Patients infected with hepatitis C virus (HCV) and their physicians have long been awaiting a more tolerable and effective treatment regimen. New agents are currently in development that directly target the HCV life cycle [direct-acting antivirals (DAAs)]. This review discusses these agents and the targets of therapy.
New Targets of Therapy
The HCV viral life cycle is shown in Fig. 1. The HCV structure encodes 10 viral proteins: 4 structural proteins and 6 nonstructural proteins (Table 1). The nonstructural proteins, particularly nonstructural 3/4A (NS3/4A), NS5A, and NS5B, compose the majority of the targets for the new DAA medications.1
|NS2||Protease: cleaves site between NS2 and NS3|
|NS3||Protease: catalyzes polyprotein cleavage at NS3-NS4A, NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B|
|NS4A||Cofactor for NS3|
|NS4B||Component of replication complex|
|NS5A||Component of replication complex|
|NS5B||RNA-dependent RNA polymerase for viral replication|
NS3/4A protease inhibitors (PIs) are the furthest along in drug development and include telaprevir and boceprevir, which have been approved for clinical use. NS3/4A PIs have high antiviral efficacy against genotypes 1 and 2 but not against genotype 3.2
NS3/4A inhibitors have a low genetic barrier to resistance; resistant strains develop quickly and prevent viral eradication with monotherapy.3, 4 HCV subtype 1a develops resistant strains to telaprevir more quickly than subtype 1b. One nucleotide change is required for subtype 1a to change the amino acid and form a resistant strain, whereas two nucleotide changes are required for subtype 1b (Fig. 2).5
Two categories of NS5B RNA polymerase inhibitors are in development: nucleoside inhibitors (NIs) and nonnucleoside inhibitors (NNIs). NIs mimic the natural substrates, are incorporated into the growing RNA chain, and cause termination of replication.6 NNIs bind to distant sites on the enzyme and cause a conformational change, which renders the polymerase ineffective.6, 7
There is a high genetic barrier to resistance with polymerase inhibitors and particularly with NIs because the active site of NS5B is highly conserved and amino acid substitutions at every position of the active site can result in a loss of function.8 Because NNIs bind to sites distant from the active center, resistance develops more frequently. Similarly, NIs have antiviral activity against all HCV genotypes because the active site of NS5B is conserved; however, NNIs have a more limited spectrum of activity.9
The NS5A viral protein and cyclophilin A host protein are also important components of the viral replication complex (Fig. 3), and agents that target these proteins, which have been termed replicase-binding inhibitors, are also in development.3 The exact mechanism by which these proteins participate in viral replication is currently under investigation, although early trials with inhibitors of these proteins have shown robust antiviral activity.10, 11
Current Practice and Future Directions
At the present time, because of the relatively high efficacy of treatment, patients infected with genotypes 2 and 3 receive 24 weeks of treatment with pegylated interferon-α (PEG-IFNα)/ribavirin (RBV).12 However, the side effects and the duration of treatment remain limitations, and DAAs are in development that will treat patients infected with genotypes 2 and 3.
The standard-of-care treatment for patients with genotype 1 infections now includes the use of telaprevir or boceprevir in combination with PEG-IFNα/RBV. Overall, the additions of telaprevir and boceprevir have improved the rates of response, but the significant side effects and the duration of treatment remain problems.13–17 Additionally, there are certain subgroups of patients who do not benefit from the addition of telaprevir or boceprevir to PEG-IFNα/RBV. Tables 2 and 3 and Fig. 4 show the results of phase 3 trials and highlight those groups that continue to have suboptimal response rates with triple therapy.13–17
|Phase 3 Trial Treatment Group||SVR (%)*|
|Phase 3 Trial Treatment Group||SVR (%)*|
|Prior Relapse||Prior Partial Response||Prior Null Response|
Generally, interferon-α is the drug that limits tolerability in the majority of patients. Thus, future regimens are being developed first to minimize interferon-α exposure and then ideally to avoid it entirely. Phase 3 trials of PIs have demonstrated that patients who achieve an extended rapid virological response can receive a shortened course of therapy (24 weeks with telaprevir and 28 weeks with boceprevir) with similar overall response rates. Thus, PIs may be considered the first interferon-α–sparing therapy.
The use of multiple DAAs is currently being studied with the goal of developing interferon-α–sparing and interferon-α–free regimens. Figure 5 shows the various combinations of therapy that are currently being studied both with and without PEG-IFNα and RBV.18 Over the next 5 to 10 years, as we work to develop an effective interferon-free regimen, there will be ongoing research to determine the shortest duration of interferon-α–sparing therapy possible. Quadruple-therapy regimens are likely the next step in this process.
Evidence showing that a sustained virological response (SVR) can be achieved with the use of DAAs and without the concurrent use of PEG-IFNα and RBV has been published recently.19 Patients with genotype 1 and a prior treatment null response were treated with an NS5A replication complex inhibitor (Daclatasvir) and an NS3 PI (Asunaprevir) alone or in combination with PEG-IFNα/RBV. All patients who received the quadruple therapy achieved SVR by 12 weeks, and 4 of 11 patients who received the all-oral regimen achieved SVR by 12 weeks. These results provide proof of concept that quadruple therapy offers hope of cure to previous null responders and that treatment regimens that do not include interferon-α are possible and likely. Many of the treatment regimens under investigation still include RBV; this is due to evidence from phase two studies of PIs showing that the use of RBV decreases viral breakthrough and relapse.20
Many of the treatment regimens under investigation still include RBV; this is due to evidence from phase two studies of PIs showing that the use of RBV decreases viral breakthrough and relapse.20
Personalized Treatment Regimens
HCV is leading the field of personalized medicine. Depending on a patient's history of treatment, degree of fibrosis, and race, a potential future treatment strategy involves the separation of patients into those with a favorable response profile and those with an unfavorable response profile and then the choice of an appropriate treatment regimen. Patients who have a favorable response profile will more frequently respond to the triple-therapy regimens that are currently available and may be the ones who will do well with the early interferon-free regimens. Patients who have an unfavorable response profile may experience improved response rates with upcoming quadruple therapy while additional interferon-α–sparing and interferon-α–free regimens are in development. Another potential future treatment algorithm may include the upfront treatment of patients with combination DAA therapy and, if the treatment fails, the initiation of a regimen that also includes PEG-IFNα/RBV (Fig. 6).
In conclusion, the development of new antiviral agents is currently underway with the ultimate goal of using DAAs to target multiple viral and host proteins to increase antiviral efficacy, prevent resistance, and improve the side effect profile of HCV treatment.