Treatment of hepatitis C virus infection in the future

Two direct-acting antivirals (DAAs) against hepatitis C virus (HCV): telaprevir and boceprevir, are now available in combination with peginterferon plus ribavirin for the treatment of chronic hepatitis C infection. Although these drugs are potent inhibitors of HCV replication, they occasionally result in severe adverse events. In the present clinical trials, in their stead, several second-generation DAAs are being investigated. Most of them are being viewed with high expectations, but they also require the combination with peginterferon plus ribavirin. In the near future, we might be using all-oral DAAs and interferon-free regimens for the treatment of HCV-infected patients, and these would be potent inhibitors of HCV and have less adverse events.


Introduction
Hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide [1]. HCV infection is one of the major causes of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide [2][3][4]. 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 [5][6][7]. 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 [8]. 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 [6]. 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 [5,7]. HCC develops at about 1-7% per year [5,7]. 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 [8][9][10][11][12]. The present standard for the judgment of SVR is undetectability of serum HCV RNA at 24 weeks posttreatment.
Preventive measures against HCV, including vaccine development, are now in progress [13]. 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 [14][15][16][17][18]. 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 [19], although even interferon is also associated with severe adverse events [20]. 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 0 untranslated region (5 0 UTR), a long open reading frame, and a 3 0 UTR. An internal ribosomal entry site (IRES), containing the 5 0 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 [21,22]. 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. Directacting 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, interferonsparing regimens and treatment with all-oral DAAs will play major roles in treating HCV-infected patients ( Figure 1).

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 [18,23]. 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 [23][24][25][26][27]. 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). Race has been shown to be a factor in the response to therapy for HCV infection [25,27]. A higher homocysteine level is also one of factors predicting a nonresponse to treatment [28]. 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 [29]. IL28B SNPs help to improve the treatment outcomes in HCV-patients treated with SOC [29][30][31][32][33][34]. In future interferon-included regimens, IL28B SNPs may also provide useful information about the treatment response even before treatment.

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 [48]. 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 [49] and previously treated patients (Table 4) [50]. 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 [48][49][50]. 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 [51]. Faldaprevir (BI 201335) is an inhibitor of  HCV NS3/4A protease and is undergoing phase III clinical trials [52,53].

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 and 6). These include interferon-sparing regimens, which are needed for the treatment of those intolerant to, or medically ineligible for peginterferon plus  ribavirin therapy [60,61]. Among treatment-experienced patients with advanced fibrosis or cirrhosis, previous relapsers are likely to respond very well to telapreviror boceprevir-based treatment, although advanced liver disease had a greater influence on SVR rates in previous nonresponders [39,42,62,63]. Of importance is interferonsparing 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 [56,[64][65][66]. 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 [67]. 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).

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.