Accepted Article
Received Date : 05-Mar-2014 Accepted Date : 16-Mar-2014 Article type
: Editorials
Second wave Anti-HCV Protease Inhibitors: Too little too late?
Stella De Nicola and Alessio Aghemo* Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Italy. Università degli Studi di Milano, Milano, Italy
Corresponding Author Alessio Aghemo, MD, PhD Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano Università degli Studi di Milano
Email address: [email protected]
Disclosures Alessio Aghemo Speaker Bureau: Gilead Sciences, Janssen, Merck, Janssen Therapeutics Advisory Board: AbbVie, Jannsen Therapeutics, Gilead Sciences, Janssen This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12543 This article is protected by copyright. All rights reserved.
Drug development for chronic hepatitis C is progressing at a furious rate; after more than 10 years
Accepted Article
spent at optimizing Pegylated Interferon and Ribavirin regimens, the ability to design drugs targeting key steps of the HCV life cycle has allowed the development of several directly acting antivirals (DAA). The NS3/4A Protease inhibitors Telaprevir and Boceprevir, have been a major breakthrough for patients and clinicians as they finally allowed patients with HCV genotype 1 to achieve high SVR rates, that top the 80% mark in some highly responsive subgroups (1-4). Unfortunately, both drugs did not solve all our problems due to a significant pill burden, clinically relevant drug-drug interactions and most importantly the fact that their efficacy is heavily relying on the activity of the PegIFN/Rbv backbone. This meaning that patients contraindicated to PegIFN/Rbv are still without any effective treatment option, treatment in patients with cirrhosis is less effective than ideal and safety of these regimens is poor in patients with borderline compensated cirrhosis.
Second wave protease inhibitors have either been licensed already (Simeprevir in North America) or are in advanced development study phases (Faldaprevir, Danoprevir and Vaniprevir). These drugs offer several benefits over TVR and BOC, especially in terms of side effect profile and pill burden. Simeprevir is a once-a day oral NS3/4A protease inhibitor with a potent antiviral efficacy on HCV genotypes 1 and 4 in combination with PR. Phase II and III trials in HCV 1 naive patients showed SVR rates ranging from 68% to 76% with this triple therapy regimen, with roughly 80% of subjects eligible to receive the short treatment duration of 24 weeks of therapy. In treatment experienced patients the SVR rates were dependent on the individual IFN sensitivity, with 85% of previous relapsers, 75% of partial responders and 51% of prior non responders reaching an SVR (57).
In this issue of Liver International, Everson et al report the results from the DAUPHINE study: a randomised Phase IIb trial of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alfa2a/ribavirin (P/R) in treatment-naive patients with HCV genotype 1 or 4 infection (8). Danoprevir/r is a twice-a-day second wave protease inhibitor with antiviral activity against genotype 1, 4 and 6; it is boosted with ritonavir, which leads to strong inhibition of CYP3A activity and increase the PI serum levels. Ritonavir boosting was developed as previous studies reported hepatotoxicity due to reactive metabolites at higher non boosted doses of Danoprevir. Ritonavir is an inhibitor of the This article is protected by copyright. All rights reserved.
human immunodeficiency virus (HIV)-1 protease. It is a dose- and time-dependent
Accepted Article
inhibitor/inducer of CYP3A and an inhibitor of P-glycoprotein (P-gp) and is widely used at low, subtherapeutic doses (i.e. 100–400 mg/day) to enhance or ‘boost’ the exposures of other HIV protease inhibitors that are extensively metabolised by the CYP3A isoenzyme (9). Danoprevir is primarily metabolised by CYP3A and is a substrate of the P-gp transporter. The current development strategy utilizes the combination of danoprevir with low-dose (100 mg) ritonavir to maximize safety, efficacy and convenience by optimizing danoprevir pharmacokinetics (10).
The DAUPHINE trial was designed to evaluate three different dosage of Danoprevir/r: 50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, assumed twice a day for 24 weeks. A study arm also explored danoprevir/r 100/100 mg, in a Response-guided therapy (RGT) algorithm, in which patients reaching an RVR received a total of 12 weeks of treatment. Treatment safety and efficacy was compared with a placebo receiving group, the PR arm. Overall the authors observed better SVR rates in higher dosage arms compared to lower dosage arms and the control PR group. SVR rates decreased with decreasing dosage of Danoprevir/r as follows: 89.1%, 78.5% and 69.1%. In the RGT arm overall the SVR rate was 66%, 71.4% in patients with an eRVR2 and 65.8% in patients without an eRVR2. This result, was the consequence of higher relapse rates in the RGT arm compared with the other active arms (25% vs 1.2%, 8.4% and 18%) and the placebo group
(20%). HCV genotype 1a emerged as a predictor of treatment failure with SVR rates generally 10 to 15% lower than in HCV-1b. The reason being the lower genetic barrier to resistance of HCV-1a to Danoprevir resistant mutations. Interleukin 28B genotype was associated with treatment outcome as HCV- 1b naïve infected patients carrying the treatment favorable IL28B CC genotype achieved a 96.6% SVR rates in the highest dosage arm. The role of IL28B CC genotype is relevant also in the RGT arm, where CC patients achieved SVR in 92% of cases. Interestingly the Danoprevir/r based regimen reached high SVR rates in HCV-4 patients, a category of patients in whom first generation protease inhibitors are not effective, with 87 to 100% of these patients reaching an SVR, independently from IL28B status. Danoprevir/r showed an acceptable safety profile especially when compared with first generation PIs. Diarrhea was the only adverse event observed with a higher incidence in active medication arms when compared with placebo arm. The incidence of discontinuation ranged from 2% to 6% across all arms.
This article is protected by copyright. All rights reserved.
The conclusions that we can draw from the DAUPHINE study is that Danoprevir/r, similarly to
Accepted Article
other second wave PIs, is clearly an improvement compared to first generatrion PIs, but unfortunately still has many of the same limitations (low genetic barrier to resistance for HCV-1a and efficacy largely based on sensibility to PegIFN) that hampered Telaprevir/Boceprevir. In an era where progress is moving extremely fast and where compelling Phase II and III data have been presented on the efficacy of IFN free regimens even in hard to cure groups of patients, the innovation carried by a PegIFN/RBV plus second wave PI regimen is hard to foresee (11). Indeed we can envision two scenarios for the future of these compounds: either they could be part of a combination of DAAs in an IFN free combination or they could be chosen based on cost/efficacy ratio in countries where access to IFN free regimens will probably be limited by national healthcare resources. The first option has been already proven to be effective in a small pilot study of Simeprevir plus Sofosbuvir, a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and high genetic barrier to resistance (12). In the Cosmos study, a 12 or 24 week course of this regimen with or without Ribavrin was able to achieve 93-100% SVR rates in HCV-1 patients, independently from Fibrosis staging and previous treatment status (13). Faldaprevir was also used as part of an IFN free regimen in combination with Deleobuvir, an NS5B non nucleoside polymerase inhibitor, in HCV-1b patients (14). Although the final results of the phase III study are not yet published, an unexpected rate of treatment discontinuations due to Deleobuvir related side effects have led to the premature interruption of the development of this combination. Although Danoprevir in combination with the NS5B nucleoside polymerase inhibitor Mericitabine provided the first proof of concept evidence that an IFN free regimen was able to obtain HCV RNA undetectability, to our knowledge this regimen has been disappointing in terms of SVR rates in clinical studies and is not being pushed forward for future developments.
Using 2nd wave PIs containing PegIFN/Rbv regimens for cost/efficacy reasons is another option
that is likely to be considered in many countries with a social healthcare system. Given the efficacy of these regimens in some subgroups of patients and the possibility to effectively treat patients with HCV-4 too, this might seem like a reasonable approach to treat patients with low priority to more expensive IFN free regimens. However this approach raises the question on whether we as clinicians should aim at granting access to IFN free regimens to the largest number of patients possible, rather than using slightly less effective and more toxic IFN containing regimens for some
This article is protected by copyright. All rights reserved.
of them. This clearly is a hot topic that cannot be solved by the single clinician, but rather requires
Accepted Article
a co-operative effort from scientific societies, stakeholders, patients associations and pharmacompanies to ensure treatment equality based on needs rather than economics.
References: 1) Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16. 2) Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417–28. 3) Poordad F, McCone J Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195–206. 4) Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17 5) Aghemo A, Degasperi E, Colombo M Directly acting antivirals for the treatment of chronic hepatitis C: unresolved topics from registration trials. Dig Liver Dis. 2013 Jan;45(1):1-7 6) Asselah T, Marcellin P. Second-wave IFN-based triple therapy for HCV genotype 1 infection: simeprevir, faldaprevir and sofosbuvir. Liver Int. 2014 Feb;34 Suppl 1:60-8. doi: 10.1111/liv.12424 7) Clark VC, Peter JA, Nelson DR. New therapeutic strategies in HCV: second-generation protease inhibitors Liver Int. 2013 Feb;33 Suppl 1:80-4 8) Everson G, Cooper C, Hézode C, et al. DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4. Liver Int. 2014 Jan 19. doi: 10.1111/liv.12471 9) Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008 42(7):1048–1059 10) Reddy MB, Chen Y, Haznedar JO, et al. Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study. Clin Pharmacokinet 2012 51(7):457–465 11) Aghemo A and De Francesco R. New horizons in hepatitis C antiviral therapy with directacting antivirals. Hepatology 2013 Jul;58(1):428-38.
This article is protected by copyright. All rights reserved.
Accepted Article
12) Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of Viral Load through 4 Weeks Post- Treatment Results of a Once-daily Regimen of Simeprevir +Sofosbuvir with or without Ribavirin in Hepatitis C Virus GT 1 Null Responders. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3–6, 2013. Abstract 155LB. 13) Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and Deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369: 630–9. 14) Gane EJ, Roberts SK, Stedman CA, et al Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010 Oct 30;376(9751):1467-7
This article is protected by copyright. All rights reserved.
Received Date : 05-Mar-2014 Accepted Date : 16-Mar-2014 Article type
: Editorials
Second wave Anti-HCV Protease Inhibitors: Too little too late?
Stella De Nicola and Alessio Aghemo* Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Italy. Università degli Studi di Milano, Milano, Italy
Corresponding Author Alessio Aghemo, MD, PhD Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano Università degli Studi di Milano
Email address: [email protected]
Disclosures Alessio Aghemo Speaker Bureau: Gilead Sciences, Janssen, Merck, Janssen Therapeutics Advisory Board: AbbVie, Jannsen Therapeutics, Gilead Sciences, Janssen This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12543 This article is protected by copyright. All rights reserved.
Drug development for chronic hepatitis C is progressing at a furious rate; after more than 10 years
Accepted Article
spent at optimizing Pegylated Interferon and Ribavirin regimens, the ability to design drugs targeting key steps of the HCV life cycle has allowed the development of several directly acting antivirals (DAA). The NS3/4A Protease inhibitors Telaprevir and Boceprevir, have been a major breakthrough for patients and clinicians as they finally allowed patients with HCV genotype 1 to achieve high SVR rates, that top the 80% mark in some highly responsive subgroups (1-4). Unfortunately, both drugs did not solve all our problems due to a significant pill burden, clinically relevant drug-drug interactions and most importantly the fact that their efficacy is heavily relying on the activity of the PegIFN/Rbv backbone. This meaning that patients contraindicated to PegIFN/Rbv are still without any effective treatment option, treatment in patients with cirrhosis is less effective than ideal and safety of these regimens is poor in patients with borderline compensated cirrhosis.
Second wave protease inhibitors have either been licensed already (Simeprevir in North America) or are in advanced development study phases (Faldaprevir, Danoprevir and Vaniprevir). These drugs offer several benefits over TVR and BOC, especially in terms of side effect profile and pill burden. Simeprevir is a once-a day oral NS3/4A protease inhibitor with a potent antiviral efficacy on HCV genotypes 1 and 4 in combination with PR. Phase II and III trials in HCV 1 naive patients showed SVR rates ranging from 68% to 76% with this triple therapy regimen, with roughly 80% of subjects eligible to receive the short treatment duration of 24 weeks of therapy. In treatment experienced patients the SVR rates were dependent on the individual IFN sensitivity, with 85% of previous relapsers, 75% of partial responders and 51% of prior non responders reaching an SVR (57).
In this issue of Liver International, Everson et al report the results from the DAUPHINE study: a randomised Phase IIb trial of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alfa2a/ribavirin (P/R) in treatment-naive patients with HCV genotype 1 or 4 infection (8). Danoprevir/r is a twice-a-day second wave protease inhibitor with antiviral activity against genotype 1, 4 and 6; it is boosted with ritonavir, which leads to strong inhibition of CYP3A activity and increase the PI serum levels. Ritonavir boosting was developed as previous studies reported hepatotoxicity due to reactive metabolites at higher non boosted doses of Danoprevir. Ritonavir is an inhibitor of the This article is protected by copyright. All rights reserved.
human immunodeficiency virus (HIV)-1 protease. It is a dose- and time-dependent
Accepted Article
inhibitor/inducer of CYP3A and an inhibitor of P-glycoprotein (P-gp) and is widely used at low, subtherapeutic doses (i.e. 100–400 mg/day) to enhance or ‘boost’ the exposures of other HIV protease inhibitors that are extensively metabolised by the CYP3A isoenzyme (9). Danoprevir is primarily metabolised by CYP3A and is a substrate of the P-gp transporter. The current development strategy utilizes the combination of danoprevir with low-dose (100 mg) ritonavir to maximize safety, efficacy and convenience by optimizing danoprevir pharmacokinetics (10).
The DAUPHINE trial was designed to evaluate three different dosage of Danoprevir/r: 50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, assumed twice a day for 24 weeks. A study arm also explored danoprevir/r 100/100 mg, in a Response-guided therapy (RGT) algorithm, in which patients reaching an RVR received a total of 12 weeks of treatment. Treatment safety and efficacy was compared with a placebo receiving group, the PR arm. Overall the authors observed better SVR rates in higher dosage arms compared to lower dosage arms and the control PR group. SVR rates decreased with decreasing dosage of Danoprevir/r as follows: 89.1%, 78.5% and 69.1%. In the RGT arm overall the SVR rate was 66%, 71.4% in patients with an eRVR2 and 65.8% in patients without an eRVR2. This result, was the consequence of higher relapse rates in the RGT arm compared with the other active arms (25% vs 1.2%, 8.4% and 18%) and the placebo group
(20%). HCV genotype 1a emerged as a predictor of treatment failure with SVR rates generally 10 to 15% lower than in HCV-1b. The reason being the lower genetic barrier to resistance of HCV-1a to Danoprevir resistant mutations. Interleukin 28B genotype was associated with treatment outcome as HCV- 1b naïve infected patients carrying the treatment favorable IL28B CC genotype achieved a 96.6% SVR rates in the highest dosage arm. The role of IL28B CC genotype is relevant also in the RGT arm, where CC patients achieved SVR in 92% of cases. Interestingly the Danoprevir/r based regimen reached high SVR rates in HCV-4 patients, a category of patients in whom first generation protease inhibitors are not effective, with 87 to 100% of these patients reaching an SVR, independently from IL28B status. Danoprevir/r showed an acceptable safety profile especially when compared with first generation PIs. Diarrhea was the only adverse event observed with a higher incidence in active medication arms when compared with placebo arm. The incidence of discontinuation ranged from 2% to 6% across all arms.
This article is protected by copyright. All rights reserved.
The conclusions that we can draw from the DAUPHINE study is that Danoprevir/r, similarly to
Accepted Article
other second wave PIs, is clearly an improvement compared to first generatrion PIs, but unfortunately still has many of the same limitations (low genetic barrier to resistance for HCV-1a and efficacy largely based on sensibility to PegIFN) that hampered Telaprevir/Boceprevir. In an era where progress is moving extremely fast and where compelling Phase II and III data have been presented on the efficacy of IFN free regimens even in hard to cure groups of patients, the innovation carried by a PegIFN/RBV plus second wave PI regimen is hard to foresee (11). Indeed we can envision two scenarios for the future of these compounds: either they could be part of a combination of DAAs in an IFN free combination or they could be chosen based on cost/efficacy ratio in countries where access to IFN free regimens will probably be limited by national healthcare resources. The first option has been already proven to be effective in a small pilot study of Simeprevir plus Sofosbuvir, a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and high genetic barrier to resistance (12). In the Cosmos study, a 12 or 24 week course of this regimen with or without Ribavrin was able to achieve 93-100% SVR rates in HCV-1 patients, independently from Fibrosis staging and previous treatment status (13). Faldaprevir was also used as part of an IFN free regimen in combination with Deleobuvir, an NS5B non nucleoside polymerase inhibitor, in HCV-1b patients (14). Although the final results of the phase III study are not yet published, an unexpected rate of treatment discontinuations due to Deleobuvir related side effects have led to the premature interruption of the development of this combination. Although Danoprevir in combination with the NS5B nucleoside polymerase inhibitor Mericitabine provided the first proof of concept evidence that an IFN free regimen was able to obtain HCV RNA undetectability, to our knowledge this regimen has been disappointing in terms of SVR rates in clinical studies and is not being pushed forward for future developments.
Using 2nd wave PIs containing PegIFN/Rbv regimens for cost/efficacy reasons is another option
that is likely to be considered in many countries with a social healthcare system. Given the efficacy of these regimens in some subgroups of patients and the possibility to effectively treat patients with HCV-4 too, this might seem like a reasonable approach to treat patients with low priority to more expensive IFN free regimens. However this approach raises the question on whether we as clinicians should aim at granting access to IFN free regimens to the largest number of patients possible, rather than using slightly less effective and more toxic IFN containing regimens for some
This article is protected by copyright. All rights reserved.
of them. This clearly is a hot topic that cannot be solved by the single clinician, but rather requires
Accepted Article
a co-operative effort from scientific societies, stakeholders, patients associations and pharmacompanies to ensure treatment equality based on needs rather than economics.
References: 1) Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16. 2) Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417–28. 3) Poordad F, McCone J Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195–206. 4) Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17 5) Aghemo A, Degasperi E, Colombo M Directly acting antivirals for the treatment of chronic hepatitis C: unresolved topics from registration trials. Dig Liver Dis. 2013 Jan;45(1):1-7 6) Asselah T, Marcellin P. Second-wave IFN-based triple therapy for HCV genotype 1 infection: simeprevir, faldaprevir and sofosbuvir. Liver Int. 2014 Feb;34 Suppl 1:60-8. doi: 10.1111/liv.12424 7) Clark VC, Peter JA, Nelson DR. New therapeutic strategies in HCV: second-generation protease inhibitors Liver Int. 2013 Feb;33 Suppl 1:80-4 8) Everson G, Cooper C, Hézode C, et al. DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4. Liver Int. 2014 Jan 19. doi: 10.1111/liv.12471 9) Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008 42(7):1048–1059 10) Reddy MB, Chen Y, Haznedar JO, et al. Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study. Clin Pharmacokinet 2012 51(7):457–465 11) Aghemo A and De Francesco R. New horizons in hepatitis C antiviral therapy with directacting antivirals. Hepatology 2013 Jul;58(1):428-38.
This article is protected by copyright. All rights reserved.
Accepted Article
12) Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of Viral Load through 4 Weeks Post- Treatment Results of a Once-daily Regimen of Simeprevir +Sofosbuvir with or without Ribavirin in Hepatitis C Virus GT 1 Null Responders. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3–6, 2013. Abstract 155LB. 13) Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and Deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369: 630–9. 14) Gane EJ, Roberts SK, Stedman CA, et al Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010 Oct 30;376(9751):1467-7
This article is protected by copyright. All rights reserved.
