Article first published online: 10 JAN 2012
DOI: 10.1111/j.1365-2893.2011.01526.x
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Keywords:
boceprevir;
direct antiviral agents against hepatitis C;
NS3/4A protease inhibitors;
NS5B polymerase inhibitors;
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Special Issue: How to Optimize Treatment of Hepatitis C
Keywords:
boceprevir;
direct antiviral agents against hepatitis C;
NS3/4A protease inhibitors;
NS5B polymerase inhibitors;
telaprevir
Abstract
Summary. About half of the patients with chronic hepatitis C are still not cured by treatment with the current standard of care, peginterferon ![[alpha]](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_vKG2ARtITXE0MrUXPx-PUkay9RE0d00IC6dEQSexO_4CEik-19x4-oQfLmjbwnaAZMIWpjPi5QRz8I0XSPpYaEKjrVDW_PL3dHZx7cnUCYRgWZCz2DaOMIvoFe-Q7V7eCec9Y6OMAUltnh=s0-d)
/ribavirin. Direct antiviral drugs may overcome the limitations of standard antiviral therapy. The most promising new agents are inhibitors of the NS3/4A protease, the NS5B polymerase and the NS5A protein. Several compounds against these targets have entered clinical evaluation. Early clinical trials have emphasized the high potential for selecting resistant Hepatitis C virus variants. Furthermore, development of several new direct antivirals was stopped because of concerns over tolerability and safety. Then, in 2010, two phase III trials with the NS3/4A protease inhibitors boceprevir (SPRINT-2) and telaprevir (ADVANCE) showed that the combination of these compounds with standard care increases sustained virologic response rates in treatment-naïve genotype 1 patients from 38–44% to 66–75%. Future goals of therapy with direct antiviral agents are to improve tolerability, shorten the duration of therapy and overcome the issue of resistance. Several studies have been initiated that combine different novel therapies, with and without interferon /ribavirin.
/ribavirin. Direct antiviral drugs may overcome the limitations of standard antiviral therapy. The most promising new agents are inhibitors of the NS3/4A protease, the NS5B polymerase and the NS5A protein. Several compounds against these targets have entered clinical evaluation. Early clinical trials have emphasized the high potential for selecting resistant Hepatitis C virus variants. Furthermore, development of several new direct antivirals was stopped because of concerns over tolerability and safety. Then, in 2010, two phase III trials with the NS3/4A protease inhibitors boceprevir (SPRINT-2) and telaprevir (ADVANCE) showed that the combination of these compounds with standard care increases sustained virologic response rates in treatment-naïve genotype 1 patients from 38–44% to 66–75%. Future goals of therapy with direct antiviral agents are to improve tolerability, shorten the duration of therapy and overcome the issue of resistance. Several studies have been initiated that combine different novel therapies, with and without interferon /ribavirin. Introduction
Despite numerous attempts to optimize peginterferon /ribavirin therapy, more than half of all patients with chronic Hepatitis C virus (HCV) genotype 1 cannot be cured with this treatment. The limitations of antiviral therapy with peginterferon /ribavirin may be overcome by direct antiviral agents (DAA), which specifically target hepatitis C viral proteins.
/ribavirin therapy, more than half of all patients with chronic Hepatitis C virus (HCV) genotype 1 cannot be cured with this treatment. The limitations of antiviral therapy with peginterferon /ribavirin may be overcome by direct antiviral agents (DAA), which specifically target hepatitis C viral proteins.Among all approaches for direct antiviral treatment of patients with chronic hepatitis C, two NS3/4A protease inhibitors have progressed into phase III development (telaprevir and boceprevir). Both compounds show a good safety profile and high antiviral efficacy. Assuming approval by regulatory agencies these drugs, in combination with peginterferon and ribavirin, will become the new standard treatment for patients with HCV genotype 1 infections.
and ribavirin, will become the new standard treatment for patients with HCV genotype 1 infections. Phase III Trials with Protease Inhibitors
Telaprevir
Treatment-naïve patients
The ADVANCE trial is a randomized placebo-controlled phase III study to investigate the efficacy and safety of telaprevir in combination with peginterferon -2a and ribavirin [1,2]. Treatment-naïve HCV genotype 1–infected patients (n = 1095) were randomized into two telaprevir arms and one control arm. Telaprevir was administered for either 8 or 12 weeks in combination with peginterferon -2a/ribavirin for 24 weeks. Patients without extended rapid virologic response (eRVR; undetectable HCV RNA at week 4 and 12) continued peginterferon -2a/ribavirin up to week 48. Patients in the control arm received peginterferon -2a/ribavirin for 48 weeks.
-2a and ribavirin [1,2]. Treatment-naïve HCV genotype 1–infected patients (n = 1095) were randomized into two telaprevir arms and one control arm. Telaprevir was administered for either 8 or 12 weeks in combination with peginterferon -2a/ribavirin for 24 weeks. Patients without extended rapid virologic response (eRVR; undetectable HCV RNA at week 4 and 12) continued peginterferon -2a/ribavirin up to week 48. Patients in the control arm received peginterferon -2a/ribavirin for 48 weeks. The sustained virologic response (SVR) rates in both telaprevir arms were superior to standard therapy, with the highest rate achieved in the 12-week telaprevir arm (75%) compared to 69% in the 8-week telaprevir arm and 44% in the peginterferon -2a/ribavirin arm [1,2].
-2a/ribavirin arm [1,2]. The ILLUMINATE trial was supplementary to ADVANCE and had the aim of investigating the effect of treatment duration on SVR rates [3]. In this trial, treatment-naïve patients with HCV genotype 1 were treated with telaprevir, peginterferon -2a and ribavirin. Patients who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue receiving peginterferon -2a/ribavirin for a total of 24 or 48 weeks of treatment. Patients not achieving an eRVR were assigned to 48 weeks of treatment. The overall SVR rate after response-guided therapy was 71.9%. Among patients who achieved an eRVR, a 24-week telaprevir-based therapy was noninferior to 48-week telaprevir-based treatment (92% SVR compared to 87.5%). The study supports response-guided therapy for telaprevir-based treatment regimens.
-2a and ribavirin. Patients who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue receiving peginterferon -2a/ribavirin for a total of 24 or 48 weeks of treatment. Patients not achieving an eRVR were assigned to 48 weeks of treatment. The overall SVR rate after response-guided therapy was 71.9%. Among patients who achieved an eRVR, a 24-week telaprevir-based therapy was noninferior to 48-week telaprevir-based treatment (92% SVR compared to 87.5%). The study supports response-guided therapy for telaprevir-based treatment regimens.Retreatment of nonresponders to SOC therapy
The REALIZE trial evaluated telaprevir-based triple therapy in patients with prior treatment failure to SOC [4]. Telaprevir was administered for 12 weeks, while pegylated interferon -2a/ribavirin combination therapy was given for 48 weeks. Telaprevir was either started simultaneously with peginterferon -2a/ribavirin or delayed until after a 4-week lead-in (LI) phase with peginterferon -2a/ribavirin. Overall, SVR rates following telaprevir-based retreatment in the simultaneous and delayed arm were superior to retreatment with standard therapy (64% and 66% vs 17%). The highest SVR rates were observed in patients with prior relapse after standard therapy (simultaneous/delayed/control: 83/88/24%), followed by partial responders (59/54/15%) and finally by nonresponders (29/33/5%).
-2a/ribavirin combination therapy was given for 48 weeks. Telaprevir was either started simultaneously with peginterferon -2a/ribavirin or delayed until after a 4-week lead-in (LI) phase with peginterferon -2a/ribavirin. Overall, SVR rates following telaprevir-based retreatment in the simultaneous and delayed arm were superior to retreatment with standard therapy (64% and 66% vs 17%). The highest SVR rates were observed in patients with prior relapse after standard therapy (simultaneous/delayed/control: 83/88/24%), followed by partial responders (59/54/15%) and finally by nonresponders (29/33/5%).Boceprevir
Treatment-naïve patients
SPRINT-2 is a randomized placebo-controlled phase III study to investigate the efficacy and safety of boceprevir in combination with peginterferon -2b and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection [5,6].
-2b and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection [5,6]. The study compared a 4-week lead-in (LI) treatment period with peginterferon -2b/ribavirin (PR), followed by (i) response-guided therapy: boceprevir plus peginterferon -2b/ribavirin (BPR) for 24 weeks with an additional 20 weeks of PR only if HCV RNA was detectable during weeks 8–24 (LI + 24 BPR ± 20 PR) or (ii) Boceprevir plus PR for 44 weeks (LI + 44 BPR) or (iii) PR plus placebo for 44 weeks (48 PR).
-2b/ribavirin (PR), followed by (i) response-guided therapy: boceprevir plus peginterferon -2b/ribavirin (BPR) for 24 weeks with an additional 20 weeks of PR only if HCV RNA was detectable during weeks 8–24 (LI + 24 BPR ± 20 PR) or (ii) Boceprevir plus PR for 44 weeks (LI + 44 BPR) or (iii) PR plus placebo for 44 weeks (48 PR). In the HCV SPRINT-2 study, 1097 treatment-naïve patients were enrolled. The overall SVR rates were superior in the boceprevir arms (66% for LI + 44 BPR and 63% for LI + 24 BPR ± 20 PR), compared with the control arm (38%, 48 PR). The SVR rates were further distinguished according to ethnicity, with 159 patients being African American/Black and 938 patients non-African American/Black. SVR rates among the non-African American/Black patients were higher than SVR rates in African American/Black patients (68%, 67% and 40% vs 53%, 42% and 23% for patients in the LI + 44 BPR, the response-guided therapy LI + 24 BPR ± 20 PR and control 48 PR arms, respectively).
Retreatment of nonresponders to SOC therapy
The HCV RESPOND-2 study was conducted in 403 patients with chronic HCV genotype 1 infections who had failed prior standard therapy [7]. HCV genotype 1 partial responders (decrease in HCV RNA of at least 2 log10 but with detectable HCV RNA throughout therapy) or relapsers to prior peginterferon /ribavirin treatment were randomized into three arms. Each patient received a 4-week LI with PR. Patients in the control arm then received PR for 44 weeks. Patients in experimental arm 1 received boceprevir and PR for 32 weeks, and those with detectable HCV RNA at week 8 received an additional 12 weeks of PR. Patients in experimental arm 2 received BPR for 44 weeks. The SVR rates were 59% in the boceprevir response-guided arm, 66% in the 44-week boceprevir treatment arm and 21% in the control group.
/ribavirin treatment were randomized into three arms. Each patient received a 4-week LI with PR. Patients in the control arm then received PR for 44 weeks. Patients in experimental arm 1 received boceprevir and PR for 32 weeks, and those with detectable HCV RNA at week 8 received an additional 12 weeks of PR. Patients in experimental arm 2 received BPR for 44 weeks. The SVR rates were 59% in the boceprevir response-guided arm, 66% in the 44-week boceprevir treatment arm and 21% in the control group.Relevance of viral and host factors for direct antiviral agents treatment
Genotype
Both protease inhibitors telaprevir and boceprevir were developed for treatment of HCV genotype 1–infected patients. Telaprevir is less active against HCV genotype 2 and markedly so against HCV genotypes 3 and 4, compared with HCV genotype 1 [8,9]. Also, boceprevir was reported to have lower antiviral activity against HCV genotypes 2 and 3 [10]. HCV genotype will therefore remain an important factor for individualized therapy. New NS3/4A protease inhibitors such as ACH-2684 and MK-5172 currently in preclinical or early clinical development are active against genotypes 1–6 and genotypes 1 and 3, respectively, and may overcome this restriction [11,12]. Nuc polymerase inhibitors that target the active centre of the NS5B polymerase have the highest potential for direct antiviral therapy of nongenotype 1 HCV. A recent phase I study shows that NS5A inhibitors such as PPI-461 also have the potential for pan-genotype activity [13].
IL28B genotype
Genome-wide association studies have recently identified single-nucleotide polymorphisms at the IL28B gene locus that are strongly associated with treatment response to SOC in patients infected with HCV genotype 1 [14–17]. The more responsive C/C variant was associated with a twofold increase in cure rate. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians.
The IL28B C/C genotype is associated with improved early antiviral kinetics and a greater likelihood of rapid and complete early virologic response in patients with HCV genotype 1 [17]. An ongoing phase II trial revealed that the non-nuc polymerase inhibitor ANA598 was able to improve RVR and EVR rates in patients with the less favourable IL28B C/T and T/T alleles, where SOC alone is less efficacious (RVR 31% vs 10% and EVR 69% vs 50% for ANA598 plus SOC vs SOC alone) [18]. The study shows that the IL28B genotype distribution may also be important for DAA treatment. Furthermore, knowledge of the IL28B genotype may be relevant for designing early phase clinical trials with small patient numbers (stratification according to IL28B genotype) [19].
Future of Treatment
Combination therapy without interferon
Triple therapy of protease inhibitors with peginterferon and ribavirin continues to be unsatisfactory for two reasons: (i) anti-HCV therapy still depends on peginterferon and ribavirin, and therefore, SOC null responders are less likely to achieve SVR; (ii) triple therapy is associated with more adverse events than previous SOC. Therefore, the next goal of anti-HCV therapy will be to develop an interferon-free regimen with better tolerability. This goal may be achievable with a combination of two or more direct antivirals that have nonoverlapping resistance profiles.
and ribavirin continues to be unsatisfactory for two reasons: (i) anti-HCV therapy still depends on peginterferon and ribavirin, and therefore, SOC null responders are less likely to achieve SVR; (ii) triple therapy is associated with more adverse events than previous SOC. Therefore, the next goal of anti-HCV therapy will be to develop an interferon-free regimen with better tolerability. This goal may be achievable with a combination of two or more direct antivirals that have nonoverlapping resistance profiles.Combination of NS3/4A inhibitor plus NS5B polymerase inhibitor
The INFORM-1 trial was the first study that investigated an interferon-free approach for treatment of chronic hepatitis C. The nuc polymerase inhibitor RG7128 and the protease inhibitor RG7227 were administered to treatment-naïve and treatment-experienced HCV genotype 1–infected patients for 2 weeks. All patients who received combination therapy achieved profound reduction in HCV RNA without evidence of treatment emergent resistance (HCV drop after 2 weeks −4.8, −4.0 and −4.9 log10 IU/mL in treatment naïve, relapsed and nonresponders to SOC) [20].
Another phase I trial also investigated an interferon-free combination of the NS3/4A protease inhibitor BI201335 and the NS5B polymerase inhibitor BI207127 plus ribavirin for 4 weeks in treatment-naïve HCV genotype 1–infected patients [21]. This combination yielded a rapid sharp drop in HCV RNA followed by a second declining phase in most patients. A majority of patients (11/15) in the BI207127 low-dose (400 mg TID) and all patients (17/17) in the high-dose (600 mg TID) arms had an HCV RNA level lower than 25 IU/mL at week 4. This combination will be investigated in a phase II trial testing different dose regimens and longer treatment using SVR as the primary endpoint.
GS-9256 is a NS3/4A protease inhibitor and GS-9190 a non-nucleoside NS5B inhibitor, which are each active against genotype 1 HCV as monotherapy. Mutations associated with resistance to GS-9256 or GS-9190 were introduced into HCV 1b replicons, and antiviral susceptibility was tested in transient replication assays. GS-9256 maintained antiviral activity in replicons bearing mutations associated with lower susceptibility to GS-9190 and vice versa, and GS-9190 maintained antiviral activity in replicons bearing mutations associated with lower susceptibility to GS-9256. The combination is now in active clinical development [22].
Combination of an NS3/4A inhibitor plus an NS5A inhibitor
A phase II study investigated the efficacy and safety of the NS5A inhibitor BMS-790052 in combination with the NS3/4A inhibitor BMS-650032, with and without peginterferon -2a/ribavirin in HCV genotype 1 patients not responding to prior SOC [23]. An interim analysis revealed RVR rates of 63% and 60% in the arms with and without interferon/ribavirin, respectively. However, between week 4 and 12, 6 of 11 patients in the interferon-free arm had viral breakthroughs, while all patients in the interferon/ribavirin-containing arm maintained viral suppression.
-2a/ribavirin in HCV genotype 1 patients not responding to prior SOC [23]. An interim analysis revealed RVR rates of 63% and 60% in the arms with and without interferon/ribavirin, respectively. However, between week 4 and 12, 6 of 11 patients in the interferon-free arm had viral breakthroughs, while all patients in the interferon/ribavirin-containing arm maintained viral suppression.Summary
Peginterferon /ribavirin has been the standard treatment for HCV for almost a decade. The most promising and clinically advanced direct anti-HCV compounds are inhibitors of the NS3/4A protease and the NS5B polymerase. Because of the risk of selecting for resistant strains, the current protease inhibitors telaprevir and boceprevir must be administered in combination with peginterferon /ribavirin. Two phase III trials with boceprevir (SPRINT-2) and telaprevir (ADVANCE) in combination with SOC have shown SVR rates in the order of 66-75% in patients with genotype 1 HCV infections. The future of anti-HCV therapy will focus on the development of interferon-free treatment regimens with better tolerability and shorter treatment duration compared with SOC.
/ribavirin has been the standard treatment for HCV for almost a decade. The most promising and clinically advanced direct anti-HCV compounds are inhibitors of the NS3/4A protease and the NS5B polymerase. Because of the risk of selecting for resistant strains, the current protease inhibitors telaprevir and boceprevir must be administered in combination with peginterferon /ribavirin. Two phase III trials with boceprevir (SPRINT-2) and telaprevir (ADVANCE) in combination with SOC have shown SVR rates in the order of 66-75% in patients with genotype 1 HCV infections. The future of anti-HCV therapy will focus on the development of interferon-free treatment regimens with better tolerability and shorter treatment duration compared with SOC.Acknowledgements and Disclosures
Bernd Kronenberger has served as a speaker or an advisory board member for Roche, Human Genome Sciences, Novartis, Gilead, Bristol-Myers Squibb, Schering Plough. Stefan Zeuzem has served as a speaker, a consultant or an advisory board member for Abbott, Achillion, Anadys, BMS, Gilead, Itherx, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, Vertex; member of speaker’s bureau: BMS, Gilead, Merck, Novartis, Roche.
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