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Keywords:

  • boceprevir;
  • IL-28B;
  • interferon-λ;
  • pegylated interferon;
  • polymerase inhibitors;
  • protease inhibitors;
  • ribavirin;
  • telaprevir

Abstract

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Chronic hepatitis C is one of the leading causes of chronic liver disease, with approximately 170 million people infected worldwide. The severity of disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Sustained virological response (SVR) is long lasting, associated with a reduced risk of cirrhosis and HCC. In the near future, standard of care (SOC) treatment of hepatitis C virus (HCV) will include the addition of direct-acting antivirals (DAAs) with a protease inhibitor to the pegylated interferon (PEG-IFN) plus ribavirin (RBV). In HCV genotype 1 patients, promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC, increasing SVR rates from less than 50% (PEG-IFN plus RBV) to 70% (in patients treated with a triple combination of PEG-IFN, RBV plus a protease inhibitor). The future management of patients with these new molecules will require good clinical practice, knowledge of indications, prediction of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet, requiring studies in special populations (human immunodeficiency virus–HCV-coinfected patients, transplanted patients, etc.) in genotype non-1 patients and in absolute non-responders. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. There is ongoing development of new molecules such as HCV enzyme inhibitors. The aim of this review is to summarize the results obtained with DAAs: protease and polymerase inhibitors.


Abbreviations
DAAs,

direct-acting antivirals;

HCC,

hepatocellular carcinoma;

PEG-IFN,

pegylated interferon;

RBV,

ribavirin;

RVR,

rapid virological response;

SVR,

sustained virological response.

Viral cycle and drug targets

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide. HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome (1), a member of the Flaviviridae family, genus Hepacivirus. The HCV lifecycle begins with virion attachment to its specific receptor. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. Then viral assembly occurs. Potentially, each step of the viral cycle is a target for drug development (Fig. 1). All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication, and are therefore potential drug discovery targets. The knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors to these enzymes (Fig. 2A and B). Several findings suggest that HCV modulation of interferon (IFN) induction and signalling attenuates the expression of IFN-stimulated genes, allowing HCV to evade the antiviral actions of the host response (2).

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Figure 1.  Hepatitis C virus (HCV) viral cycle. Potentially, each step of the viral cycle is a target for drug development. The HCV lifecycle starts with virion attachment to its specific receptor (not clearly identified). The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. Then, viral assembly occurs.

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image

Figure 2.  (a) Hepatitis C virus (HCV) genome and potential drug discovery targets. The HCV, identified in 1989, is an enveloped Flavivirus with a 9.6 kb single-strand RNA genome. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication, and are therefore potential drug discovery targets. The knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors to these enzymes. (b) Protease and polymease inhibitors in development for the treatment of hepatitis C.

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Activation of the interferon pathway

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Type 1 IFNs are the major antiviral cytokines. HCV infection may induce host-signalling pathways leading to IFN secretion (3–5). Double-stranded RNA (dsRNA) viruses are known to induce IFN-signalling pathways; the dsRNA is recognized by cellular pattern recognition receptors such as toll-like receptor-3 (TLR3) and retinoic acid-inducible gene-I (RIG-I). Although HCV is a single-stranded RNA virus, its replication may produce some dsRNA because of its RNA-dependent RNA polymerase NS5B. This dsRNA may activate the IFN-signalling pathway (6). The activation of TLR3 after the binding of dsRNA activates a cascade of events. IFN stimulatory factor-3 (IRF3) is phosphorylated and transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) are activated. Phosphorylated IRF3 forms a dimer and translocates into the nucleus, where it binds to DNA to regulate the expression of IFN-β. Receptors such as RIG-I and melanoma differentiation-associated protein-5 (Mda5) recruit the IFN-β promoter stimulator 1 (IPS-1 or cardif) after the binding of dsRNA (3). IPS-1 plays an important role in the activation of IRF3, IRF7 and NF-κB. IRF-7 forms a dimer and translocates into the nucleus to induce IFN-α/β. IRF-3 dimers also collaborate with NF-kB to induce IFN-α/β. IFN-α/β binds to a receptor at the cell surface, inducing the activation of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT)-signalling pathway.

In collaboration with IRF-9 and IFN-stimulated gene factor-3 (ISGF3), Jak/STAT signalling induces the activation of IFN-stimulated response elements, activating the transcription of IFN-α/β-stimulated genes (5). This results in the production of proteins such as RNAse L and protein kinase R that will target the degradation of viral RNAs and block their translation (2, 7) (Fig. 3).

image

Figure 3.  Hepatitis C virus (HCV) and immune response. Activation of toll-like receptor 3 (TLR3) leads to the recruitment of IkB kinase (IKK)-related kinases, TANK-binding kinase 1 (TBK1) and IKKi. These kinases, together with adaptators TANK and NAP1, catalyse the phosphorylation of interferon (IFN) stimulatory factor-3 (IRF-3). Phosphorylated IRF-3 forms a dimer, translocates into the nucleus, binds to DNA in collaboration with transcription factor activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) and regulates the expression of IFN-β. The HCV NS3-4A serine protease may block the phosphorylation and effector action of IRF-3. After the recognition of viral RNA, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein-5 (Mda5) recruit IFN-β promoter stimulator-1 (IPS-1) via caspase recruitment domain (CARD–CARD) interaction. IPS-1 is localized in the mitochondria and acts as an adaptator that plays a critical role in the activation of IRF-3 and IRF-7. IPS-1 is targeted and inactivated by the serine protease NS3/4A from HCV. IRF-7 forms a dimmer and translocates into the nucleus to induce IFN-α/β. Endogenous IFN -α/β bind to a common receptor (IFNAR-1/2) expressed at the cell surface of target cells. Receptor engagement leads to the recruitment of Tyk2 and Jak1. Together with IRF-9, the two kinases induce the activation of signal transducers and activators of transcription (STAT)1 and STAT2, which, together with ISGF3G/IRF9, bind to cis-acting IFN-stimulated elements (ISREs), thereby activating the transcription of IFN-α/b-inducible genes such as PKR, IL-8, OAS. The HCV core protein has been shown to induce the expression of SOCS3 (suppressor of cytokine signalling 3), which can suppress Janus kinase (Jak)/STAT.

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Results of standard of care treatment: combined pegylated interferon and ribavirin

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

The main goal of treatment in chronic hepatitis C is the prevention of cirrhosis and hepatocellular carcinoma (HCC) by eradicating the virus. At present, therapy results in a SVR in approximately 55% of patients with hepatitis C (8–10). In patients with HCV genotype 2 or 3, sustained virological response (SVR) rates reach 80%; in genotype 1 patients, SVR rates reach less than 50% (8, 9).

It has been shown that some IFN-stimulated genes were highly expressed in non-responders; thus, pre-activation of the IFN system in patients appears to limit the effect of IFN antiviral therapy. Failure to respond to exogenous pegylated interferon (PEG-IFN) in non-responders could indicate a blunted response to IFN (11). Based on existing results, the SVR appears to be long lasting with this treatment option as well as associated with a reduction in the risk of cirrhosis and HCC (12).

Prediction of treatment response

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Independent groups have found single nucleotide polymorphisms (SNPs) near the interleukin (IL)-28B region associated with the treatment response, thus opening a window for personalized medicine (13, 14). All patients were from different ethnicities, were infected by genotype 1 and received PEG-IFN plus ribavirin (RBV). Ge et al. (13) analysed 1137 patients with HCV genotype 1 infection, and identified several SNPs near the IL-28B gene on chromosome 19 that were significantly more frequent in responders than that in non-responders.

A strong association was also reported between rs12979860 and both early virological response (EVR) and SVR in IFN-naïve patients treated with Peg-IFN-α2a/RBV (14). These results extend previous findings showing an association between EVR and SVR in patients treated with Peg-IFN-α2a monotherapy and conventional IFN/RBV. In addition, when all previously described SNPs were ranked, rs12979860 was found to drive the association with response to therapy. Finally, we performed a study showing the association between rs12979860 and early HCV decline in response to IFN treatment. Although all of the identified variants lie in or near the IL-28B gene, none of them has an obvious effect on the function of this gene (15).

New direct-acting antivirals

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

New drug therapies such as protease and polymerase inhibitors called new direct-acting antivirals (DAAs) are under development (16). In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the standard of care (SOC). The final results of the phase III study have shown that SVR rates are increased from less than 50% (PEG-IFN plus RBV) to 70% (in PEG-IFN plus RBV plus the protease inhibitor).

Telaprevir; Genotype 1, naïve patients, phases II and phases III

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

The protease inhibitor NS3/4A telaprevir is being developed by the companies Vertex (Cambridge, MA, USA) and Tibotec (Mechelen, Belgium). In a randomized, double-blind, placebo-controlled phase II Prove-1 (USA) and Prove-2 (Europe) trials, telaprevir is being administered for 12 weeks with PEG-IFN-α2a plus RBV (17, 18). Data from these trials show that the triple-therapy regimen increases the rate of rapid virological response (RVR) and SVR. The Prove-1 trial (17) included 250 treatment-naïve genotype 1 chronic hepatitis C patients in the US. Participants were randomly assigned to four regimens:

  • Telaprevir (750 mg 98 h) plus PEG-IFN-α2a plus RBV for 12 weeks (n=17).
  • The same regimen, followed by PEG-IFN/RBV without telaprevir for 12 weeks (n=79).
  • The same regimen, followed by PEG-IFN/RBV without telaprevir for 36 weeks (n=79).
  • Standard therapy with PEG-IFN/RBV for 48 weeks (n=75).

Patients in all telaprevir arms were significantly more likely to achieve an RVR, compared with the standard therapy control group (79 vs 11% respectively).

The SVR rate was substantially higher in the 24-week telaprevir arm compared with the 12-week telaprevir arm (61 vs 35% respectively). Among patients who achieved an RVR, the relapse rate was 33% in the 12-week telaprevir group compared with 2% in the 24-week telaprevir group. Adverse events leading to treatment discontinuation were more frequent in the telaprevir arms than that in the standard therapy group (13 vs 3% respectively). In the Prove-2 study (18), 323 chronic HCV genotype 1-infected treatment-naïve patients without cirrhosis were included. The patients were randomized to receive:

  • SOC: PEG-IFN-α2a plus RBV plus placebo for 48 weeks (n=82).
  • Telaprevir plus PEG-IFN for 12 weeks (n=78).
  • Telaprevir plus PEG-IFN plus RBV for 12 weeks (n=82).
  • The same regimen for 12 weeks, and then PEG-IFN/RBV for 12 weeks (n=81).

The SVR was 68% in the triple-therapy arm (telaprevir plus PEG-IFN plus RBV for 12 weeks, followed by PEG-IFN plus RBV for 12 weeks) and 48% in the SOC regimen.

In summary, the results of Prove-1 and Prove-2 demonstrate that RBV is essential to maximize SVR rates and reduce relapse in patients treated with telaprevir. Also, SVR rates as high as 65% may be possible in genotype 1 patients treated with a 12-week triple-therapy regimen, followed by a 12-week standard combination-therapy regimen. Telaprevir was associated with increased rates of certain adverse effects including rash, gastrointestinal events and anaemia. The rate of discontinuation for adverse events during the first 12 weeks of Prove-1 and Prove- 2 was two-fold to three-fold higher in recipients of telaprevir-based triple therapy than that with the SOC. The maculopapular rash has generated the most concern, but this event resolved upon treatment discontinuation in all patients.

Illuminate study (Fig. 4)

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Figure 4.  ILLUMINATE study: The Phase 3 open-label study, ILLUMINATE, evaluated genotype 1-naïve patients randomized to two durations of therapy (telaprevir plus pegylated interferon-α2a and ribavirin) among those who achieved an extended rapid viral response (eRVR) (19). Sustained virological response (SVR) was 92% among patients randomized to 24 weeks (n=162). SVR was 87.5% (Δ4.5%, two-sided 95% CI=−2.1 to +11.1%) among patients randomized to 48 weeks (n=160). Overall, SVR was 71.9% (intent-to-treat analysis). Among patients who achieved eRVR, a 24-week telaprevir-based regimen was non-inferior to a 48-week telaprevir-based regimen (92% SVR compared with 87.5%).

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This Phase 3 open-label study evaluated patients randomized to two durations of therapy among those who achieved an extended rapid viral response (eRVR) (19). Five hundred and forty HCV genotype 1 treatment-naïve patients were treated with telaprevir (12 weeks, 750 mg q8 h), PEG-IFN-α2a and RBV. Patients who achieved eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue receiving PEG-IFN-α2a and RBV for 24 or 48 weeks of the total treatment. Patients who did not achieve eRVR were assigned to 48 weeks of treatment. Seventy-two percentage (n=389) of patients achieved RVR; 65.2% (n=352) of patients achieved eRVR. Three hundred and twenty-two (59.6%) patients were randomized (1:1) to either a 24 or a 48-week arm. SVR was 92% among patients randomized to 24 weeks (n=162). SVR was 87.5% (Δ4.5%, two-sided 95% confidence interval=−2.1 to +11.1%) among patients randomized to 48 weeks (n=160). Overall, SVR was 71.9% [intent-to-treat (ITT) analysis]. Thirty-six patients (6.7%) discontinued treatment because of virological failure. Ninety-four patients (17.4%) had permanent discontinuation of all study drugs for adverse events. Fatigue (n=22) and anaemia (n=12) were the most common adverse events leading to discontinuation. Treatment discontinuation because of anaemia and rash was necessary in three (0.6%) and six (1.1%) patients, respectively, during the telaprevir treatment phase.

In conclusion, among patients who achieved eRVR, a 24-week telaprevir-based regimen was not inferior to the 48-week telaprevir-based regimen (92% SVR compared with 87.5%). Response-guided treatment led to 71.9% overall SVR and nearly two-thirds of patients were eligible for a shorter duration of treatment. Permanent discontinuation of all study drugs because of adverse events occurred in 17.4% of patients. These results support response-guided therapy for telaprevir-based regimens in treatment-naïve patients

Advance study (Fig. 5)

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Figure 5.  ADVANCE study is a three-arm double-blind, randomized, placebo-controlled Phase 3 study assessing the efficacy and safety of two telaprevir-based response-guided regimens compared with pegylated interferon-α2a (PEG-IFN-α2a) and ribavirin (RBV) in treatment-naïve patients with chronic genotype 1 HCV infection (20). A significantly greater proportion of patients achieved SVR with 12-week and 8-week telaprevir-based combination regimens (75 and 69% respectively) compared with PEG-IFN-α2a and the RBV 48-week control arm (44%, P<0.0001). RVR, rapid virological response; SVR, sustained virological response.

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This study is a three-arm double-blind, randomized, placebo-controlled Phase 3 study assessing the efficacy and safety of two telaprevir-based response-guided regimens compared with PEG-IFN-α2a and RBV in treatment-naïve patients with chronic genotype 1 HCV infection (20). Treatment arms were (a) telaprevir 750 mg q8 h in combination with PEG-IFN-α2a and RBV for 8 weeks, followed by additional weeks of SOC; (b) telaprevir 750 mg q8 h in combination with PEG-IFN-α2a and RBV for 12 weeks, followed by additional weeks of SOC; and (c) PEG-IFN-α2a and RBV for 48 weeks (control arm). Patients in the telaprevir arms achieving an eRVR (undetectable HCV RNA at weeks 4 and 12) received a total of 24 weeks of therapy while those who did not received a total of 48 weeks of therapy. A significantly greater proportion of patients achieved SVR with 12-week and 8-week telaprevir-based combination regimens (75 and 69% respectively) than that with PEG-IFN-α2a and RBV 48 weeks control arm (44%, P<0.0001). The most common (>25%) adverse events in the telaprevir arms were fatigue, pruritus, nausea, headache, anaemia, rash, influenza-like illness, insomnia, pyrexia and diarrhoea. Discontinuation of treatment because of adverse events occurred in 7 and 8% of patients in the telaprevir regimens and 4% in PEG-IFN-α-2a and RBV, because of rash in 0.5, 1.4 and 0.0% and because of anaemia in 3.3, 0.8 and 0.6% in the 8 weeks of telaprevir combined with PEG-IFN-α2a and RBV, 12 weeks of telaprevir with PEG-IFN-α2a and RBV and control arms respectively.

In conclusion, telaprevir-based therapy improved the SVR rates in genotype 1 treatment-naïve patients, including subgroups with an impaired response to PR. The benefit:risk profile was greater in the 12-week telaprevir-based regimen than that in than 8-week regimen. With response-guided therapy, most treatment-naïve patients were eligible for the 24-week treatment regimen, and attained high rates of SVR. Discontinuation of treatment because of rash was minimized by stopping medication sequentially.

Telaprevir; Genotype 1, experienced patients, phases II and phases III

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Prove III study

In HCV-genotype 1-infected patients in whom initial PEG-IFN-α and RBV treatment failed, retreatment with telaprevir in combination with PEG-IFN-α2a and RBV (approximately 50%) was more effective than retreatment with PEG-IFN-α2a and RBV alone (approximately 15%) (21). Telaprevir is now in phase III of clinical development.

Realize study (Fig. 6) is a Phase 3, randomized, double-blind, placebo-controlled study conducted in 662 genotype 1 chronic hepatitis C patients who did not achieve a viral cure after at least one prior treatment with IFN-based therapy (22). There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. Patients were randomized 2:2:1 to the two telaprevir arms and the control arm respectively. As in all Phase 3 studies of telaprevir, patients received no more than 12 weeks of telaprevir in combination with PEG-IFN and RBV. In REALIZE, the telaprevir arms included 12 weeks of telaprevir in combination with PEG-IFN and RBV with 36 weeks of PEG-IFN and RBV alone for a total of 48 weeks of treatment. One of the telaprevir treatment arms was designed to evaluate whether there was any further improvement in viral cure rates when delaying the start of telaprevir for 4 weeks when patients received 4 weeks of PEG-IFN and RBV alone, compared with a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the delayed telaprevir start treatment arm in any of the subgroups of patients. The overall SVR rates for the telaprevir simultaneous and delayed start arm were 64 and 66%, respectively, based on an ITT analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous, delayed start arm and control arm, respectively, were 83, 88 and 24% in relapsers (P<0.0001); 59, 54 and 15% in partial responders, (P<0.0001); and 29, 33 and 5% in null responders respectively (P<0.001).

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Figure 6.  REALIZE study was a Phase 3, randomized, double-blind, placebo-controlled study conducted in 662 genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one prior treatment with interferon-based therapy (22). There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. Sustained virological response (SVR) rates for the telaprevir simultaneous start arm and the delayed start arm were 64 and 66%, respectively, overall, based on an intent-to-treat analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83, 88 and 24% in relapsers (P<0.0001); 59, 54 and 15% in partial responders, (P<0.0001); and 29, 33 and 5% in null responders, (P<0.001).

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Boceprevir; Genotype 1, naïve patients, phases II and phases III

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Boceprevir (Schering Plough-MSD, Kenilworth, NJ, USA) is a specific inhibitor of the viral protease NS3/4A. Sprint-1 study is a phase 2 study in HCV genotype 1 patients evaluating boceprevir (800 mg TID) in three treatment regimens (23):

  • Four weeks of combination standard treatment (PEG-IFN-α2b plus RBV) (lead-in), followed by the addition of boceprevir to the combination for a total of 28 or 48 weeks;
  • Boceprevir in combination with PEG-IFN plus RBV for 28 or 48 weeks; and
  • Boceprevir in combination with PEG-IFN/low-dose RBV for 48 weeks, compared with PEG-IFN-α2b plus RBV for 48 weeks.

The results showed that boceprevir combined with SOC appears to be safe for use up to 48 weeks. This combination substantially improved the SVR rates with 28 weeks of therapy and nearly doubled the SVR compared with the current SOC (48 weeks) in this trial. The use of a 4-week lead-in with SOC before adding boceprevir appears to reduce the incidence of viral breakthrough. The most common adverse events reported in the boceprevir arms were fatigue, anaemia, nausea and headache.

Sprint-2 study (Fig. 7) is a phase 3 international double-blind randomized study including genotype 1-naïve patients (938 non-Black and 159 Black) that compared a 4-week lead-in treatment period with PEG-IFN-α2b/RBV, followed by (i) PEG-IFN-α2b/RBV R plus placebo for 44 weeks; (ii) response-guided therapy: boceprevir plus PEG-IFN-α2b/RBV for 24 weeks, with an additional 20 weeks of PEG-IFN-α2b/RBV only if detectable HCV RNA occurred during weeks 8–24; or (iii) boceprevir plus PEG-IFN-α2b/RBV for 44 weeks (24). The SVR in non-Black patients was 40% for 48 PEG-IFN-α2b/RBV and significantly higher (P<0.0001) in both the boceprevir arms. With response-guided therapy (67%) and a lead-in phase, followed by 44 weeks of boceprevir plus PEG-IFN-α2b/RBV (68%), the corresponding SVR in Black patients were 23, 42 (P=0.044) & 53% (P=0.004). In non-Black patients receiving ≥1 dose of boceprevir or placebo, the respective SVRs were 42, 70 and 71%. Anaemia was reported in 29% of controls vs 49% in the boceprevir arms, leading to a dose reduction in 13 and 21% and discontinuation in 1 and 2% respectively .

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Figure 7.  SPRINT-2 study is a phase 3 international double-blind randomized study including genotype 1-naïve patients (938 non-black & 159 black) and compared a 4-week lead-in treatment period with pegylated interferon (PEG-IFN)-α2b/ribavirin (RBV), followed by (i) PEG-IFN-α2b/RBV plus placebo for 44 weeks; (ii) response-guided therapy: boceprevir plus PEG-IFN-α2b/RBV for 24 weeks, with an additional 20 weeks of PEG-IFN-α2b/RBV only if detectable HCV RNA during weeks 8–24; or (iii) boceprevir plus PEG-IFN-α2b/RBV for 44 weeks (24). boceprevir plus PEG-IFN-α2b/RBV significantly increased sustained virological response (SVR) (approximately 70%) in both arms over standard of care. Compared with 44 weeks of triple therapy after the lead-in period, response-guided therapy with lead-in plus 24 boceprevir plus PEG-IFN-α2b/RBV±20 PEG-IFN-α2b/RBV produced comparable SVR.

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In conclusion, boceprevir plus PEG-IFN-α2b/RBV significantly increased SVR (approximately 70%) in both arms over SOC. Although anaemia occurred more often with boceprevir, it rarely led to treatment discontinuation. Compared with 44 weeks of triple therapy after the lead-in period, response-guided therapy with a lead-in plus 24 weeks of boceprevir plus PEG-IFN-α2b/RBV±20 PEG-IFN-α2b/RBV produced comparable SVR.

Respond 2 study (Fig. 8)

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Figure 8.  RESPOND 2 study: this phase III randomized trials demonstrated that combination therapy with boceprevir yields higher sustained SVR rates for patients with hepatitis C virus (HCV) genotype 1 who did not respond to or relapsed after treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) were reported (25). In this trial, three arms were randomly selected from 403 HCV genotype 1 patients who previously failed treatment–partial/non-responders or relapsers. At 24 weeks after the end of treatment, the control arm achieved an SVR of 21%. Adding boceprevir to the treatment increased SVR to 59% for the second arm and 67% for the third arm. It was noted that previous relapsers had better SVR than non-responders in all arms.

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The final results of this trial showed that combination therapy with boceprevir results in higher sustained SVR rates in patients with HCV genotype 1 who did not respond to or relapse after treatment with PEG-IFN and RBV (25). In this trial, three arms were randomly selected from 403 HCV genotype 1 patients who previously failed treatment–partial/non-responders or relapsers.

  • The control arm received PEG-IFN-α2b and RBV for 48 weeks.
  • The second arm received 4 weeks of lead-in therapy of PEG-IFN-α2b and RBV, followed by response-guided therapy of PEG-IFN-α2b and RBV combined with 800 mg of boceprevir three times a day.
  • The third arm received 4 weeks of lead-in therapy of PEG-IFN-α2b and RBV, followed by 44 weeks of PEG-IFN-α2b and RBV combined with 800 mg of boceprevir.

At 24 weeks after the end of treatment, the control arm achieved an SVR of 21 percent. Adding boceprevir to the treatment increased the SVR to 59% in the second arm and 67% in the third arm. It was found that previous relapsers had better SVR than non-responders in all arms.

There are many other molecules in development [Fig. 2B; (26–32)] for future use to obtain combinations of antivirals with additive potency, which lack cross resistance and with a good safety profile. Several protease inhibitors are in development.

Polymerase inhibitors

Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Two types of polymerase inhibitors have been developed (i) nucleoside analogues and (ii) non-nucleoside inhibitors. Nucleoside analogues act as chain terminators interfering with the initiation of RNA transcription and elongation. In contrast to nucleoside analogues, which target the active site of HCV polymerase, non-nucleoside inhibitors have been designed to bind to several discrete sites on the HCV polymerase. The resistance profiles of nucleoside analogues, non-nucleoside inhibitors and protease inhibitors are all distinct. Thus, agents from different classes may act in a complementary fashion to increase the efficacy of treatment and prevent the development of resistance.

interferon λ

PEG-IFN-λ (IL-29) is a novel IFN under development for hepatitis C. PEG-IFN-λ is a member of the Type III IFN-λ family, which includes IL-28A, IL-28B and IL-29 (also known as IFN-λ 2, 3, and 1 respectively). Type III IFNs signal through a different receptor than that of type I IFNs, such as IFN-α. The native human IFN-λ proteins are generated by the immune system in response to viral infection. A Phase 1b clinical trial was performed in patients with relapsed HCV, in which PEG-IFN-λ was administered for 4 weeks in combination with RBV (33).

The Phase 2b study will enroll approximately 600 patients with genotypes 1–4 chronic HCV infection (ZymoGenetics, Seattle, WA, USA and BMS). This study will assess the safety and antiviral efficacy of the three specified doses of PEG-IFN-λ compared with PEG-IFN-α2a. Each cohort of approximately 150 patients will include at least 100 genotype 1 patients. Weekly subcutaneous doses of PEG-IFN-λ or PEG-IFN-α2a will be administered for 48 weeks in HCV genotype 1 or 4 patients and for 24 weeks in genotype 2 or 3 patients. All patients will also receive daily RBV.

Perspectives: interferon-sparing regimen with direct-acting antiviral combination

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

The goals for a DAA combination should be to increase antiviral efficacy, to reduce resistance and to limit severe toxicity. A first study of combination DAAs in patients was the proof-of-concept INFORM-1 study (34). In this randomized, placebo-controlled double-blind trial, 87 patients with HCV genotype 1 infection were randomized to receive up to 13 days of either oral combination therapy with RG7227/danaprevir, an NS3/4A protease inhibitor, and RG7128, a nucleoside polymerase inhibitor, or with matched placebos. Both agents had already been administered to patients for 12 weeks in combination with PEG-IFN plus RBV. This combination achieved profound antiviral suppression that was greater than the additive effects of either treatment alone. The median reduction in HCV-RNA from baseline was 5 logs, which fell below the level of detection in 88% of the patients who received the highest dose of both danaprevir (900 mmg b.i.d.) and RG7128 (1000 mg b.i.d.). No evidence of resistance to either compound was observed during this study. No serious adverse event was reported. The antiviral efficacy was similar in naïve and treatment-experienced patients, including non-responders. Because the total duration of therapy was only 13 days, all patients rolled over into PEG-IFN and RBV treatment. The rates of RVR, early virological and end of treatment responses were markedly increased by the 2 weeks of pretreatment. In the final cohort of patients who received the highest dose of RG7227 and RG7128, 100% achieved ETR after 24 weeks PEG-IFN and RBV treatment. The final SVR results will certainly be interesting.

At present, several studies of combination DAAs are ongoing in patients with treatment-naïve HCV infection. All studies include an NS3/4A protease inhibitor, combined with an agent targeting the HCV polymerase complex – either a non-nucleoside NS5B, nucleoside NS5B or NS5A inhibitor.

The following combinations are under development in phase 2a clinical studies:

  • GS9256 (NS3/4A inhibitor) and GS9190 (non-nucleoside polymerase inhibitor)(Gilead, Foster City, CA, USA) (26)
  • BI201335 (NS3/4A inhibitor) and BI297127 (non-nucleoside polymerase inhibitor) (Boehringer, Ridgefield, CT, USA) (27)
  • BMS-650032 (NS3/4A inhibitor) and BMS-790052 (NS5a inhibitor) (BMS) (28)
  • Telaprevir (NS3/4A inhibitor) with VX-222 (non-nucleoside polymerase inhibitor)(Vertex)
  • RG7227 (NS3/4A inhibitor)/ritonovir and RG7128 (nucleoside polymerase inhibitor) (Roche)
  • ABT-450 (NS3/4A inhibitor)/ritonovir and ABT-072 (non-nucleoside polymerase inhibitor) (Abbott)
  • IDX320 (NS3/4A inhibitor) and IDX184 (nucleoside polymerase inhibitor) (Idenix)

Conclusion

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

The final results of phase III studies are available for two protease inhibitors (telaprevir and boceprevir). The near future SOC will include triple therapy with the protease inhibitor, PEG-IFN and RBV in genotype 1 patients. Also, telaprevir appears effective given either with PEG-IFNα2a or 2b (35). Adding a protease inhibitor to PEG-IFN and RBV increases the SVR rates from less than 50% to 70% in patients with genotype I. Once several DAA become available, treatment strategies will include a combination of several drugs with different mechanisms of action (protease inhibitors plus polymerase inhibitors) that could hopefully result in IFN- and/or RBV-sparing regimens. In the future, combinations of antivirals with additive potency that lack cross resistance and with good safety profiles may become available.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References

Tarik Asselah is a speaker for Roche, Schering Plough/MERCK, BMS and Gilead. Patrick Marcellin is an investigator, speaker and expert for Roche, Schering Plough, Gilead, BMS, Novartis, Tibotec and Intermune. He receives a grant from Roche, Schering Plough and Gilead. He is an investigator and expert for Vertex, MSD, and Biolex; an expert for Pharmasset and Zymogenetics; and an investigator for Boehringer.

Neither author received a salary, regular remuneration or royalties from any drug company or owns any stock options.

References

  1. Top of page
  2. Abstract
  3. Viral cycle and drug targets
  4. Activation of the interferon pathway
  5. Results of standard of care treatment: combined pegylated interferon and ribavirin
  6. Prediction of treatment response
  7. New direct-acting antivirals
  8. Telaprevir; Genotype 1, naïve patients, phases II and phases III
  9. Telaprevir; Genotype 1, experienced patients, phases II and phases III
  10. Boceprevir; Genotype 1, naïve patients, phases II and phases III
  11. Perspectives: interferon-sparing regimen with direct-acting antiviral combination
  12. Conclusion
  13. Acknowledgements
  14. Conflicts of interest
  15. References
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