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79 Induction of virus-neutralizing antibodies is associated with viral clearance in a single-source outbreak of hepatitis C
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Saturday, 29 April
General Session 3
1
7
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THE HCV NS3 PROTEASE INHIBITOR SCH 503034 IN C O M B I N A T I O N WITH PEG-IFN~-2b IN THE TREATMENT OF HCV-1 PEG-IFN~-2b N O N - R E S P O N D E R S : A N T I V I R A L ACTIVITY A N D HCV V A R I A N T ANALYSIS
S. Zeuzem 1, C. Sarrazin 1, F. Wagnel2, R. Rouzier 3, N. Forestier1, S. Gupta4, M. Hussain4, A. Shah4, D. Cutler4, J. Zhang4. 1Saarland
University Hospital, Homburg, Germany," 2pAREXEL International GmbH, Berlin, Germany," SCentre CAP, Montpellier, France," 4SeheringPlough Research Institute, Kenilworth, NJ, USA Introduction and Aims: The Hepatitis C virus (HCV) NS3 protease is critical for viral replication and may inhibit host responses to endogenous and exogenous IFN. SCH 503034 is a novel, orally available HCV NS3 protease inhibitor. In this study the safety, antiviral activity, and emergence of resistant strains of SCH 503034 plus PEG-IFNa-2b was evaluated in HCV-1 PEG-IFN~-2b non-responders. Methods: This was a multi-center, open-label study, in which adults with HCV-1 who previously failed PEG-IFN~-2b • Ribavirin therapy (<2 log reduction in HCV RNA after 12 wks) received in random sequence, (A) SCH 503034 oral capsules (200mg or 400 mg) as a monotherapy for 7d, (B) PEG-IFN~-2b (1.5 gg/kg/QW) as monotherapy for 14d, and (C) PEG-IFN~-2b (1.5 gg/kg/QW) + SCH 503034 (200mg or 400mg) for 14d, in a 3-way crossover design with a 2 3-wk washout between treatments. HCV RNA viral load was determined by real-time PCR (Taq-ManTM/LOQ 29 IU/ml) and selection of variants under antiviral therapy assessed by direct sequencing. Safety was assessed by clinical laboratory values, ECG, vital signs and adverse events. Results: Twenty-two patients completed all three treatment periods (SCH 503034 200mg cohort, n 12, 400mg cohort, n 10). Mean baseline HCV RNA was 6.3 log10 IU/ml (range 5.6 6.8) in the 200 mg cohort and 5.6 log10 IU/ml (range 4.0 6.2) in the 400 mg cohort. Four of 10 patients in the 400 mg combination group became HCV RNA negative (<29 IU/ml) during treatment. Mean max log10 reductions in HCV RNA (IU/ml) were 2.4 (range 1 4.5) and 2.9 (range 2.3 4.1) for 200mg and 400mg SCH 503034 + PEG-Intron, respectively. HCV sequence analysis revealed a single variant at position T54 in 1 patient (200mg cohort). The most frequently reported AE's during combination treatment were headache, myalgia and rigors. Conclusions: The combination of SCH 503034 plus PEG-IFN~-2b provided potent antiviral activity in HCV-1 PEG-IFNa-2b non-responders which was greater than either drug as monotherapy. SCH 503034 antiviral activity and safety are being further evaluated in Phase II studies assessing 24 and 48 wks of combination treatment.
I
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I N D U C T I O N OF V I R U S - N E U T R A L I Z I N G A N T I B O D I E S IS A S S O C I A T E D WITH VIRAL C L E A R A N C E IN A S I N G L E - S O U R C E O U T B R E A K OF HEPATITIS C
M.B. Zeisel 1, J.M. Pestka 1, P. Schfirmann 1, B. Bartosch2, F.L. Cosset2, A. Patel 3, H. Meisel 4, K. Rispeter5, H.E. Blum 1, M. Roggendorf5, T.F. Baumert 1. 1Dept. Medicine II, University of Freiburg, Freiburg,
Germany," 2LVRTG, IFR128 BioSeiences Lyon-Gerland, EArS Lyon, France," 3MRC Virology Unit, Institute of Virology, University of Glasgow, UK," 4Institute of Virology, Humboldt-University (Charitd), Berlin, Germany," 5Institute of Virology, University of Essen, Germany B a c k g r o u n d and A i m : Antibodies with virus-neutralizing properties have been detected in acute and chronic hepatitis C virus (HCV) infection. However, the role of antibodies for clearance or persistence of HCV is still elusive. Women accidentally infected with a single HCV strain (AD78) during Rhesus prophylaxis represent a unique cohort for evaluating the role of humoral response in HCV disease outcome. Retroviral HCV pseudotypes (HCVpp) are a convenient model system allowing the study of antibody-mediated neutralization of HCV entry into hepatoma cells and hepatocytes. Thus, we used this system to evaluate the presence of virusneutralizing antibodies in the sera of 45 women drawn 0 6 months (early phase) and 10 17 years (late phase) after HCV infection. Methods: HCVpp bearing E1 and E2 glycoproteins from the single-strain consensus sequence (AD78) were generated and used to study antibodymediated inhibition of HCVpp entry. Results: HCVpp derived from the viral consensus sequence (HCVpp AD78) efficiently infected Huh-7 hepatoma cells in a dose-dependent manner similarly to HCVpp generated from an infectious HCV control isolate (HCV-J strain). Virus-neutralizing antibodies were present in the early phase sera from patients with both resolved and chronic hepatitis C. However, whereas patients with resolving hepatitis C exhibited a high frequency of neutralizing antibodies in the early phase of infection (83% of patients, mean titre 1/140), only 50% of patients without viral clearance had evidence for virus-neutralizing antibodies (mean titre 1/50; p < 0.05). Analysis of late phase samples revealed the presence of neutralizing antibodies in a large fraction (63%, mean titre 1/230) of patients chronically infected with HCV. In contrast, only a minority (27%, mean titre 1/10) of patients who resolved hepatitis C exhibited neutralizing antibodies 10 17 years following viral clearance. Conclusion: In this single-source outbreak of hepatitis C, viral clearance is associated with the induction of neutralizing antibodies. Interestingly, neutralizing antibodies decrease or disappear after recovery from infection. Furthermore, our results indicate that HCV can persist despite the presence of antibodies neutralizing the transmitted virus. This single-source outbreak provides a unique opportunity to define the role of virus-neutralizing antibodies for viral clearance and evaluate mechanisms of viral escape in HCV persistence.
Saturday, 29 April
General Session 3
1
7
•
THE HCV NS3 PROTEASE INHIBITOR SCH 503034 IN C O M B I N A T I O N WITH PEG-IFN~-2b IN THE TREATMENT OF HCV-1 PEG-IFN~-2b N O N - R E S P O N D E R S : A N T I V I R A L ACTIVITY A N D HCV V A R I A N T ANALYSIS
S. Zeuzem 1, C. Sarrazin 1, F. Wagnel2, R. Rouzier 3, N. Forestier1, S. Gupta4, M. Hussain4, A. Shah4, D. Cutler4, J. Zhang4. 1Saarland
University Hospital, Homburg, Germany," 2pAREXEL International GmbH, Berlin, Germany," SCentre CAP, Montpellier, France," 4SeheringPlough Research Institute, Kenilworth, NJ, USA Introduction and Aims: The Hepatitis C virus (HCV) NS3 protease is critical for viral replication and may inhibit host responses to endogenous and exogenous IFN. SCH 503034 is a novel, orally available HCV NS3 protease inhibitor. In this study the safety, antiviral activity, and emergence of resistant strains of SCH 503034 plus PEG-IFNa-2b was evaluated in HCV-1 PEG-IFN~-2b non-responders. Methods: This was a multi-center, open-label study, in which adults with HCV-1 who previously failed PEG-IFN~-2b • Ribavirin therapy (<2 log reduction in HCV RNA after 12 wks) received in random sequence, (A) SCH 503034 oral capsules (200mg or 400 mg) as a monotherapy for 7d, (B) PEG-IFN~-2b (1.5 gg/kg/QW) as monotherapy for 14d, and (C) PEG-IFN~-2b (1.5 gg/kg/QW) + SCH 503034 (200mg or 400mg) for 14d, in a 3-way crossover design with a 2 3-wk washout between treatments. HCV RNA viral load was determined by real-time PCR (Taq-ManTM/LOQ 29 IU/ml) and selection of variants under antiviral therapy assessed by direct sequencing. Safety was assessed by clinical laboratory values, ECG, vital signs and adverse events. Results: Twenty-two patients completed all three treatment periods (SCH 503034 200mg cohort, n 12, 400mg cohort, n 10). Mean baseline HCV RNA was 6.3 log10 IU/ml (range 5.6 6.8) in the 200 mg cohort and 5.6 log10 IU/ml (range 4.0 6.2) in the 400 mg cohort. Four of 10 patients in the 400 mg combination group became HCV RNA negative (<29 IU/ml) during treatment. Mean max log10 reductions in HCV RNA (IU/ml) were 2.4 (range 1 4.5) and 2.9 (range 2.3 4.1) for 200mg and 400mg SCH 503034 + PEG-Intron, respectively. HCV sequence analysis revealed a single variant at position T54 in 1 patient (200mg cohort). The most frequently reported AE's during combination treatment were headache, myalgia and rigors. Conclusions: The combination of SCH 503034 plus PEG-IFN~-2b provided potent antiviral activity in HCV-1 PEG-IFNa-2b non-responders which was greater than either drug as monotherapy. SCH 503034 antiviral activity and safety are being further evaluated in Phase II studies assessing 24 and 48 wks of combination treatment.
I
•
I N D U C T I O N OF V I R U S - N E U T R A L I Z I N G A N T I B O D I E S IS A S S O C I A T E D WITH VIRAL C L E A R A N C E IN A S I N G L E - S O U R C E O U T B R E A K OF HEPATITIS C
M.B. Zeisel 1, J.M. Pestka 1, P. Schfirmann 1, B. Bartosch2, F.L. Cosset2, A. Patel 3, H. Meisel 4, K. Rispeter5, H.E. Blum 1, M. Roggendorf5, T.F. Baumert 1. 1Dept. Medicine II, University of Freiburg, Freiburg,
Germany," 2LVRTG, IFR128 BioSeiences Lyon-Gerland, EArS Lyon, France," 3MRC Virology Unit, Institute of Virology, University of Glasgow, UK," 4Institute of Virology, Humboldt-University (Charitd), Berlin, Germany," 5Institute of Virology, University of Essen, Germany B a c k g r o u n d and A i m : Antibodies with virus-neutralizing properties have been detected in acute and chronic hepatitis C virus (HCV) infection. However, the role of antibodies for clearance or persistence of HCV is still elusive. Women accidentally infected with a single HCV strain (AD78) during Rhesus prophylaxis represent a unique cohort for evaluating the role of humoral response in HCV disease outcome. Retroviral HCV pseudotypes (HCVpp) are a convenient model system allowing the study of antibody-mediated neutralization of HCV entry into hepatoma cells and hepatocytes. Thus, we used this system to evaluate the presence of virusneutralizing antibodies in the sera of 45 women drawn 0 6 months (early phase) and 10 17 years (late phase) after HCV infection. Methods: HCVpp bearing E1 and E2 glycoproteins from the single-strain consensus sequence (AD78) were generated and used to study antibodymediated inhibition of HCVpp entry. Results: HCVpp derived from the viral consensus sequence (HCVpp AD78) efficiently infected Huh-7 hepatoma cells in a dose-dependent manner similarly to HCVpp generated from an infectious HCV control isolate (HCV-J strain). Virus-neutralizing antibodies were present in the early phase sera from patients with both resolved and chronic hepatitis C. However, whereas patients with resolving hepatitis C exhibited a high frequency of neutralizing antibodies in the early phase of infection (83% of patients, mean titre 1/140), only 50% of patients without viral clearance had evidence for virus-neutralizing antibodies (mean titre 1/50; p < 0.05). Analysis of late phase samples revealed the presence of neutralizing antibodies in a large fraction (63%, mean titre 1/230) of patients chronically infected with HCV. In contrast, only a minority (27%, mean titre 1/10) of patients who resolved hepatitis C exhibited neutralizing antibodies 10 17 years following viral clearance. Conclusion: In this single-source outbreak of hepatitis C, viral clearance is associated with the induction of neutralizing antibodies. Interestingly, neutralizing antibodies decrease or disappear after recovery from infection. Furthermore, our results indicate that HCV can persist despite the presence of antibodies neutralizing the transmitted virus. This single-source outbreak provides a unique opportunity to define the role of virus-neutralizing antibodies for viral clearance and evaluate mechanisms of viral escape in HCV persistence.