dosing schedules, durations, and stopping rules; the pill burden was large; the rates of resistance-associated variants (RAVs) were high; and there were many potential drug-drug interactions. Moreover, the first real-world data raised important safety issues, especially among patients with compensated cirrhosis, and PegIFN remained a necessity18. The development of antiviral therapy has moved at an incredible pace during the 3 years following the first proof-of-concept that chronic HCV infection could be eradicated without PegIFN19. At the moment, IFN-free regimens, in which multiple classes of DAAs are combined, revolutionize the treatment of chronic HCV infection. Short and well-tolerated regimens have reported SVR rates of around 95%, even among patients with cirrhosis2024. Unfortunately, the high costs of the DAAs currently make these drugs unavailable for the majority of patients worldwide. Also, in wealthy countries it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget, even though modeling data indicated that the IFN-free regimens are cost effective in the long term. As a consequence, physicians are often limited to treat only those patients with advanced liver disease, the specific population on which we will focus in the current review.
    Life cycle of the hepatitis C virus
    Hepatitis C virus is a small enveloped virus of approximately 55–65 nanometers in size and is a member of the genus Hepacivirus, belonging to the Flaviviridae family. It contains a single-stranded RNA genome of positive polarity. This genome is approximately 9600 nucleotides in length and consists of a highly conserved 59 untranslated region, followed by a single open reading frame that encodes a polyprotein of 3010 to 3033 amino acids. Cellular and viral proteases cleave this large protein into ten smaller viral gene products: three structural proteins (core, E1, and E2); an ion channel (p7); and six nonstructural proteins (NS2, NS3A, NS4A, NS4B, NS5A, and NS5B) (Figure 1). Structural proteins are required for assembly and are used for the determination of the seven main HCV genotypes (and subgenotypes)5. The p7 and NS2 protease are required for the release of infectious particles. The other nonstructural proteins (NS3A, NS4A, NS4B, NS5A, and NS5B) are closely involved in HCV replication25. NS3 and its cofactor NS4A form a stable heterodimeric complex, which cleaves the HCV polyprotein at four sites. NS4B is the presumed central organizer of the HCV replicase complex and a main inducer of intracellular membrane rearrangements. The NS5A protein is essential for RNA replication and assembly of infectious virus particles. The RNA-dependent NS5B protein is the RNA polymerase catalyzing the amplification of the viral RNA genome25,26. Figure 2 shows the entry of HCV into the hepatocytes, as well as its life cycle and replication process26. In addition, several host factors have been involved in the HCV life cycle, which may represent new targets for antiviral treatment. These include epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2), which are two receptor tyrosine kinases that have recently been identified as HCV entry factors27. Another host factor, microRNA-122 (miR-122), is a hepatocyte-abundant microRNA which binds to the 5’ untranslated region of the HCV genome. Hereby, it is thought to promote HCV RNA stability and accumulation and to protect the HCV genome from the innate immune response28. Cyclophilin A (CypA) is a protein that is involved in the replication of HCV by binding to the NS5A protein of all HCV genotypes29. Lastly, apolipoprotein E (apoE) is a component of lipoviral particles, which is involved in the HCV infection of hepatocytes30.


    Figure 1. The hepatitis C virus (HCV) genome.
    The hepatitis C virus (HCV) genome encoding three structural proteins and seven non-structural proteins. The direct-acting antivirals are listed below the proteins and include the NS3/4A (or protease) inhibitors, the NS5A inhibitors, and the NS5B polymerase inhibitors (both nucleosides and non-nucleosides). The direct-acting antivirals approved by the US Food and Drug Administration and the European Medicines Agency are highlighted in bold.

    39ab5450-541f-4ec1-869a-519a6dd589fd_figure2.gif
    Figure 2. Life cycle of the hepatitis C virus.
    Adapted from Feeney et al.26. Schematic overview of the life cycle of the hepatitis C virus (HCV). In order to enter the hepatocyte, HCV interacts with co-receptors, resulting in its endocytosis. Then the virus fuses with the endosome and uncoats its RNA. Host ribosomes translate the RNA into a polyprotein, which is cleaved by host and virally encoded proteases into the three structural and seven non-structural proteins. The non-structural proteins form a complex on a “membranous web” that replicates HCV RNA. The Golgi assembles the HCV RNA with viral structural proteins, leading to the formation of infectious viral particles, which are exocytosed from the cell. © 2015 BMJ Publishing Group Ltd. All rights reserved.
    Mechanism of action of antiviral drugs
    Although still not fully elucidated, IFN is thought to induce a large number of genes (called IFN-stimulated genes) with antiviral properties, leading to a multi-faceted attack on the virus. In addition, it also has some direct antiviral actions as well as important interactions with the adaptive and innate immune responses31. RBV is a guanosine analogue with activity against several RNA and DNA viruses. Different hypotheses regarding its mechanism of action have been proposed, of which the theory of lethal mutagenesis seems most reasonable31. Protease inhibitors target the NS3/4A serine protease and thereby inhibit the cleavage of this protein and thus HCV replication26. Current approved “-previrs” include telaprevir, boceprevir, simeprevir, and paritaprevir (Figure 1). The NS5A inhibitors, also known as “-asvirs”, target another nonstructural protein and block the replication of HCV RNA at the stage of membranous web biogenesis32. So far, daclatasvir, ledipasvir, and ombitasvir have been approved (Figure 1). Both NS3/4A protease inhibitors and NS5A inhibitors have very potent antiviral activity but exhibit a low barrier to viral resistance. The NS5B inhibitors, or “-buvirs”, can be divided into two main classes: nucleos(t)ide inhibitors and non-nucleotide inhibitors (Figure 1). By binding to the active site of the NS5B RNA-dependent RNA polymerase, nucleos(t)ide inhibitors (e.g., sofosbuvir) cause premature chain termination. The non-nucleotide inhibitors (e.g., dasabuvir) bind outside the active site, causing a conformational change, and thereby decrease the polymerase activity of the enzyme26.
    Current treatment regimens

    There are extensive data from phase III or IV studies on the efficacy of IFN-free regimens, but patients with compensated and decompensated cirrhosis were often underrepresented. Currently, more data are emerging from real-world studies on the efficacy of these regimens, which included patients with the most severe cirrhosis. Table 1–Table 4 show the data from phase III or IV studies available on the efficacy of IFN-free antiviral therapy. Below, we will discuss the treatment regimensin a more conceptual way for the treatment of patients with compensated cirrhosis.

    Table 1. Rates of SVR for patients with compensated cirrhosis HCV genotype 1 (phase III/IV studies).


    a. Abbreviations: ASV, asunaprevir; BCV; beclabuvir; DCV, daclatasvir; DSV, dasabuvir; ELB, elbasvir; GPV, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OMB, ombitasvir; PAR/r, paritaprevir/ritonavir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir


    RegimenDurationPatientsSVR rateStudy (reference)
    LDV – SOF ± RBV12–24 weeksNaïve97–100%ION-121
    LDV – SOF ± RBV12–24 weeksTE82–100%ION-220
    LDV – SOF
    LDV – SOF - RBV
    24 weeks
    12 weeks
    TE
    TE
    97%
    96%
    SIRIUS84
    SIM – SOF12 weeksNaïve
    TE
    88%
    79%
    OPTIMIST-222
    SIM – SOF ± RBV12 weeksNaïve
    TE
    75%
    73–88%
    Trio Network85
    SIM – SOF ± RBV12 weeksNaïve
    TE
    87–93%
    80–82%
    HCV-Target86
    OMB – PAR/r – DSV + RBV12–24 weeksNaïve
    TE
    94–95%
    90–97%
    TURQUOSE-II23
    OMB – PAR/r – DSV12 weeksTE100%TURQUOSE-III24
    GPV – ELB12 weeksNaïve97%C-EDGE87
    SIM – SOF12 weeksNaïve
    TE
    95%
    92%
    Pearlman et al.88
    SIM – SOF12 weeksNaïve
    TE
    83%Aqel et al.89
    SIM – SOF ± RBV12 weeksNaïve
    TE
    91–94%
    88–95%
    Saxena et al.46
    SIM – SOF12 weeksNaïve and TE87%Shiffman et al.90
    DCV – ASV – BCV ± RBV12 weeksNaïve and TE87–98%Unity-291
    VPV – SOF12 weeksNaïve and TE99%ASTRAL-145


    Table 2. Rates of SVR for patients with compensated cirrhosis HCV genotype 2–4 (phase III/IV studies).

    a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir

    HCV GenotypeRegimenDurationPatientsSVR rateStudy (reference)
    HCV genotype 3DCV – SOF12 weeksNaïve and TE58–97%ALLY-343
    HCV genotype 2
    HCV genotype 3
    SOF + RBV12 weeks
    12 weeks
    Naïve91%
    34%
    FISSION40
    HCV genotype 2
    HCV genotype 3
    SOF + RBV12 weeks
    12 weeks
    Naïve94%
    21%
    POSITRON39
    HCV genotype 3
    HCV genotype 2
    HCV genotype 3
    SOF + RBV24 weeks
    12 weeks
    24 weeks
    Naïve
    TE
    TE
    92%
    78%
    62%
    VALENCE92
    HCV genotype 2

    HCV genotype 3

    HCV genotype 3
    SOF + RBV



    16 weeks
    24 weeks
    16 weeks
    24 weeks
    16 weeks
    24 weeks
    TE

    Naïve

    TE
    87%
    100%
    57%
    82%
    47%
    76%
    BOSON STUDY44



    HCV genotype 2SOF + RBV12 weeksNaïve
    TE
    67%
    76%
    Trio Network85
    HCV genotype 2

    HCV genotype 3
    SOF + RBV

    SOF + RBV
    12 weeks
    16 weeks
    12 weeks
    16 weeks
    TE

    TE
    60%
    78%
    19%
    61%
    FUSION39

    HCV genotype non-1SOF – VPV12 weeksNaïve and TE100%ASTRAL-145
    HCV genotype 2SOF – VPV12 weeksNaïve and TE100%ASTRAL-293
    HCV genotype 3SOF – VPV12 weeksNaïve and TE91%ASTRAL-393
    HCV genotype 3DCV – SOF + RBV12 weeks
    16 weeks
    Naïve and TE83%
    89%
    ALLY-3+94

    Table 3. Rates of SVR for patients with decompensated cirrhosis HCV genotype 1 (phase III/IV studies).

    a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir

    b. *Also included patients with HCV genotype 2, 3, and 4

    c. #Fewer than 10 patients were included in a specific subgroup



    RegimenDurationPatientsSVR rateStudy (reference)
    LDV – SOF ± RBV12 – 24 weeksNaïve and TE86–89%SOLAR-182
    LDV – SOF ± RBV12 – 24 weeksNaïve and TE84–92%SOLAR-295
    SOF + RBV
    SIM – SOF
    SIM – SOF + RBV
    12 weeks
    12 weeks
    12 weeks
    Naïve and TE
    Naïve and TE
    Naïve and TE
    52%
    74%
    66%
    HCV-Target96
    DCV – SOF + RBV12 weeksNaïve and TE56–94%*ALLY-197
    LDV – SOF
    LDV – SOF + RBV
    DCV – SOF
    DCV – SOF + RBV
    12 weeks
    12 weeks
    12 weeks
    12 weeks
    Naïve and TE
    Naïve and TE
    Naïve and TE
    Naïve and TE
    81%
    86%
    60%#
    82%
    UK cohort EAP81

    SIM – SOF ± RBV12 weeksNaïve and TE69–79%Saxena et al.46
    SIM – SOF ± RBV12 weeksNaïve and TE68%Aqel et al.89
    SIM – SOF12 weeksNaïve and TE67–77%Shiffman et al.90
    SIM – SOF
    SIM – SOF + RBV
    12 weeks
    12 weeks
    Naïve and TE
    Naïve and TE
    52–65%
    44–65%#
    Backus et al.98
    SOF – VPV
    SOF – VPV + RBV
    SOF – VPV
    12 weeks
    12 weeks
    24 weeks
    Naïve and TE88%
    96%
    92%
    ASTRAL-499

    Table 4. Rates of SVR for patients with decompensated cirrhosis HCV genotype non-1 (phase III/IV studies).
    a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced

    b. *Also included patients with HCV genotype 2, 3, and 4

    c. #Fewer than 10 patients were included in a specific subgroup

    HCV genotypeRegimenDurationPatientsSVR rateStudy (reference)
    HCV genotype 4LDV – SOF ± RBV12 – 24 weeksNaïve and TE57–86%SOLAR-295
    HCV genotype 2
    HCV genotype 3
    SOF + RBV12 weeksNaïve and TE81%
    39%
    HCV-Target96
    HCV genotype 2
    HCV genotype 3
    HCV genotype 4
    DCV – SOF + RBV12 weeksNaïve and TE80%#
    83%#
    100%#
    ALLY-197
    HCV genotype 3
    Other HCV genotypes
    than 1 and 3
    LDV – SOF ± RBV
    DCV – SOF ± RBV
    LDV – SOF + RBV
    DCV – SOF ± RBV
    All 12 weeks

    Naïve and TE

    43–59%#
    70–71%#
    89%
    85–100%#
    UK cohort EAP81

    HCV genotype 2SOF + RBV12 weeksNaïve and TE44–71%#Backus et al.98
    HCV genotype non-1SOF – VPV
    SOF – VPV + RBV
    SOF – VPV
    12 weeks
    12 weeks
    24 weeks
    Naïve and TE50–100%#
    85–100%#
    50–100%#
    ASTRAL-499
    HCV genotype 1
    In the Western world, HCV genotype 1 is the most prevalent (>50%). The initial development of DAAs was therefore mainly focused on this genotype. Although IFN-free therapy is preferred, the combination of a second-generation NS3/4A protease inhibitor, a NS5A inhibitor, or a NS5B inhibitor with PegIFN and RBV for 12–48 weeks has been assessed3336. Although not approved, even the addition of a NS3/4A protease inhibitor and a NS5A inhibitor to PegIFN and RBV for 24 weeks could have been an option for the treatment of chronic HCV genotype 1 infection37. For patients who are unable to tolerate PegIFN, the combination of a NS5B inhibitor and RBV was assessed, but phase III studies were never performed due to the lack of efficacy. When focusing on the regimens that did reach SVR rates of more than 90%, the optimal regimen consists of at least two classes of DAAs, with or without the addition of RBV. The combination of a NS5B inhibitor with a NS5A inhibitor and/or a NS3/4A protease inhibitor is enough to create a high barrier to resistance2022. In cirrhotic patients, some regimens show lack of efficacy, which could be improved by the addition of RBV and/or the extension of antiviral therapy to 24 weeks. As the development of novel DAAs is still ongoing, recent data have shown that second-generation regimens, including a NS5A inhibitor and a NS3/4A protease inhibitor, may be equally effective for this genotype38. Thus, inclusion of a NS5B inhibitor may not be a necessity.
    Since there is a difference in efficacy among patients with HCV genotype 1a and 1b, different regimens were applied among these patients23,24. RAVs that are present at baseline or emerge during antiviral therapy may account for this difference between the two subtypes. Therefore, before initiating most regimens, subtyping of the HCV genotype 1 is required. However, lower response rates in patients with HCV genotype 1a seem to be a problem only when a NS3/4A protease inhibitor is incorporated into the treatment regimen20,21,23. At the price of additional side effects, this effect may be partly overcome by adding RBV to the treatment regimen.
    HCV genotype 2
    Historically, patients with HCV genotype 2 were the easiest to treat, even when patients had cirrhosis. Currently, an IFN-free combination including a NS5B inhibitor and RBV seems sufficient to clear the virus3941. When patients are intolerant to RBV, a regimen with a NS5B inhibitor and a NS5A inhibitor could be an attractive option, as both have antiviral activity against this genotype. This combination, however, has not been extensively investigated in clinical trials42.
    HCV genotype 3
    Patients with HCV genotypes 2 and 3 were found to be relatively IFN sensitive and required a shorter duration of therapy with lower doses of RBV to achieve higher rates of SVR as compared to patients with HCV genotypes 1 and 4. Even with PegIFN and RBV, however, HCV genotype 3 was more difficult to cure than genotype 2, particularly in patients with established cirrhosis. In the current IFN-free era, HCV genotype 3 has actually replaced HCV genotype 1 as the most challenging genotype. In contrast to its effect in non-cirrhotic patients with HCV genotype 3, the combination of a NS5B inhibitor and RBV in cirrhotic patients is suboptimal and has a high virological relapse rate3941. The addition of a NS5A inhibitor to this regimen could improve response rates, but the incremental efficacy of a 12-week regimen remains limited43. Although the duration has not been investigated within clinical trials, current guidelines recommend a 24-week regimen including a NS5B inhibitor and a NS5A inhibitor with or without RBV. So far, none of the currently approved DAAs have optimal antiviral activity against HCV genotype 3, so the “re-introduction” of PegIFN for this genotype needs to be considered among those who are able to tolerate its side effects44. Recently, a pan-genotypic regimen for 12 weeks, including a NS5B and NS5A inhibitor, seemed highly effective for HCV genotype 3, even among treatment-experienced patients with cirrhosis45.
    HCV genotype 4
    When PegIFN-based treatment was considered, patients with HCV genotype 4 used to be grouped with patients infected with HCV genotype 1. With the DAAs, these patients respond to the same regimens as well, and possibly even better. Although data in cirrhotic patients are scarce, due to the low prevalence of this genotype in most Western countries, the combination of a NS5B inhibitor and RBV is a plausible option. A regimen including two DAAs from separate classes (a NS5B inhibitor, a NS5A inhibitor, or a second-generation NS3/4A protease inhibitor) could also be used to eradicate chronic HCV genotype 4. When physicians want to reduce the chance of virological relapse, RBV could be added to the regimen, provided that patients are able to tolerate this.
    Decompensated cirrhosis
    In general, patients with decompensated cirrhosis (Child-Pugh B/C) have lower response rates than patients with compensated cirrhosis (Child-Pugh A)46. Reasons for these lower response rates may include reduced drug delivery due to shunting leading to HCV reservoirs, altered drug metabolism and uptake due to impaired liver synthetic function, or impaired immune responses which are present in cirrhotic patients47.

    Obviously, among patients with decompensated cirrhosis, the IFN-free regimens are far better tolerated as compared to the PegIFN and RBV combination therapy, which has been the standard of care for the last 15 years. However, as more real-world data are emerging, safety issues regarding the use of DAAs among those patients with the most advanced liver disease have arisen. Two patients with hepatic decompensation developed severe drug-induced liver injury leading to death and liver transplantation. Both patients were treated with sofosbuvir, a NS5A inhibitor, and RBV48. A recent study by Welker et al. described the occurrence of lactate acidosis among patients treated with sofosbuvir-based regimens, with or without the addition of RBV49. Whether the clinical deterioration could be attributed to the use of DAAs or RBV or whether this is merely in line with the poor natural history of patients with decompensated cirrhosis remains a matter of debate. Likewise, the occurrence of hepatic decompensation during antiviral treatment has been reported for several treatment regimens, leading the FDA to discourage the use of dasabuvir, ombitasvir, and paritaprevir/ritonavir for patients with decompensated liver disease50. Also, because of the real-world safety issues which were encountered with the first-generation protease inhibitors telaprevir and boceprevir among patients with cirrhosis and low platelets or low albumin levels, one could argue that protease inhibitors may not represent an ideal class of DAAs for those with the most severe cirrhosis18. Simeprevir, a first-generation second-wave protease inhibitor, has actually never been registered for patients with decompensated cirrhosis. It is clear that further studies with a focus on the safety profile of the IFN-free regimens among patients with decompensated liver disease are urgently needed. It would be highly relevant to be able to predict which of these patients can and cannot be safely treated with the IFN-free regimens.
    Resistance-associated variants
    The high efficacy of IFN-free regimens will lead to high rates of SVR, even among the population that was difficult to treat and/or difficult to cure in the era of IFN-based therapy. However, as pointed out earlier, lower response rates were observed among patients with advanced liver disease. The emergence of RAVs seems a relevant factor in case antiviral therapy is not successful. Although heterogeneous methods were used to detect RAVs, it has been estimated that 53–91% of patients with virological relapse harbor HCV isolates that are resistant to one, two, or three DAAs51. The presence of RAVs before IFN-free treatment initiation could be an important cause of virological failure as well, and fuels the ongoing debate of whether we should perform pretreatment viral sequencing. Relevant in this respect is that the second-generation DAAs, which are coming shortly, are thought to have a higher genetic barrier to resistance. Another option to overcome the RAVs are the advanced cellular drugs that target the host factors involved in the HCV life cycle, which have the general advantage of being pan-genotypic. Silencing of miR-122 in vitro showed remarkable inhibition of HCV replication and led to the possibility of targeting miR-122 as an antiviral strategy28,52. Other possible options include the HCV entry inhibitors erlotinib and dasatinib, or the cyclophilin inhibitor alisporivir27,53. In combination with DAAs, the drugs targeting host factors could be effective, especially for those patients with resistant viral strains. Still, in order to globally eradicate HCV, an effective vaccine seems necessary54.
    Clinical relevance of successful antiviral therapy
    In parallel with the impressive development of highly potent and well-tolerated DAAs, various cohort studies increased our understanding of the clinical relevance of these new drugs. Over the last couple of years, many researchers have published results that indicate that patients who attain SVR have a beneficial clinical outcome in terms of both liver-related and liver-unrelated endpoints. The growing body of evidence in favor of SVR is, obviously, relevant for patients and physicians. However, it is also very much needed for policy-makers who need to decide on the reimbursement of the highly effective but costly IFN-free regimens.
    Liver histology
    In contrast to what was believed during the largest part of the last century, it is now widely accepted that hepatic fibrosis can regress in cases where the underlying cause of liver damage is adequately treated. Chronic HCV infection is probably the liver disease in which this is best documented. The largest histological study in which patients underwent a second liver biopsy 24 weeks after cessation of antiviral therapy indicated that, on average, the degree of hepatic fibrosis regressed among those with SVR and was rather stable among those without SVR55. The most impressive result of this study, however, was that 75 of the 153 patients with cirrhosis before therapy no longer scored a METAVIR F4 in their post-treatment liver biopsy. Yet, from a previous study from Japan, we already learned that regression of hepatic fibrosis is likely to take more time56. Shiratori et al. included 593 patients in whom the time to the post-treatment liver biopsy ranged from 1 to 10 years. Among those with SVR, the authors found that regression of fibrosis was more pronounced in cases where the biopsy was repeated after more than 3 years of follow-up. Still, even in cases with much longer follow-up, histological studies have been unable to show that all HCV-infected patients with cirrhosis who attained SVR improve their METAVIR F4 score. The concept of a point of no return with respect to the extent of liver damage seems plausible, especially because the vascular abnormalities within a cirrhotic liver have never been shown to improve, and shunting of blood through vascularized portacaval septa can lead to hypoperfusion of liver parenchyma, with hypoxemia as a contributing factor for hepatic inflammation and fibrosis5759. On the other hand, the semi-quantitative fibrosis scores may also be somewhat too crude to appreciate all histological improvements following the eradication of HCV infection. Indeed, a recent study assessed the change in the total area of fibrosis among 38 Italian patients with cirrhosis who attained SVR60. Among the minority (39%), in whom the METAVIR F4 score was not reduced after a median duration of 5.6 years in between both liver biopsies, the total area of hepatic fibrosis was still significantly reduced. While the discussion on whether cirrhosis is reversible is ongoing, it may actually be more relevant to consider the relationship between HCV eradication and the clinical sequelae of cirrhosis61.
    Liver-related morbidity and mortality
    Most of the Western studies that assessed the association between HCV eradication and hepatic decompensation or HCC have solely included patients with advanced liver disease, who are most at risk for these cirrhosis-related complications. However, as we have long depended on IFN-based treatment regimens, these studies predominantly included cirrhotic patients with relatively favorable characteristics. Veldt et al. were one of the first groups to show that the incidence in liver failure was markedly reduced among patients with chronic HCV infection and advanced liver fibrosis who attained SVR62. Interestingly, this beneficial outcome was apparent immediately upon HCV clearance. Hereafter, larger studies with longer follow-up duration not only confirmed these results but also showed a significant association between SVR and a reduced occurrence of HCC, with strong hazard ratios (HRs) adjusted for many potential confounders6365. In a recent meta-analysis, in which the results of all available cohort studies among patients with advanced liver disease were pooled, the results indicated that within this population the HR of SVR for the occurrence of HCC was 0.23 (95% confidence interval [CI] 0.16–0.35)66. Combining studies that included patients with all stages of fibrosis resulted in a pooled HR of 0.24 (95% CI 0.18–0.31) regarding SVR and HCC occurrence, although these studies were mostly performed in Japan, where the incidence of HCC is substantially higher. Considering the potential benefits of SVR on these cirrhosis-related morbidities, it is not surprising that patients with cirrhosis who clear their chronic HCV infection have a reduced liver-related mortality65,67. Still, it is noteworthy that patients with advanced liver disease are not free from cirrhosis-related complications following HCV eradication. A combined cohort including 1000 patients with advanced liver fibrosis and IFN-induced SVR showed that the annual risk of HCC remains at about 1% following HCV eradication in patients with cirrhosis68. The risk of HCC depends on age, the presence of diabetes mellitus, and laboratory markers of liver disease severity. One may thus expect a rising incidence of HCC following successful antiviral therapy in the era of DAAs, which will enable older patients with more advanced liver disease to attain SVR.
    Extrahepatic consequences
    While a large number of studies indicated potential liver-related benefits of SVR, more recent efforts have focused on the association between antiviral therapy and extrahepatic disease. With respect to patient-reported outcomes, eradication of HCV infection decreases both the frequency and the severity of fatigue8. This may be an important reason for the improved HRQoL which has been observed upon SVR69. Although difficult to quantify in daily practice, these effects are probably more directly noticeable for patients and their health-care providers than the prevention of future clinical complications.

    Even a few years ago, it was reported that the risk of diabetes mellitus is about three times lower among patients with SVR as compared to patients without SVR70. The deteriorating consequences of diabetes mellitus are diverse but surely include renal failure and cardiovascular events. A reduced incidence of both of these solid endpoints in cases of antiviral therapy use was recently shown in a nationwide cohort study from Taiwan, in which 12,384 treated patients and 24,768 propensity score-matched untreated controls were included. The cumulative 8-year incidences of end-stage renal disease (0.15% vs. 1.32%), acute coronary syndrome (2.21% vs. 2.96%), and ischemic stroke (1.31% vs. 1.76%) were significantly lower among treated as compared to untreated patients (p<0.05 for all), and the effect of antiviral therapy remained statistically significant in multivariate analysis71. These findings were immediately confirmed, and assigned to SVR, in a large population-based study which is expected to include about 80% of all IFN-treated chronic HCV-infected patients in Scotland72. Apart from diabetes mellitus, we were recently presented with another possible explanation for these findings, as Gragnani et al. showed that HCV eradication led to the disappearance of cryoglobulinemia and resolved manifestations of the mixed cryoglobulinemia syndrome in nearly all patients73. Other potential extrahepatic benefits of SVR that have been presented within recent years include a reduced occurrence of malignant lymphomas and reduced hospitalization because of acute alcohol intoxication or violence-related injuries72,74. Through these effects on extrahepatic morbidity, patients with SVR have not only a reduced liver-related mortality but also a reduced liver-unrelated mortality72,75.
    All-cause mortality
    The most important new insights with regard to the clinical benefit of antiviral therapy probably concern the association between SVR and a prolonged overall survival as the most definitive clinical endpoint. In 2011, Backus et al. were the first to show that SVR was statistically significantly associated with a reduced all-cause mortality (HR 0.70, 0.64, and 0.51 for HCV genotype 1, 2, and 3, respectively) in a large cohort of 16,864 patients with chronic HCV infection who were followed for a median duration of 3.8 years76. However, these results were derived from the specific patient population of American veterans, among which there is substantial comorbidity, risk behavior, and a rather high mortality rate. Another report extended this finding to the general HCV-infected patient population with advanced liver disease67. Among the 530 patients with chronic HCV infection and advanced liver fibrosis who were followed for a median of 8.4 years, the cumulative 10-year overall survival was 91% among those with SVR, versus 74% among those without SVR (HR 0.26, 95% CI 0.14–1.49). In contrast to those who were unsuccessfully treated, patients with SVR had a survival rate that was comparable to that of the age- and sex-matched general population77. Importantly, in both reports, the HR of SVR for all-cause mortality was extensively adjusted for baseline characteristics known to influence both the chance of successful IFN therapy and the long-term clinical outcome. Various representable cohorts have confirmed the strong association between SVR and reduced all-cause mortality hereafter72,78. The pooled HR of SVR was 0.50 (95% CI 0.37–0.76) based on all studies which did not specifically include patients with advanced fibrosis and 0.26 (95% CI 0.18–0.37) when only studies among those with advanced liver disease were considered79.
    Decompensated cirrhosis
    The above-described studies, which suggest a clinical benefit of SVR, were performed among patients treated with IFN-based regimens, so that even those included with cirrhosis had relatively favorable baseline characteristics. Indeed, in the IFN era, patients with decompensated cirrhosis were frequently withheld from antiviral therapy but were also unlikely to attain SVR if treatment was initiated. Consequently, the clinical relevance of attaining SVR is largely unknown apart from the fact that achievement of SVR would be desirable to prevent HCV recurrence in cases of liver transplantation. Because of the beneficial safety profile of the DAAs, our experience with antiviral therapy in patients with chronic HCV infection and decompensated cirrhosis is increasing rapidly. Still, because these therapeutic options have just surfaced, studies with sufficient follow-up to assess the true clinical impact of IFN-free therapy among the patients with the most advanced liver disease have to be awaited. In the meantime, several interesting observations in the short term have been presented, which focus on the Model for End-Stage Liver Disease (MELD) score. Deterding et al. treated 34 HCV-infected patients with Child-Pugh B/C with various IFN-free regimens. At 12 weeks post-treatment, the MELD score improved in 68%, remained stable in 23%, and worsened in 10% of patients80. Based on the first experiences in England, Foster et al. reported the change in MELD score 4 weeks after the cessation of DAA therapy81. Of the 220 patients, 105 (47.7%) had no significant change in MELD score; in 92 (41.8%) patients, MELD score improved by ≥2 points; and in 23 (10.5%) patients, MELD score worsened by ≥2 points. Additional analyses indicated that the MELD score more frequently improved rather than declined among younger patients (<65 years) and patients with a high albumin level (>35 g/L). Still, MELD improvements are mostly moderate, so the important question of whether liver transplantation can really be averted remains. If not, the slight improvement in MELD score may actually negatively impact the patient’s chances on the waiting list. Because clinical trials showed excellent SVR rates with IFN-free therapy among liver transplant recipients with chronic HCV infection, it may be questioned whether patients with decompensated cirrhosis should be treated before or after transplantation82,83. Within the next 2 years, more data will hopefully become available, which may be able to guide this decision for the individual patient. Preferably, patients with decompensated cirrhosis should therefore be treated within registry studies during the upcoming years.
    Conclusion
    The implementation of IFN-free treatment regimens has broadened the horizon for patients with chronic HCV infection tremendously. Within a timeframe of 5 years, important treatment developments resulted in near-perfect SVR rates, even among patients with the most advanced liver disease. As successful antiviral therapy may be lifesaving, these developments were long awaited. Some hurdles have to be taken, however, before the health burden of this chronic disease can truly be reduced. For instance, the access to DAAs needs to be broadened so that patients can be treated regardless of the severity of hepatic fibrosis. Reducing the costs of these drugs probably remains a key factor before this goal can be achieved. As developments are still ongoing, prices will hopefully fall as a result of mutual competition. Also, it is important to increase the number of patients who are diagnosed, as the majority of patients are currently unaware of their chronic viral hepatitis. Pan-genotypic regimens are currently being evaluated in phase III trials as well, which will hopefully simplify antiviral therapy even more. Until that time, treatment selection is required and prioritizing treatment is needed to limit the economic burden. Treating those with advanced hepatic disease first seems reasonable, but remains far from ideal.
    Abbreviations
    DAAs, direct-acting antivirals; FDA, US Food and Drug Administration; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; HRQoL, health-related quality of life; IFN, interferon; MELD, Model for End-Stage Liver Disease; miR-122, microRNA-122; PegIFN, pegylated interferon alpha; RAVs, resistance-associated variants; RBV, ribavirin; SVR, sustained virological response.
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