Review
======

Introduction
------------

Hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide \[[@B1]\]. HCV infection is one of the major causes of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide \[[@B2]-[@B4]\]. Approximately 30% of patients who develop acute hepatitis C recover spontaneously, signaled by improved symptoms, normalized liver-related chemistries, loss of HCV RNA from serum, and the development of HCV antibody \[[@B5]-[@B7]\]. In chronic hepatitis C, the progression of liver fibrosis is slow, but steady. It has been reported that the progression rate of liver fibrosis is 0.10-0.13 U/year in untreated patients \[[@B8]\]. Progression of chronic HCV infection is not linear in time, probably because many cofactors are involved in changing the rate of development of fibrosis, cirrhosis, and HCC \[[@B6]\]. Cirrhosis rates become significant after 20 years of HCV infection. About 20-30% of patients could develop a progressive liver disease leading to cirrhosis and HCC \[[@B5],[@B7]\]. HCC develops at about 1-7% per year \[[@B5],[@B7]\]. It has been demonstrated that subjects who achieve sustained virological response (SVR) have a clear advantage at histological and clinical levels compared to those who do not achieve SVR \[[@B8]-[@B12]\]. The present standard for the judgment of SVR is undetectability of serum HCV RNA at 24 weeks post-treatment.

Preventive measures against HCV, including vaccine development, are now in progress \[[@B13]\]. But the standard of care (SOC), peginterferon and ribavirin therapy, and new standard of care (NSOC), combination protease inhibitors such as telaprevir or boceprevir with peginterferon plus ribavirin therapy, have been approved for the eradication of HCV in US, Europe, and Japan \[[@B14]-[@B18]\]. Even with these advances in antiviral therapies against HCV, SVR rates were \~70% in HCV genotype-1 treated with NSOC and \~80% in HCV genotype-2/3 treated with SOC. Rash also occurs in 56% of patients treated with NSOC, compared to 34% of patients treated with SOC alone. Other adverse events were still present \[[@B19]\], although even interferon is also associated with severe adverse events \[[@B20]\]. When we treat patients infected with HCV in daily clinical practice, it seems important to be aware of the potential treatments of HCV in the near future, as the development of new drugs is always ongoing.

HCV belongs to the flaviviridae family, and HCV genome is a positive-strand \~9.6-kb RNA. HCV has a 5^′^ untranslated region (5^′^UTR), a long open reading frame, and a 3^′^UTR. An internal ribosomal entry site (IRES), containing the 5^′^UTR and part of the core coding region, forms a stem-loop structure and supports translation initiation of HCV genome in a cap-independent manner \[[@B21],[@B22]\]. HCV genome encodes a single precursor polyprotein that is processed by host signal peptidases and HCV proteases, resulting in structural (core, envelopes E1 and E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. Direct-acting antivirals (DAAs) against HCV are classified into several categories: 1) HCV NS3/4A protease inhibitors, 2) HCV NS5B polymerase inhibitors, 3) HCV NS5A inhibitors, and others. In the near future, interferon-sparing regimens and treatment with all-oral DAAs will play major roles in treating HCV-infected patients (Figure [1](#F1){ref-type="fig"}).

![**Treatments for chronic hepatitis C in the present and future.** PegIFN, peginterferon; RBV, ribavirin.](2001-1326-2-9-1){#F1}

Standard of care (SOC) treatment for HCV infection
--------------------------------------------------

Interferon, combination interferon plus ribavirin, and peginterferon plus ribavirin increased SVR rate from \~5% to \~40-80%, depending on the HCV genotypes \[[@B18],[@B23]\]. Peginterferon plus ribavirin treatment for 48 weeks, the SOC treatment for HCV genotype 1-infected patients, leads to only \~50% SVR in those patients with high viral loads, who were mostly null-responders or relapsers \[[@B23]-[@B27]\]. On the other hand, peginterferon plus ribavirin treatment for 24 weeks, the SOC treatment for HCV genotype 2-infected patients, leads to \~80% SVR in those patients (Table [1](#T1){ref-type="table"}). Race has been shown to be a factor in the response to therapy for HCV infection \[[@B25],[@B27]\]. A higher homocysteine level is also one of factors predicting a nonresponse to treatment \[[@B28]\]. Because the favorable interleukin 28B (IL28B) associated-single nucleotide polymorphisms (SNPs), leading to better response, exist at substantially greater frequency in European than African populations, they also explain approximately half of the difference in response rates between African-Americans and patients of European ancestry \[[@B29]\]. IL28B SNPs help to improve the treatment outcomes in HCV-patients treated with SOC \[[@B29]-[@B34]\]. In future interferon-included regimens, IL28B SNPs may also provide useful information about the treatment response even before treatment.

###### 

Standard of care treatment and sustained virological response rates for chronic hepatitis C patients

  **References**   **G**      **Number of patients**                 **Naïve or re-treatment**   **Formula of therapy**                 **Duration of treatment (weeks)**   **SVR rates (%)**   **Notes**
  ---------------- ---------- -------------------------------------- --------------------------- -------------------------------------- ----------------------------------- ------------------- -----------
  \[[@B24]\]       G1         298                                                                Peginterferon alfa-2a plus ribavirin   48                                  46                   
  285                         Interferon alfa-2b plus ribavirin      48                          36                                                                                             
  145                         Peginterferon alfa-2a plus placebo     48                          21                                                                                             
  \[[@B24]\]       G2/G3      140                                                                Peginterferon alfa-2a plus ribavirin   48                                  76                   
  145                         Interferon alfa-2b plus ribavirin      48                          61                                                                                             
  69                          Peginterferon alfa-2a plus placebo     48                          45                                                                                             
  \[[@B24]\]       G4         13                                                                 Peginterferon alfa-2a plus ribavirin   48                                  77                   
  11                          Interferon alfa-2b plus ribavirin      48                          36                                                                                             
  9                           Peginterferon alfa-2a plus placebo     48                          22                                                                                             
  \[[@B25]\]       G1 (98%)   100                                                                Peginterferon alfa-2b plus placebo     48                                  19                  Blacks
  100                         Peginterferon alfa-2a plus ribavirin   48                          52                                     Non-Hispanic Whites                                     
  \[[@B26]\]       G2/3       732                                                                Peginterferon alfa-2a plus ribavirin   16                                  65                   
  731                         Peginterferon alfa-2a plus ribavirin   24                          76                                                                                             
  \[[@B27]\]       G1         269                                    naive                       Peginterferon alfa-2a plus ribavirin   48                                  34                  Latino
  300              naive      Peginterferon alfa-2a plus ribavirin   48                          49                                     Non-Latino                                              

G, genotype; SVR, sustained virological response.

New standard of care (NSOC) treatment for HCV infection
-------------------------------------------------------

In 2011, telaprevir and boceprevir were the first approved DAAs against HCV. The triple combination therapy of telaprevir or boceprevir plus ribavirin and peginterferon-alfa is the NSOC treatment for chronic HCV genotype 1-infected patients \[[@B35]-[@B42]\]. Telaprevir (VX-950) is a potent, selective inhibitor of NS3/4A protease, which is essential for HCV replication \[[@B43]\]. SVR rates among treatment-naïve patients were \~70% in telaprevir-included regimens \[[@B35],[@B36],[@B38],[@B40]\]. The SVR rates among patients with no previous response were 30\~40% and those among patients with a previous relapse were 70\~75%, both in telaprevir-included regimens \[[@B37],[@B39]\]. SVR rates were significantly higher in telaprevir-included regimens than in SOC among patients who had a previous relapse (83-88% vs. 24%), a partial response (54-59% vs. 15%) and non- response (29-33% vs. 5%) \[[@B39],[@B44]\]. Thus, SVR rates were higher among patients who had previously had relapses than among nonresponders. Response-guided therapy is also useful in the telaprevir-included regimen (Table [2](#T2){ref-type="table"}) \[[@B40]\]. Boceprevir (SCH 503034) is a potent ketoamide inhibitor of HCV NS3 serine protease \[[@B45]\]. The addition of boceprevir to SOC results in higher SVR rates in both treatment-naïve and re-treated patients infected with HCV genotype 1 (Table [3](#T3){ref-type="table"}) \[[@B41],[@B42]\]. SVR rates were significantly higher in boceprevir-included regimens than in SOC among patients who had a prior relapse (69-75% vs. 29%) or a prior nonresponse (40-52% vs. 7%) \[[@B42]\]. Viewed from the clinical data of first-generation protease inhibitors, telaprevir and boceprevir, these drugs showed potent inhibition of HCV, although they occasionally led to severe adverse events \[[@B46],[@B47]\].

###### 

New standard of care treatment with telaprevir for chronic hepatitis C patients

  **References**   **G**          **Number of patients**   **Naïve or re-treatment**   **Formula of therapy, and duration of treatment (weeks)**   **SVR rates (%)**   **Notes**
  ---------------- -------------- ------------------------ --------------------------- ----------------------------------------------------------- ------------------- ------------------
  \[[@B35]\]       G1             79                       naive                       T12PR24                                                     61                  PROVE1 Study
  79               naive          T12PR48                  67                                                                                                          
  17               naive          T12PR12                  35                                                                                                          
  75               naive          PR48                     41                                                                                                          
  \[[@B36]\]       G1             81                       naive                       T12PR24                                                     69                  PROVE2 Study
  82               naive          T12PR12                  60                                                                                                          
  78               naive          T12P12                   36                                                                                                          
  42               naive          PR48                     46                                                                                                          
  \[[@B37]\]       G1             115                      re-treatment                T12PR24                                                     51                  PROVE3 Study
  113              re-treatment   T12PR48                  53                                                                                                          
  111              re-treatment   T24P24                   24                                                                                                          
  114              re-treatment   PR48                     14                                                                                                          
  \[[@B38]\]       G1             363                      naive                       T12PR                                                       73                  ADVANCE Study
                                  364                      naive                       T8PR                                                        67                  
                                  49                       naïve                       PR48                                                        44                  
  \[[@B39]\]       G1             145                      re-treatment                T12PR48                                                     93                  REALIZE Study
                                  141                      re-treatment                Lead-in T12 PR48                                            89                  
                                  68                       re-treatment                PR48                                                        24                  
  \[[@B40]\]       G1             162                      naïve                       T12PR24 (RGT)                                               92                  ILLUMINATE Study
                                  160                      naïve                       T12PR48 (RGT)                                               88                  
                                  118                      naïve                       T12PR48 (non-RGT)                                           64                  
                                  100                      naïve                       Discontinued treatment before wk 20                         23                   

###### 

New standard of care treatment with boceprevir for chronic hepatitis C patients

  **References**   **G**          **Number of patients**   **Naïve or re-treatment**   **Formula of therapy, and duration of treatment (weeks)**   **SVR rates (%)**   **Notes**
  ---------------- -------------- ------------------------ --------------------------- ----------------------------------------------------------- ------------------- ---------------
  \[[@B41]\]       G1             363                      naive                       PR48                                                        38                  SPRINT-2
  368              naive          PR4+BocPR24+PR22         63                                                                                                          
  366              naive          PR4+BocPR44              66                                                                                                          
  \[[@B42]\]       G1             80                       re-treatment                PR48                                                        21                  HCV RESPOND-2
  162              re-treatment   PR4+BocPR24+PR22         59                                                                                                          
  161              re-treatment   PR4+BocPR44              66                                                                                                          

PR48 group received peginterferon alfa-2a and ribavirin for 48 weeks; T12PR12, T12PR24 or T12 PR48 group received telaprevir for 12 weeks and peginterferon alfa-2a and ribavirin for 12, 24 or 48 weeks, respectively; T12P12 group received telaprevir and ribavirin for 12 weeks; T24P24 group received telaprevir and peginterferon alfa-2a for 24 weeks; RGT, response-guided therapy; Boc, boceprevir.

Second-generation HCV NS3/4A inhibitors
---------------------------------------

Simeprevir (TMC435) is an investigational HCV NS3/4A protease inhibitor administered orally once daily, and it is currently in phase III clinical development \[[@B48]\]. It differs from the first generation protease inhibitors in terms of its once-daily administration. Superior efficacies of simeprevir and peginterferon plus ribavirin were observed compared to those of peginterferon plus ribavirin alone in treatment-naive \[[@B49]\] and previously treated patients (Table [4](#T4){ref-type="table"}) \[[@B50]\]. Although anemia and rash, respectively, were notable adverse events in boceprevir and telaprevir, those of simeprevir and peginterferon plus ribavirin did not differ from those of peginterferon plus ribavirin alone in phase II studies \[[@B48]-[@B50]\].

###### 

New standard of care treatment with other drugs (second-generation DAAs) chronic hepatitis C patients

  **References**      **G**                                     **Number of patients**   **Naïve or re-treatment**   **Formula of therapy, and duration of treatment (weeks)**   **SVR rates (%)**   **Notes**
  ------------------- ----------------------------------------- ------------------------ --------------------------- ----------------------------------------------------------- ------------------- -----------------------------------------------------------------------------------------
  \[[@B48],[@B49]\]   G1                                        78                       Naïve                       TMC435 12 W peginterferon/ribavirin RGT                     82.1                TMC435 (simeprevir) 75 mg daily
  75                  TMC435 24 W peginterferon/ribavirin RGT   74.7                                                                                                                                 
  77                  TMC435 12 W peginterferon/ribavirin RGT   80.5                     TMC435 150 mg daily                                                                                         
  79                  TMC435 24 W peginterferon/ribavirin RGT   86.1                                                                                                                                 
  77                  Placebo                                   64.9                                                                                                                                 
  \[[@B48],[@B50]\]   G1                                        27                       Relapsers                   PR PR48                                                     37                   
  79                  TMC435 100 mg PR48                        85                                                                                                                                   
  79                  TMC435 150 mg PR48                        85                                                                                                                                   
  23                  Partial responders                        PR PR48                  9                                                                                                           
  68                  TMC435 100 mg PR48                        57                                                                                                                                   
  69                  TMC435 150 mg PR48                        75                                                                                                                                   
  16                  Null responders                           PR PR48                  19                                                                                                          
  50                  TMC435 100 mg PR48                        46                                                                                                                                   
  51                  TMC435 150 mg PR48                        51                                                                                                                                   
  \[[@B55]\]          G1                                        12                                                   3 mg daclatasvir PR48                                       42                  Treatment-naïve or less than 4 wks of exposure to ribavirin or interferon-based therapy
  12                  10 mg daclatasvir PR48                    83                                                                                                                                   
  12                  60 mg daclatasvir PR48                    83                                                                                                                                   
                                                                12                                                   Placebo PR48                                                25                   

MK-5172, a novel P2-P4 quinoxaline macrocyclic peptide, maintained potency across a genetically diverse panel of genotype 1a and 1b sequences from plasma of HCV-infected patients. This drug is to be used in combination with peginterferon plus ribavirin or with other DAAs \[[@B51]\]. Faldaprevir (BI 201335) is an inhibitor of HCV NS3/4A protease and is undergoing phase III clinical trials \[[@B52],[@B53]\].

HCV NS5A and NS5B inhibitors
----------------------------

HCV NS5A inhibitor daclatasvir (BMS-790052) with potent clinical effects has been found in the HCV replicon system \[[@B54]\]. Daclatasvir is a potent NS5A replication complex inhibitor and increases the antiviral potency of peginterferon and ribavirin \[[@B55]\] (Tables [4](#T4){ref-type="table"}).

###### 

New drugs (DAA combinations) for the treatment of hepatitis C in phase II study

  **Drug name/category**                        **Drug name/category**                        **Company**
  --------------------------------------------- --------------------------------------------- ------------------------------
  ABT-450r/Protease inhibitor                   ABT-072/Polymerase inhibitor                  Abbott/Enanta
  ABT-450r/Protease inhibitor                   ABT-267/NS5A inhibitor                        Abbott/Enanta
  ABT-450r/Protease inhibitor                   ABT-333/Polymerase inhibitor                  Abbott/Enanta
  Daclatasvir (BMS-79002)/ NS5A inhibitor       Sofosbuvir (GS-7977)/ Polymerase inhibitor    Bristol-Myers Squibb/Gilead
  Daclatasvir (BMS-79002)/ NS5A inhibitor       Simeprevir (TMC435)/ Protease inhibitor       Bristol-Myers Squibb/Janssen
  Danoprevir (RG7227)/ Protease inhibitor       Setrobuvir (ANA 598)/ Polymerase inhibitor    Genentech
  Danoprevir (RG7227)/ Protease inhibitor       Mericitabine (RG7128)/ Polymerase inhibitor   Genentech
  GS-9256                                       Tegobuvir (GS-9190)/ Polymerase inhibitor     Gilead
  Incivek (Telaprevir)/ Protease inhibitor      VX-222/Polymerase inhibitor                   Vertex
  Mericitabine (RG7128)/ Polymerase inhibitor   Incivek (Telaprevir)/ Protease inhibitor      Genentech/Vertex
  Simeprevir (TMC435)/ Protease inhibitor       Daclatasvir (BMS-79002)/ NS5A inhibitor       Janssen/Bristol-Myers Squibb
  Simeprevir (TMC435)/ Protease inhibitor       Sofosbuvir (GS-7977)/ Polymerase inhibitor    Janssen/ Gilead
  Simeprevir (TMC435)/ Protease inhibitor       TMC647055/NNI inhibitor/Ritonavir             Janssen
  Sofosbuvir (GS-7977)/ Polymerase inhibitor    GS-5885/ NS5A inhibitor                       Gilead
  VX-135/Polymerase inhibitor                   GSK2336805/ NS5A inhibitor                    Vertex/GSK
  VX-135/Polymerase inhibitor                   Simeprevir (TMC435)/ Protease inhibitor       Vertex/Janssen

HCV advocate: <http://hcvadvocate.blogspot.ca/p/quick-reference-guide_21.html> accessed on 2013/2/24.

###### 

New drugs for the treatment of hepatitis C in phase III study (combinations with peginterferon plus ribavirin, or DAA combinations)

  ***Combination with peginterferon plus ribavirin***                                                                
  ----------------------------------------------------- ------------------------------------------------------------ ----------------------
  Daclatasvir (BMS-79002)                               NS5A inhibitor                                               Bristol-Myers Squibb
  Simeprevir (TMC435)                                   Protease inhibitor                                           Janssen
  Sofosbuvir (GS-7977)                                  Polymerase inhibitor                                         Gilead
  ***DAA combinations***                                                                                             
  **Drug name/Category**                                **Drug name/Category**                                       **Company**
  ABT-450r/Protease inhibitor                           ABT-267/NS5A inhibitor and/or ABT-333/Polymerase inhibitor   Abbott/Enanta
  Daclatasvir (BMS-79002)/ NS5A inhibitor               Asunaprevir (BMS-650032)/Protease inhibitor                  Bristol-Myers Squibb
  Faldaprevir (BI201335)/ Protease inhibitor            GS-5885/NS5A inhibitor                                       Boehringer Ingelheim
  Sofosbuvir (GS-7977)/ Polymerase inhibitor            BI207127/Polymerase inhibitor                                Gilead
  Sofosbuvir (GS-7977)/ Polymerase inhibitor            GS-5885/NS5A inhibitor                                       Gilead

HCV advocate: <http://hcvadvocate.blogspot.ca/p/quick-reference-guide_21.html> accessed on 2013/2/24.

Sofosbuvir (GS-7977/PSI-7977) is a nucleotide inhibitor of HCV NS5B polymerase. Triple therapy including peginterferon plus ribavirin and sofosbuvir cures \>90% of patients treated for 12 or 24 weeks regardless of HCV genotype \[[@B56]\]. However, SVR rates of sofosbuvir plus ribavirin were \~76% for interferon-naive patients and \~11% for prior null responders in HCV genotype 1 patients \[[@B56],[@B57]\]. Sofosbuvir plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1 leads to higher RVR rates and SVR rates than SOC (88-94% vs. 21%; and 56-83% vs. 43%, respectively) \[[@B58]\]. It was also reported that sofosbuvir in combination with low- or full- dose ribavirin for 24 weeks leads to higher efficacy in difficult-to-treat HCV infected genotype 1 patients \[[@B59]\].

HCV drugs in the future
-----------------------

New drugs for the treatment of hepatitis C are now being investigated in phase II and phase III clinical trials (Tables [5](#T5){ref-type="table"} and [6](#T6){ref-type="table"}). These include interferon-sparing regimens, which are needed for the treatment of those intolerant to, or medically ineligible for peginterferon plus ribavirin therapy \[[@B60],[@B61]\]. Among treatment-experienced patients with advanced fibrosis or cirrhosis, previous relapsers are likely to respond very well to telaprevir- or boceprevir-based treatment, although advanced liver disease had a greater influence on SVR rates in previous nonresponders \[[@B39],[@B42],[@B62],[@B63]\]. Of importance is interferon-sparing combinations that might potentially be used in all patients who cannot use interferon such as subjects with decompensated cirrhosis or low platelet count. Some DAAs are potent inhibitors independently of HCV genotypes \[[@B56],[@B64]-[@B66]\]. The all-oral combination of daclatasvir plus sofosbuvir, with or without ribavirin, leads to higher SVR rates in treatment-naive patients chronically infected with HCV genotypes 1, 2 and 3 \[[@B67]\]. We may select the combination of several drugs according to personal features and/or HCV genotypes. In the near future, all-oral DAAs will treat HCV-infected patients (Figure [1](#F1){ref-type="fig"}).

Conclusions
===========

We expect that all-oral DAAs and interferon-free regimens will be applied in the treatment of HCV-infected patients and that they will have more potent efficacy and less adverse events. Further studies are now ongoing.

Competing interests
===================

Dr. Tatsuo Kanda reports receiving lecture fees from Chugai Pharmaceutical, MSD, Ajinomoto, GlaxoSmithKlein and Mitsubishi Tanabe Pharma, and Prof. Osamu Yokosuka received grant support from Chugai Pharmaceutical, Bayer, MSD, Daiichi-Sankyo, and Mitsubishi Tanabe Pharma.

Authors' contributions
======================

TK drafted the manuscript and all authors read through and made corrections to the manuscript. All authors read and approved the final manuscript.
