Clinical Liver Disease
Volume 1, Issue 1, pages 24–27, February 2012
Alison B. Jazwinski M.D., M.H.S., Andrew J. Muir M.D., M.H.S.‡,*
Article first published online: 6 MAR 2012
Copyright © 2012 the American Association for the Study of Liver Diseases
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DAA, direct-acting antiviral; HCV, hepatitis C virus; ILLUMINATE, Illustrating the Effects of Combination Therapy With Telaprevir; NI, nucleoside inhibitor; NNI, nonnucleoside inhibitor; NS, nonstructural; PEG-IFNα, pegylated interferon-α; PI, protease inhibitor; RBV, ribavirin; RESPOND-2, Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2; RGT, response-guided therapy; SPRINT-2, Serine Protease Inhibitor Therapy 2; SVR, sustained virological response.
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
Figure 1. Viral life cycle. HCV enters the cell by receptor-mediated endocytosis. Positive-strand RNA is released into the cytoplasm, and then it is translated into a polyprotein. Polyprotein processing occurs: the bonds between the proteins are cleaved, and this results in four structural proteins and six nonstructural proteins. Viral replication occurs through the creation of negative-strand RNA, which serves as a template for the production of positive-strand RNA; that RNA is then packaged and released from the cell.
(Click table to enlarge)
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
Figure 2. Telaprevir resistance. One common location for the development of strains resistant to telaprevir is position 155. In patients with genotype 1a, the nucleotide sequence is AGA, which codes for arginine. Only one nucleotide change is required to result in the AAA sequence, which codes for lysine. This is in contrast to genotype 1b: two nucleotide changes are required for the AAA sequence and the change to lysine.
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
Figure 3. Replication complex. The viral nonstructural proteins, in addition to host proteins such as cyclophilin A, make up the replication complex and are the targets of the new DAA therapy. The exact roles of many of these proteins are still being elucidated, although inhibitors directed at them have potent antiviral activity.
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
Figure 4. SVR rates according to the fibrosis score in the REALIZE study. SVR indicates a negative viral load 24 weeks after the completion of therapy. The REALIZE study evaluated the efficacy of telaprevir in prior treatment relapsers, partial responders, and null responders. The results came from subgroup analyses.
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Abbreviations: ILLUMINATE, Illustrating the Effects of Combination Therapy With Telaprevir; RGT, response-guided therapy; SPRINT-2, Serine Protease Inhibitor Therapy 2.
* SVR indicates a negative viral load 24 weeks after the completion of therapy.
† In the ADVANCE trial of telaprevir,13 the T12PR group received telaprevir plus PR for 12 weeks and then PR alone for 12 weeks if HCV RNA results were negative at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point. The T8PR group received telaprevir plus PR for 8 weeks, then a placebo plus PR for 4 weeks, and finally PR for 12 or 36 weeks (depending on the HCV RNA levels at weeks 4 and 12).
‡ In the ILLUMINATE trial of telaprevir,15 all patients received 12 weeks of telaprevir plus PR. The HCV RNA level was assessed at weeks 4 and 12. If HCV RNA results were negative at weeks 4 and 12, patients were randomized into two groups: the T12PR24 group, which received another 4 weeks of therapy, and the T12PR48 group, which received another 28 weeks of therapy. Patients who did not achieve negative HCV RNA results at weeks 4 and 12 received 28 additional weeks of PR (i.e., the T12PR48 RGT group).
§ In the SPRINT-2 trial of boceprevir,16 the RGT group received PR for 4 weeks and then boceprevir for 24 weeks plus PR for 28 weeks. If patients had negative HCV RNA results at weeks 8 and 24, they stopped therapy at 28 weeks; if patients had detectable HCV RNA, they continued for another 20 weeks. The BPR48 group received lead-in PR for 4 weeks and then boceprevir plus PR for 44 weeks.
(Click to enlarge table)
Abbreviations: RESPOND-2, Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2; RGT, response-guided therapy.
* SVR indicates a negative viral load 24 weeks after the completion of therapy.
† In the REALIZE trial of telaprevir,14 the T12PR48 group received telaprevir plus PR for 12 weeks and then PR for 36 weeks. The Li-T12PR48 group received PR for 4 weeks, then telaprevir plus PR for 12 weeks, and finally PR for 32 weeks.
‡ In the RESPOND-2 trial of boceprevir,17 the RGT group received PR for 4 weeks and then boceprevir plus PR for 32 weeks. Patients with negative HCV RNA results at weeks 8 and 20 stopped treatment at week 36; patients with detectable HCV RNA received therapy for another 12 weeks. The BPR48 group received lead-in PR for 4 weeks and then boceprevir plus PR for 44 weeks.
§ Not studied.
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.
Figure 5. Combinations of DAAs currently under study. Trials are being conducted that include regimens of quadruple therapy (2 DAAs plus PEG-IFNα/RBV) as well as regimens using RBV but not PEG-IFNα and regimens using only DAAs.
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).
Figure 6. Potential future treatment strategies.
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.