Article Text
Abstract
Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-N1 plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.
- Antiviral therapy
- boceprevir
- CHC
- DAA
- HCV
- hepatitis C
- HTA
- new standard of care
- perspectives
- PI
- protease inhibitor
- telaprevir
- treatment
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- Antiviral therapy
- boceprevir
- CHC
- DAA
- HCV
- hepatitis C
- HTA
- new standard of care
- perspectives
- PI
- protease inhibitor
- telaprevir
- treatment
Up to 200 million persons worldwide are infected with hepatitis C virus (HCV).1 Chronic hepatitis C (CHC) constitutes a major global health concern as it is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma.2 The goal of HCV therapy is to prevent these complications through viral eradication. For the past decade, CHC has been treated with a combination of pegylated interferon α (peg-IFN-α) and ribavirin. Viral eradication rates have remained suboptimal over this time period, particularly in those patients with genotype 1 HCV, which is responsible for approximately 60% of worldwide infections.3 Sustained virological response (SVR) rates for genotype 1 HCV are approximately 40% following 48 weeks of peg-IFN/ribavirin and are even lower in patients of African descent, HIV co-infection, or those with high viral loads or advanced fibrosis.4–7 A significant step forward in the quest for host factors that mediate the response to interferon therapy was the recent discovery of a group of single nucleotide polymorphisms in the region of the IL28B (type 3 λ interferon) gene through genome-wide association studies.8 The IL28B genotype at the rs12979860 locus is the most powerful baseline predictor of SVR in genotype 1 patients treated with peg-IFN/ribavirin, with SVR in approximately 70% of patients with the favourable CC genotype of the IL28B rs12979860 polymorphism compared with 25–30% in those with the CT or TT genotype.
HCV therapy has been revolutionised recently by the development and approval of direct-acting antiviral agents (DAA), borne out of intense study of the viral life cycle and the elucidation of the crystal structure of several critical viral proteins.9–11 In contrast to the non-specific antiviral activity of IFN and ribavirin, DAA are designed to inhibit viral proteins involved in the HCV life cycle. The complexity of the viral machinery allows for numerous potential targets including the NS3/4A serine protease, NS5A replication complex protein, NS5B RNA-dependent RNA polymerase, and NS4B and NS3 helicase proteins. The first two approved agents of this new class of DAA, telaprevir (Incivek; Vertex Pharmaceuticals Cambridge, MA, USA) and boceprevir (Victrelis; Merck & Co Whitehouse Station, NJ, USA), both inhibitors of the NS3/4A protease, are indicated for use in patients with genotype 1 HCV, and mark the beginning of an extraordinary new era in HCV therapy. The coming years are expected to bear witness to newer DAA with simplified dosing regimens and/or minimal toxicity, which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. Indeed, recent proof-of-concept studies have vindicated the hope held for years by many investigators that HCV can be eradicated without IFN.12–15
The new SOC in CHC treatment
Since the approval of telaprevir and boceprevir in a number of countries, triple therapy with peg-IFN/ribavirin and a protease inhibitor (PI) has supplanted peg-IFN/ribavirin alone as the new standard of care (SOC) for genotype 1 HCV infection. It is imperative that clinicians providing care for patients with hepatitis C become familiar with both new agents, including dosing regimens, response rates, stopping rules, potential side effects and medication interactions. In addition, a complete approach should include an understanding of the concept of resistance and a discussion with the patient at some level about the possibility of this outcome if therapy fails.
Telaprevir
Telaprevir is a selective peptidomimetic NS3/4A PI that forms a covalent, reversible enzyme-inhibitor complex. Its efficacy in combination with peg-IFN/ribavirin in both treatment-naive and treatment-experienced patients with genotype 1 HCV was established in the large multicentre phase 2b PROVE 1, PROVE 2 and PROVE 3 trials.16–19 Through these early trials, superior response rates were observed with the addition of telaprevir to peg-IFN/ribavirin, driven by high rates of rapid virological response and low rates of relapse. Ribavirin was found to be an essential component of the regimen. The concept of response-guided therapy (RGT), in which treatment duration is determined by viral response early in the course of therapy, was introduced. The two major adverse effects of telaprevir were found to be rash and anaemia.
A phase 3 study in treatment-naive patients was carried out in the pivotal ADVANCE study, which compared telaprevir-based regimens to SOC in 1088 patients with treatment-naive genotype 1 CHC.20 Randomisation was performed into one of three treatment arms: telaprevir 750 mg every 8 h plus peg-IFN-α-2a/ribavirin for 8 weeks followed by additional weeks of peg-IFN/ribavirin (T8PR), telaprevir plus peg-IFN/ribavirin for 12 weeks followed by additional weeks of peg-IFN/ribavirin (T12PR), or peg-IFN/ribavirin for 48 weeks (PR48, control arm). Patients in the telaprevir arms who achieved undetectable HCV RNA at weeks 4 and 12 (extended rapid viral response; eRVR) were treated for a total of 24 weeks of therapy, whereas those who did not achieve eRVR were treated for 48 weeks total (table 1).
Significantly higher SVR rates were observed in both telaprevir arms compared with controls with 75% and 69% in the T12 and T8 groups achieving SVR, respectively, compared with 44% in the PR48 group (p<0.0001). Re-analysis using revised criteria, as requested by the US Food and Drug Administration (counting SVR12 as SVR when 24-week follow-up was not available, and counting patients with HCV RNA between the lower limit of detection and lower limit of quantitation at week 24 follow-up as SVR), resulted in SVR rates in the package insert of 79%, 72% and 46%, respectively. Relapse rates were observed to be 9% in each telaprevir arm and 28% in the control arm. In the now approved T12PR regimen group, 58% of patients achieved an eRVR, of whom 89% went on to SVR. In African-American patients, the addition of telaprevir increased SVR rates to 62% and 58% in the T12PR and T8PR groups, respectively, from 25% in the PR group. Similarly, a significantly improved SVR rate (62%) was also observed in those patients with bridging fibrosis or cirrhosis in the T12PR group versus controls (33%). Adverse events mandating discontinuation of study drugs occurred more frequently in the telaprevir groups: 10% in both groups versus 7% in the PR48 group. Of note, grade 3 rash occurred in 6% of patients in the T12PR group versus 4% in the T8PR group. Telaprevir was associated with an incremental decline in haemoglobin of 1.0–1.5 g/dl relative to peg-IFN/ribavirin alone during the period of telaprevir dosing. Also of note, anorectal complaints under several descriptors were common in telaprevir-treated patients at 29% versus 7% in controls (table 2).
The ILLUMINATE study firmly established the foundation for RGT in treatment-naive patients receiving telaprevir-based regimens.21 All patients were treated with 12 weeks of telaprevir plus peg-IFN/ribavirin, with those achieving an eRVR subsequently randomly assigned to either 12 or 36 additional weeks of peg-IFN/ribavirin. Sixty-five per cent of the 540 study patients achieved eRVR. The authors concluded that the 24-week telaprevir-based regimen was non-inferior to the 48-week regimen, with SVR rates of 92% versus 88%, respectively. High SVR rates were achieved with RGT upon eRVR regardless of race, ethnicity, as well as the presence or absence of advanced fibrosis. However, data at present are insufficient to support RGT in patients with cirrhosis, because of the few patients with cirrhosis enrolled in the ILLUMINATE trial there was a trend towards higher SVR rates in patients with eRVR who were treated for 48 weeks; further investigation is needed in the cirrhotic patient population to determine optimal treatment duration after eRVR.
The phase 3 REALIZE trial evaluated telaprevir-based therapy in treatment-experienced patients.22 Six hundred and sixty-two genotype 1 relapsers, partial responders and null responders (<2 log decline in HCV RNA at week 12 of previous therapy) were randomly assigned to receive either 48 weeks of peg-IFN/ribavirin (control group) or one of two telaprevir regimens: peg-IFN/ribavirin for 4 weeks followed by telaprevir 750 mg every 8 h plus peg-IFN/ribavirin for 12 weeks followed by peg-IFN/ribavirin for an additional 32 weeks (delayed start arm) or telaprevir 750 mg every 8 h plus peg-IFN/ribavirin for 12 weeks followed by peg-IFN/ribavirin for 36 weeks (simultaneous start arm). Among relapsers, the SVR rate was 88% in the telaprevir delayed start arm and 83% in the simultaneous start arm compared with 24% in the control group. For previous partial responders, the SVR rate was 54% and 59% in the delayed and simultaneous start arms, respectively, versus 15% in controls. Finally, 33% and 29% of null responders achieved SVR in the delayed and simultaneous start arms, respectively, versus 5% in control. While both telaprevir-based regimens were superior to control, the lead-in (delayed start) regimen did not significantly improve SVR rates over simultaneous start. Importantly, subgroup analysis demonstrated that the presence of cirrhosis minimally affected SVR rates in telaprevir-treated relapsers while cirrhotic partial responders and null responders had significantly decreased SVR rates. The achievement of SVR was particularly infrequent in the latter group (14%, with n=50), while bridging fibrosis or cirrhosis in partial responders had significantly higher SVR rates (44%, with n=25). Further subgroup analysis demonstrated that the degree of HCV RNA decline after the 4-week lead-in for peg-IFN/ribavirin was useful in predicting SVR, particularly in null responders who had SVR rates of 54% when a 1 log or greater decline was achieved versus only 15% in those with less than 1 log decline at week 423 (table 1). Previous relapsers are allowed for RGT, as the phase II clinical trial PROVE 3 and the Study 107 demonstrated 94% SVR in relapsers with eRVR on 24-week total treatment duration.18
Telaprevir is now approved for the treatment of genotype 1 CHC in oral tablets at a dose of 750 mg to be taken three times a day (TID) in combination with peg-IFN/ribavirin.24 As established by the aforementioned studies, the three-drug regimen is given for 12 weeks, followed by RGT of either 12 or 36 additional weeks peg-IFN/ribavirin depending on both viral response and previous treatment status. For treatment-naive patients and previous relapsers, those with undetectable HCV RNA at weeks 4 and 12 are eligible for truncated therapy with 12 more weeks of peg-IFN/ribavirin. The exception to this guideline is those treatment-naive patients with cirrhosis with undetectable HCV RNA at weeks 4 and 12, in whom 36 additional weeks of peg-IFN/ribavirin is suggested. All previous partial and null responders are instructed to receive 12 weeks of the three-drug regimen followed by 36 weeks of peg-IFN/ribavirin. Stopping rules for discontinuation of the entire regimen include HCV RNA greater than 1000 IU/ml at weeks 4 or 12 or detectable HCV RNA at week 24 (table 3).
As telaprevir is a potent inhibitor of CYP3A, its use is contraindicated in those patients concurrently taking medications that are also highly dependent on CYP3A clearance, in which elevated concentrations are associated with serious events. Noteworthy inclusions on this list include but are not limited to lovastatin, simvastatin and atorvastatin, PDE5 inhibitors when used for pulmonary artery hypertension, ergot products and alfuzosin. Similarly, the concurrent use of medications that strongly induce CYP3A such as rifampicin and St John's Wort (Hypericum perforatum), which can thereby cause reduced exposure, should be avoided. Clinicians should consult the list of contraindicated drugs and the more extensive list of drugs with potential interactions, available in the package insert regularly. Dose reduction of telaprevir and telaprevir monotherapy are strictly prohibited in order to minimise the emergence of viral resistance.
Boceprevir
Boceprevir is also a selective peptidomimetic NS3/4A PI that forms a covalent but reversible enzyme-inhibitor complex. The phase 2b SPRINT-1 trial demonstrated improved viral eradication rates with the addition of boceprevir to SOC and also suggested a potential role for a 4-week lead-in period of peg-IFN/ribavirin before the initiation of boceprevir to achieve optimal SVR rates and minimise the rates of virological resistance with the three-drug regimen.25 The inclusion of a low-dose ribavirin arm demonstrated not only the importance of including ribavirin but the need for initial dosing at previously established levels.
The phase 3 SPRINT-2 trial studied boceprevir in combination with peg-IFN-α-2b and ribavirin in 1097 (938 non-black and 159 black) treatment-naive genotype 1 HCV patients.26 All patients received a 4-week lead-in of peg-IFN/ribavirin and were then randomly assigned to receive placebo plus peg-IFN/ribavirin for an additional 44 weeks, boceprevir 800 mg TID plus peg-IFN/ribavirin for an additional 44 weeks, or RGT with boceprevir 800 mg TID plus peg-IFN/ribavirin for an additional 24 weeks, followed by 20 more weeks of peg-IFN/ribavirin if serum HCV RNA was detectable at any time during weeks 8–24. All patients with detectable HCV RNA at week 24 were discontinued from the study. Non-black and black patient cohorts were analysed separately (table 1).
In the non-black cohort, the SVR rate in the control arm was 40% and was significantly higher in both boceprevir groups: 68% (p<0.0001 vs control) in the boceprevir/peg-IFN/ribavirin 48-week treatment group and 67% (p<0.0001 vs control) in the RGT group. The SVR rate in the control arm of the black cohort was predictably lower (23%), but also significantly improved in the boceprevir groups at 53% (p=0.004 vs control) in the boceprevir/peg-IFN/ribavirin 48-week treatment group and 42% (p=0.04 vs control) in the RGT group. Modified intent-to-treat analysis, including only patients who received at least one dose of boceprevir, demonstrated SVR rates of 53% and 47%, respectively. High responsiveness to peg-IFN/ribavirin in the non-black cohort as evidenced by a 1 log or greater decline in HCV RNA during the lead-in period was strongly predictive of SVR in all groups compared with those with less than 1 log decline (82% vs 39% in the boceprevir/peg-IFN/ribavirin 48-week treatment group, 82% vs 29% in the RGT group, and 52% vs 5% in the control group). Lower relapse rates were observed in the non-black cohort boceprevir arms: 8% in the boceprevir/peg-IFN/ribavirin 48-week treatment group and 9% in the RGT group versus 23% in the control group, although this was not the case in the black cohort (17% and 12% vs 14%, respectively).
Discontinuation of therapy secondary to adverse events in SPRINT-2 was similar across the three arms at 16% in the SOC group, 16% for the lead-in plus boceprevir/peg-IFN/ribavirin group and 12% for the RGT group. Anaemia was more common in the boceprevir-treated patients at 49% compared with 29% in controls. While dose reduction secondary to anaemia was required more often in patients receiving boceprevir compared with controls (21% vs 13%), treatment discontinuation was rare (2% vs 1%, respectively). Unlike the telaprevir programme, erythropoietin use was permitted with boceprevir and was more frequent in the boceprevir arms. A modest increment in neutropenia of unclear clinical significance was noted with boceprevir, as was an increased incidence of dysgeusia. Dysgeusia is common with boceprevir, but is rarely if ever drug limiting (table 2).
The phase 3 RESPOND-2 trial studied boceprevir-based regimens in treatment-experienced patients.27 Previous non-responders in the study were ‘partial’ responders, that is they had experienced a 2 log or greater reduction in HCV RNA by week 12 of previous therapy, but had persistent viraemia at week 24, or those who relapsed, having attained undetectable HCV RNA at the end of treatment but not achieving SVR. Control and experimental arm regimens were similar to that of SPRINT-2 except that the period of triple therapy was longer in the RGT group: peg-IFN/ribavirin for 48 weeks (control), 4-week lead-in of peg-IFN/ribavirin followed by either boceprevir plus peg-IFN/ribavirin for 44 weeks or RGT with boceprevir plus peg-IFN/ribavirin for an additional 32 weeks if serum HCV RNA was undetectable at week 8 or boceprevir plus peg-IFN/ribavirin for an additional 32 weeks followed by 12 more weeks of peg-IFN/ribavirin if serum HCV RNA was detectable at week 8. Patients with detectable HCV RNA at week 12 were discontinued from the study.
SVR rates were significantly higher in both the boceprevir plus peg-IFN/ribavirin 44-week group (66%) and RGT group (59%) compared with controls (21%). Previous relapsers had higher SVR rates than previous non-responders in all three arms as expected. Those patients with a 1 log or greater decline in HCV RNA at the end of the 4-week lead-in period of peg-IFN/ribavirin had the highest SVR rates of 79% when followed by boceprevir plus peg-IFN/ribavirin the 44-week group and 73% in the RGT group. Those patients in the boceprevir groups with less than 1 log decline in HCV RNA during the lead-in period had significantly higher SVR rates than similar patients in the control group (34% and 33%, respectively, vs 0% in the control group). Discontinuation secondary to adverse events was reported at 3%, 12% and 8% in the three arms, respectively. Anaemia was more common in the boceprevir groups (43–46%) versus controls (20%), although overall treatment discontinuation secondary to anaemia was rare in all groups at 0% in the control group and 0–3% in the boceprevir groups (table 1).
Boceprevir is now approved for the treatment of genotype 1 CHC in oral tablets at a dose of 800 mg TID in combination with peg-IFN/ribavirin.28 All patients are to receive a 4-week lead-in of peg-IFN/ribavirin with the addition of boceprevir TID in combination with peg-IFN/ribavirin thereafter. Duration is determined by RGT based on the HCV RNA level at treatment weeks (TW) 8, 12, and 24. For treatment-naive patients with undetectable HCV RNA at TW8 and TW24, three-drug therapy is terminated at TW28. In treatment-naive patients with detectable HCV RNA at TW8 and undetectable HCV RNA at TW24, the three-drug regimen is completed to TW36 (not TW28, as in the SPRINT-2 trial) followed by peg-IFN/ribavirin alone to TW48. In previous partial responders or relapsers with undetectable HCV RNA at TW8 and TW24, the three-drug regimen is continued to TW36. Analogous to slower responders among treatment-naive patients, those with detectable HCV RNA at TW8 and undetectable HCV RNA at TW24 are treated with the extended course of the three-drug regimen to TW36 followed by peg-IFN/ribavirin alone to TW48. Treatment is determined to be futile if HCV RNA is 100 IU/ml or greater at TW12 or detectable at TW24, at which points all three drugs should be discontinued. The week 12 stopping rule in the label is different from that in the phase III clinical trials, in which futility was different between naive (no futility rule at 12 weeks) and treatment-experienced patients (HCV RNA detectability at 12 weeks). A uniform stopping rule was introduced after the phase III trials based on the observation that patients with HCV RNA of 100 IU/ml or greater at TW12 are unlikely to achieve SVR. Package instructions state that RGT was not studied in those who had less than a 2 log decline in HCV RNA during previous peg-IFN/ribavirin therapy and providers are therefore encouraged to treat these patients for 44 weeks of boceprevir with peg-IFN/ribavirin after the 4-week lead in. This longer 48-week duration of therapy, including 44 weeks of boceprevir, is also suggested for those with poor IFN responsiveness at week 4 or those with compensated cirrhosis whether treatment naive or experienced (table 3).
As is the case with telaprevir, boceprevir is a potent inhibitor of CYP3A, although its major metabolic pathway is via α-ketoreductase. It is therefore contraindicated for concurrent use with medications that are also highly dependent on CYP3A clearance, in which elevated concentrations are associated with serious events. It is also contraindicated with the concurrent use of medications that strongly induce CYP3A to avoid loss of efficacy. As for telaprevir, familiarity with the drugs listed as contraindicated or capable of potential interactions with boceprevir, which overlap considerably with those listed for telaprevir, is essential for the clinician. Dose reduction and monotherapy is strictly prohibited (box 1).
Current considerations in the treatment of CHC-infected patients
Up to 200 million people infected with CHC worldwide.
CHC is a major cause of chronic liver disease, cirrhosis requiring transplantation and hepatocellular cancer.
Viral eradication rates in genotype 1 HCV was suboptimal with peg-IFN/ribavirin and significantly improved with the addition of now approved protease inhibitors.
Boceprevir and telaprevir are the first two DAA to be commercially available and are soon to be followed by many new DAA, which are likely to be more potent and dosed more easily.
Special considerations
In some parts of the world, telaprevir and boceprevir are either not available for use in the treatment of patients with genotype 1 CHC or are available at a cost that prohibits their widespread use. We recommend that practitioners in these countries continue to use peg-IFN/ribavirin dual therapy in highly selected patients, particularly those with the favourable IL28B ‘CC’ genotype or those with advanced liver disease in whom delaying treatment would not be advised.
A second patient population worth mentioning is those who fail PI-based therapy. Trials of additional DAA regimens are expected in PI failure patients in the near future. We remain optimistic about the potential to achieve viral cure even in these patients given preliminary results from trials of quad therapy regimens and regimens combining multiple classes of DAA discussed in detail below as well as data that suggest that resistant viral variants that emerge during therapy clear over time.
Resistance-associated amino acid variants
The use of DAA can improve SVR rates with decreased duration of therapy, yet also raises concerns regarding the development of resistant viral variants. Replication of HCV occurs rapidly and is prone to replication errors, which continuously produce resistant variants.29–31 However, these resistance-associated amino acid variants (RAV) are usually less fit in terms of replication and/or infectious virus production and therefore present in much smaller quantities than wild-type (WT) virus.32 Despite this, it has been demonstrated that selective pressure in the setting of DAA therapy or further mutations can favour the emergence of RAV.33–35
In vivo resistance to both telaprevir and boceprevir has been observed in multiple clinical studies. Telaprevir monotherapy, for example, selects for RAV within 1–2 weeks of starting therapy.34 Ongoing therapy may select for the emergence of additional resistant variants and/or a viral population increasingly rich in RAV; however, these often have impaired replicative fitness. Similarly, boceprevir monotherapy leads to the development of RAV, which show cross-resistance to telaprevir.36 Concomitant ribavirin administration is clearly important in terms of reducing virological breakthrough, as demonstrated in the PROVE 2 study in which virological breakthrough occurred in only 2% of patients treated with triple therapy as opposed to 26% in those treated with peg-IFN and telaprevir alone.19 The PROVE studies further demonstrated that while RAV might emerge with DAA treatment, they do not necessarily impact the risk of virological breakthrough in the setting of combination therapy. The development of RAV does appear to occur more frequently in genotype 1a patients as opposed to genotype 1b patients, as evidenced by analysis in SPRINT-2 and RESPOND-2 (RAV present in 48–58% 1a vs 41–48% 1b in those patients not achieving SVR, respectively), which probably accounts for the slightly lower SVR rate in genotype 1a patients.26 27
Although not common, RAV are detectable at baseline in up to 5% of treatment-naive patients, more commonly in genotype 1a (5.8%) patients than 1b patients (1.4%) as genotype 1b HCV has a higher genetic barrier to resistance.37 38 The clinical significance of these baseline RAV remains unclear, with early evidence suggesting no significant impact of baseline RAV on SVR rates in patients treated with telaprevir combination therapy in PROVE 1 and 2 or with boceprevir combination therapy in SPRINT-2.16 17 26 37
Sequencing studies have demonstrated that RAV tend to regress over weeks to months following cessation of DAA therapy, allowing WT virus to re-emerge and leading to the undetectability of RAV 2 years after cessation of therapy in over 80%.36 39 40 Because of their intrinsic unresponsiveness to interferon and consequent higher chances of treatment failure with PI, previous null responders appear to be at greatest risk of harbouring RAV and present a population for which ‘quad regimens’ with a peg-IFN/ribavirin backbone and two DAA, or multiple DAA with a high barrier to resistance will probably provide significant increments in efficacy. At present, individualised treatment decisions in null responders, weighing the patient's stage of liver disease, previous tolerance of therapy, and individual motivation are required. As in all patients, strict adherence to stopping rules are essential to minimise the emergence of RAV in patients undergoing treatment. Despite the concerns about resistance, the fact that HCV is not genomically archived, the data on the replacement of RAV with WT virus over time and the emergence of other classes of drugs without cross-resistance to PI provide considerable reassurance, and lead to the conclusion that no class of patients should be categorically denied PI-based therapy based upon resistance concerns alone.
Predicting response based on IL28B genotype
Early studies on the relationship between IL28B genotype and PI-based regimens indicate that in treatment-naive patients the largest increment in SVR relative to peg-IFN/ribavirin occurs in patients with a T allele at the rs12979860 locus.41 42 Patients with the CC genotype have minimal to moderate increments in SVR, but are highly likely to require only 24–28 weeks of therapy. In treatment-experienced patients, in whom the CC genotype is less frequent than in the general population, IL28B is less of a differentiator for the prediction of response.42 43 The IL28B CC genotype in treatment-naive patients was a positive predictor in the SPRINT-2 and ADVANCE trials to select appropriate candidates for RGT. However, the data are insufficient to support withholding PI from patients based upon IL28B genotype.
HCV life cycle: novel agents in clinical development
HCV is a positive-strand RNA virus that encodes one single polyprotein that is cleaved into 10 structural and non-structural proteins by both viral enzymes (NS2/3 and NS3/4A proteases) and cellular signal peptidase/signal peptide peptidase.44–46 The viral replication machinery is composed of the non-structural proteins NS3, NS4A, NS4B, NS5A and NS5B. These form a replication complex associated with intracellular membranes, which can be visualised under electron microscopy as a ‘membranous web’. The replication complex produces a negative-stranded RNA copy of the genome, which is used to form positive-strand RNA as the virus replicates. The functions of some of these protein components of the viral life cycle, for example, the RNA-dependent RNA polymerase NS5B, are well understood. However, many functions of other non-structural proteins remain controversial. Nevertheless, most of the non-structural proteins have been examined as targets for drug development. The HCV virion is an enveloped virus with two surface glycoproteins: E1 and E2, the latter of which is believed to play a role in viral entry. Viral proteins are embedded in the phospholipid bilayer envelope, which in turn surrounds the viral genome and core protein. Exhaustive research has yielded a theorised model of HCV infection whereby the virus interacts with hepatocyte glucosaminoglycans, low-density lipoprotein receptors, entry factors scavenger receptor type B1 and CD81 followed by movement to tight junctions formed by claudulin 1 and occludin.47 Potential drug targets include these viral glycoproteins and entry factors.
Finally, host cell factors required by HCV for replication represent an additional category of potential drug targets. Among the numerous potential host targets, cyclophilins have become the first to demonstrate this proof of concept. Cyclophilin A is a cellular peptidyl-prolylisomerase that acts on HCV viral proteins and is required for its replication.48 Cyclophilins are targets of the well-established immunosuppressant ciclosporin A, which has served as a launching point for the development of non-immunosuppressive analogues with activity against HCV, such as alisporivir (table 4).
Direct-acting antiviral agents
Protease inhibitors
The catalytic NS2/3 cystein protease domain forms a dimer with two composite active sites.49 Even though the structure has been solved, no drug development was reported against that target site. The chymotrypsin-fold NS3/4A serine protease comprises an active site with a catalytic residue triad and oxyanion hole50 (figure 1). The first generation inhibitors are peptides based on the non-prime side residues of the NS4A-4B cleavage site. They contain an α-ketoamide moiety in place of the scissile amide bond. Macrocyclisation on the basis of active peptidomimetic compounds has led to a second generation of inhibitors binding to the protease active site. Beyond the two approved agents, several macrocyclic and linear PI are in the drug development and clinical trial pipeline, for example, asunaprevir (BMS-650032), danoprevir (ITMN191/R7227), vaniprevir (MK-7009), MK-5172, BI 201335 and simeprevir (TMC435).
NS4B inhibitors
An arginine-rich motif within the NS4B C-terminus was shown to bind RNA specifically, offering a novel mechanism to incorporate the viral genome into the replication machinery, with clemizole hydrochloride identified to block that RNA-binding function in cell culture substantially.52 Clemizole is still under preclinical evaluation.
NS5A inhibitors
NS5A domain I has been crystallised, containing a zinc-binding domain that is involved in RNA binding.53 Domain II was found to stimulate RNA binding via an interaction with cyclophilin A.54 Domain III was recently shown to regulate the production of infectious virus in a genotype 1a HCV cell-culture system of infection, associated with a C-terminal serine/threonine cluster.55 Daclatasvir (BMS-790052) is the first-in-class inhibitor of NS5A, likely to target domain I. It exhibits high potency and broad genotype coverage in replicon and cell culture, and was subsequently confirmed as a potent inhibitor in phase 1/2 clinical trials. Other NS5A inhibitors in clinical development are ABT-267, GS-5885 and PPI-461.
Polymerase inhibitors
Two classes of NS5B inhibitors have been developed. Nucleos(t)ide analogues (Nuc) are active site inhibitors that mimic the natural polymerase substrate causing chain termination. Valopicitabine (NM283) was the first Nuc investigated in patients, but showed only low antiviral efficacy and was stopped because of gastrointestinal side effects. Other Nuc have been developed that are more potent and have provided convincing results in recent clinical trials, for example, mericitabine (R7128) and PSI-7977. Non-nucleoside inhibitors (NNI) bind at four different sites outside of the polymerase active centre. Drugs are differentiated upon their binding sites and chemical scaffolds. NNI site 1 inhibitors bind to the benzimidazole site (thumb 1), for example, BI 207127 and tegobuvir (GS-9190). NNI site 2 inhibitors, such as filibuvir (PF-00868554) and VX-222, bind to the thiophene allosteric pocket in the thumb domain (thumb 2). NNI site 3 and 4 inhibitors bind to the palm domain, benzothiadiazine site (palm 1), for example ANA598, and benzofuran site (palm 2), for example, ABT-333. All NNI inhibit the catalytic efficiency of the NS5B polymerase from a distance as a result of allosteric mechanisms56 (figure 2).
Clinical trials containing a peg-IFN/ribavirin backbone
As previously discussed, combination therapies of boceprevir or telaprevir with peg-IFN have shown their ability to suppress HCV replication potently and also overcome resistance to single agents. A triple therapy combining the macrocyclic NS3/4A PI simeprevir with peg-IFN/ribavirin is in a phase 3 clinical trial following phase 2 trials showing high rates of efficacy in both treatment-naive and experienced patients with once daily dosing and a favourable safety profile.56 Other PI have demonstrated similar incremental efficacy when combined with peg-IFN/ribavirin,13 57 as has a first-in-class NS5A.12 Nucleotides against the highly conserved active site of NS5B have equivalent antiviral activity against different HCV genotypes and subtypes and a high barrier to resistance.56 SVR rates of more than 90% were reported in the PROTON trial for the pyrimidine analogue NS5B inhibitor PSI-7977 plus peg-IFN/ribavirin in genotype 1 CHC independent of predictors of poor interferon response.
The potential for interferon-free therapy
NS3/4A PI plus nucleoside analogue polymerase inhibitor
The INFORM-1 trial provided the proof of principle that a peg-IFN-free DAA combination therapy in treatment-naive and experienced genotype 1 CHC patients can effectively suppress HCV replication.14 The strongest antiviral activity was observed in treatment-naive patients when combining the macrocyclic NS3/4A PI danoprevir with the Nuc NS5B polymerase inhibitor mericitabine at the highest dose levels. Similar responses were also achieved in previous null responders.
NS3/4A PI plus non-nucleoside polymerase inhibitor
The SOUND-C1 trial demonstrated potent antiviral activity in treatment-naive genotype 1 CHC, combining a PI with an NNI, BI 201335 and BI 207127, respectively, plus ribavirin. Higher response rates were observed in genotype 1b compared with genotype 1a with RVR rates for PI/NNI/ribavirin from 73% to 100% depending on the dosing of the respective DAA.57 The SOUND-C2 trial confirmed potent antiviral activity; however, the ribavirin-sparing arm showed substantial but lower response rates than other arms of the trial.13 In another study, patients were randomly assigned for 4-week dual, triple or quadruple therapy, combining the PI GS-9256 and the NNI GS-9190 with or without ribavirin or peg-IFN/ribavirin. RVR rates varied from 100% in PI/NNI/peg-IFN/ribavirin to 38% in PI/NNI/ribavirin, and only 7% in the dual PI/NNI therapy, combining only the two DAA.58 The low response rate in the latter group was related to the frequent occurrence of RAV, which highlights the important role of peg-IFN and ribavirin to prevent drug resistance in DAA-containing regimens. The ZENITH trial assessed the antiviral activity of telaprevir and the NNI VX-222 in a dual regimen, as well as with ribavirin in triple or peg-IFN/ribavirin in quadruple therapy for treatment-naive genotype 1 CHC. The quadruple therapy was associated with high antiviral activity, comparable to SVR rates in peg-IFN/ribavirin plus telaprevir, and without viral breakthrough on treatment. Furthermore, 38–50% of the patients were able to undergo only 12 weeks of therapy, with 82–93% achieving SVR12.59
NS3/4A PI plus NS5A inhibitor
Genotype 1 CHC, treatment-experienced null responders were randomly assigned to receive an all-oral combination of a NS5A inhibitor and a PI, daclatasvir (BMS-790052) and asunaprevir (BMS-650032), respectively, or a combination of the two DAA with peg-IFN/ribavirin for 24 weeks.60 The DAA-alone group showed a viral breakthrough in 55%, including all genotype 1a HCV-infected patients, whereas all genotype 1b-infected patients achieved SVR. The quadruple therapy with the peg-IFN/ribavirin backbone in that study was highly effective, with all (10/10) patients achieving SVR after treatment completion.61 A Japanese study confirmed these data, showing SVR12 in 90% of genotype 1b previous null responders receiving dual therapy alone.15 The subtype of genotype 1 is proving to be more impactful in a number of DAA regimens (including, to a modest degree, telaprevir and boceprevir) than with peg-IFN/ribavirin, and will require attention and possible refinements in study designs in future years. The quadruple therapy with the peg-IFN/ribavirin backbone was highly effective, with all patients achieving SVR after treatment completion.61
Nucleos(t)ide studies
The highly impactful recent phase 2 ELECTRON trial demonstrated a 100% SVR with a 12-week PSI-7977/ribavirin regimen in genotypes 2 and 3.62 As the kinetics of viral decline with this drug are similar for genotype 1 HCV, the ELECTRON trial has led to the hypothesis that similar results might be attainable pangenotypically. The phase 2b QUANTUM trial was planned as the first interferon-free, all-nucleotide study with an SVR endpoint, combining a pyrimidine and purine analogue, PSI-7977 and PSI-938, respectively. Supported by data from the NUCLEAR and interferon-free arms of the ELECTRON trial, QUANTUM was thought to address all genotypes. However, the purine analogue PSI-938 was stopped because of hepatotoxicity. Larger trials are needed to investigate Nuc-associated adverse events, safety issues and resistance development, while PSI-7977 has so far demonstrated no evidence of RAV. Several phase 3 interferon-free trials for PSI-7977 have been announced, for example, FISSION and POSITRON, exploring the safety and efficacy of PSI-7977 plus ribavirin in genotypes 2/3, or NEUTRINO, planned for mid-2012 to enrol patients who cannot take interferon, independent of their HCV genotype (table 4).
Host-targeting agents
Cyclophilin A-binding molecules
The cyclophilin A-binding molecule alisporivir is among the most advanced and promising host-targeting agent (HTA), with a broad genotype coverage from 1 to 4 and potent anti-HCV activity. Alisporivir inhibits HCV replication by preventing a cyclophilin A-induced cis-trans isomerisation in domain II of NS5A. The selection of resistant HCV genotype 1b replicons against alisporivir was reported to be difficult, with an average of 20 weeks compared with less than 2 weeks in NS3/4A PI or NS5B inhibitors.63 A phase 2 trial demonstrated the superiority of alisporivir when administered once a day with peg-IFN/ribavirin in achieving SVR in genotype 1 CHC patients. The triple therapy showed 76% SVR compared with 55% in the peg-IFN/ribavirin control arm, and only 24 weeks treatment duration needed for SVR in patients with RVR.64 One case of SVR in a genotype 3 CHC patient was reported after alisporivir monotherapy for 29 days.65
MiR-122 targeting agents
MicroRNA are endogenous small non-coding RNA that regulate gene expression by interfering with the translation and stability of target transcripts. The liver-specific microRNA miR-122 is required for HCV RNA replication and is involved in the expression of over 100 cellular genes. Miravirsen (SPC3649) is a locked nucleic acid-modified oligonucleotide complementary targeting miR-122 seed sequences.66 The drug specifically recognises miR-122, which is subsequently sequestered and unavailable for HCV, leading to a long-lasting suppression of HCV viraemia without evidence of RAV or side effects in animal studies with chimpanzees66 and early clinical trials in humans. Miravirsen showed an extraordinarily high barrier to resistance with no evidence of RAV in any previous study.68
Entry inhibitors
Inhibition of viral entry is an attractive alternative to other drug targets; however, the complex mechanisms and various factors involved in this process are only partly understood. ITX-5061 is the first-in-class HCV entry inhibitor targeted against scavenger receptor type B1, which is in clinical development.
Interferon-sparing regimens and future perspectives
The availability of numerous drugs belonging to different classes stimulates multiple DAA and HTA combination trials. New agents need to maintain antiviral efficacy while simplifying therapy, but also need to improve response rates. An all-oral HCV therapy is an ambitious but achievable goal for future CHC treatment.68 To reach this goal, we need to address several important issues in future clinical trials. Naturally existing variants are of substantial relevance to the success of DAA-containing regimens,69 but may be of limited clinical significance at present as they are likely to be suppressed by the peg-IFN/ribavirin backbone. Therefore, peg-IFN/ribavirin needs to be replaced by another backbone with a low chance of resistance development. Furthermore, regimens should be applicable across all genotypes, while to date most DAA are restricted to genotype 1 HCV. Not least, many practical issues need to be improved for future generation antiviral agents, in particular drug–drug interactions, side effects and overlapping safety issues, dosing, as well as futility rules, which restrict their applicability at present. Keywords for future HCV regimens are thus easy to define but will be challenging to address—all-oral, pan-genotypic, simple, safe and tolerable (box 2).
Future perspectives in the treatment of CHC-infected patients
DAA/HTA with improved SVR rates and decreased duration of therapy.
Newer DAA with simplified dosing regimens and/or minimal toxicity.
Viral eradication in most if not all CHC patients who undergo treatment.
Peg-IFN/ribavirin replaced by another backbone with low chance of resistance development.
Regimens applicable across all HCV genotypes and subtypes.
References
Footnotes
Competing interests SZ has served as a consultant for Abbott, Achillion, Anadys, BMS, Boehringer, Gilead, iTherX, Janssen, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec and Vertex. IMJ has served as a consultant for Abbott, Achillion, Boehringer-Inghelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen/Tibotec, Merck, Novartis, Pfizer, Pharmasset, Roche/Genentech and Vertex, and as a speaker for Bristol-Myers Squibb, Gilead, Merck and Vertex. The remaining authors disclose no competing interests.
Provenance and peer review Commissioned; externally peer reviewed.
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