- Email: [email protected]
[605] THERAPEUTIC PEPTIDE VACCINATION AGAINST CHRONIC HEPATITIS C VIRUS INFECTION
05G. VIRAL HEPATITIS
-
G) HEPATITIS C
-
CLINICAL (THERAPZ NEW COMPOUNDS, RESISTANCE)
sustained virological response rates (SVR) of -80%. Recent studies demonstrate that shorter treatment duration, especially in rapid virological responders, does not compromise SVR rates. Due to different ribavirin dosages and treatment duration used in these trials the role ofribavirin still remains unclear. We conducted a multicentre, prospective, randomised, controlled trial investigating whether a 12 week PEG-IFN a-2a (180 mcg/wk) monotherapy (followed by a 12 wk combination Peg-IFN/RBV (180 mcg/wk+RVB 800mgid = group B) treatment is as effective as a 24 wk standard combination therapy (= group A) with Peg-IFN/RBV Methods: 226/241 screened pts were randomly assigned 1:l to group A and B. End of treatment (EOT) and SVR were assessed by qualitative RT-PCR (i50TU/ml). This non-inferiority study was based on a one-sided 95%confidence interval with a difference of 15% in SVR among group A and B with a power of 80%. Results: 19 pts (8.4%) discontinued treatment before wk 24, 3/226 individuals are still under follow-up. EOT response was 96/103 patients in group A (93%) and 94/95 pts in group B (99%). SVR rates were 83/97 pts (85%) in group A versus 69/95 pts (73%) in group B. Relapse rates were 8% vs 21% in group A and B (p < 0.005). Conclusion: Shortened RBV treatment (group B) seems to be non inferior referring to EOT response (group A vs B: 93% vs 99%) concerning our defined statistical criteria. However, there is a trend of higher SVR in the 24 wk combination arm (group A vs B: 85% vs 73%) explained by a higher relapse rate of 21% in the shortened ribavirin treatment group B. A shortened ribavirin treatment of 12 weeks compromises SVR rates in HCV infected patients with genotype 2 and 3, confirming the results ofthe Accelerate Study. SVR data stratified for low and high virological load, RVR and genotype will be presented at EASL.
16051 THERAPEUTIC PEPTIDE VACCINATION AGAINST CHRONIC HEPATITIS C VIRUS INFECTION C.S. Klade', H. Wedemeyeg, C. Sarrazin3, C. Firbas4, B. Jilma4, E. Tauber'. Intercell AG, Vienna, Austria; 2Departnient of' Gastroenterology, Hepatology and Endocrinology, Medical School of Hannooel; Hunnooer; 'Innere Medizin IT, Saurbnd Unioersity Hospitul, Hontliurg, Germany; Depurtnzent of C h i d Pharnzucology, Medical Uniuersity Vienna, Vienna, Austria E-mail: [email protected]
'
Novel treatments of chronic HCV infection are urgently needed and therapeutic vaccination aiming at restoring HCV specific CD8 and CD4 T cell immunity is a promising approach. We have identifed disease relevant epitopes by comprehensive analysis of overlapping synthetic peptides covering conserved regions of HCV using PBMC from therapy responders and spontaneous resolvers. 1C41 is a prototypic peptide vaccine containing 5 HLA-A*0201 CTL, several promiscuous T-helper epitopes and poly-Larginine as synthetic adjuvant. Safety, immunogenicity and > I log RNA declines in several chronic HCV patients refractory to standard therapy have been reported previously. Here we show correlation of individual immune and RNA responses: CD4 responses (proliferation or IFN-gamma secretion) were not sufficient for RNA response, but a prerequisite for IFN secreting CD8 T cells. Tetramer specific CD8 T cells and a partial shift from a CCR7+ central memory (chronic HCV) towards a CCR7- effector memory phenotype (acute HCV) were also not associated with >1 log RNA declines. The single parameter correlating with RNA response was an increase of HCV specific TFN-gamma secreting CD8+ CTL above a critical threshold of 50 SFUimio PBMC. This was only occasionally reached, typically in patients with pre-existing immunity to vaccine epitopes, and responses were dominated by a single well known epitope (NS3-1073). Analysis of viral sequences revealed broad cross reactivity of NS3-1073 CTL with naturally occurring sequences. Importantly, a single amino acid exchange at an anchor positon, leading to significantly reduced recognition of this epitope was observed during vaccination further corroborating the causal relationship of CD8+ CTL induction and HCVRNA decline.
S229
Consequently, a clinical trial aiming at intensifying T cell responses was performed: 50 healthy volunteers received either one of 5 regimes: 8 vaccinations biweekly, 16 vaccinations biweekly or weekly (all s.c.), 8 vaccinations hi-weekly i.d. with or without topic application of the TLR7 agonist imiquimod. The optimal schedule resulted in increased responder rates, 5-fold stronger CD8 responses sustained for at least 20 weeks and broader induction of CTL responses (median 3 instead previously 1 epitopes per individual). The optimized schedule is now applied in a trial in chronic HCV patients naive to standard therapy.
16061 COMPARISON OF PEGINTERFERON a-2a AND RIBAVIRIN FOR 12 OR 24 WEEKS IN PATIENTS WITH HCV GENOTYPE 2/3:THE NORDYNAMIC TRIAL M. Lagging', C. Pedersen', M. Rauning Buh13, M. Farkkila4, N. Langeland5, K. Morch5, G. Norlcrans' . 'Dept. gfInf2ctious Disemes, Gothenburg lJnioersity, Sweden; 2Dept. of Infhctious Diseuses, Syddansk Uniuer~xit?,;'Dept. of l n f d i o u s Diseuses, Aurhus Uniuersih~,Denmurk; Helsinki Uniuer~xity,Finlund; 'Dept. of 4Dept. of Gustrornterolog~~, Infictious Diseuses, Bergen Uniuer~xi&Norwuy E-mail: [email protected]
Background and Aims: Prior trials investigating the efficacy of shorter treatment duration than 24 weeks for HCV genotype 2/3 infected patients have yielded differing results. The aim of this study was to compare the efficacy of 12 versus 24 weeks of combination therapy, as well as to attempt to identify patients achieving SVR using liver biopsy evaluation, TP-l 0 levels, a-interferon concentrations, ribavirin concentrations, and HCVRNA measurement using Roche COBAS TaqMan at baseline, day 3, day 7, day 8, week 4, and week 8. Methods: 392 genotype 213 infected patients at 31 centers in Denmark, Finland, Norway, and Sweden were randomized at baseline to peginterferon a-2a 180~g/weekplus ribavirin 800mgiday for 12 or 24 weeks. All patients have completed 24 weeks of follow-up as of October 2006, and at the time of the meeting final results will be available. Results: Preliminary analysis of 340 patients reveals SVR rates of 56% (29 of 52) vs. 87% (39 of 45) for genotype 2 and 65% (82 of 127) vs. 83% (96 of 116) for genotype 3 for 12 and 24 weeks of treatment respectively. Younger patients were statistically more likely to achieve SVR (p i 0.0001, Mann-Whitney U-test). For patients below 40 years of age, 85% (63 of 74) achieved SVR with 12 weeks of therapy as compared to 92% (58 of 63) with 24 weeks. For patients with age 3 40 years, the SVR rate was 46% (48 of 105) and 79% (77 of 98) for 12 and 24 weeks of therapy respectively. Conclusion: Our preliminary analysis suggests that approximately 6 of 10 genotype 2/3 patients achieve SVR with as little as 12 weeks of combination therapy and that younger patients are more likely to benefit from shorter treatment duration, but that higher SVR rates are noted in patients receiving 24 weeks of therapy.
-
G) HEPATITIS C
-
CLINICAL (THERAPZ NEW COMPOUNDS, RESISTANCE)
sustained virological response rates (SVR) of -80%. Recent studies demonstrate that shorter treatment duration, especially in rapid virological responders, does not compromise SVR rates. Due to different ribavirin dosages and treatment duration used in these trials the role ofribavirin still remains unclear. We conducted a multicentre, prospective, randomised, controlled trial investigating whether a 12 week PEG-IFN a-2a (180 mcg/wk) monotherapy (followed by a 12 wk combination Peg-IFN/RBV (180 mcg/wk+RVB 800mgid = group B) treatment is as effective as a 24 wk standard combination therapy (= group A) with Peg-IFN/RBV Methods: 226/241 screened pts were randomly assigned 1:l to group A and B. End of treatment (EOT) and SVR were assessed by qualitative RT-PCR (i50TU/ml). This non-inferiority study was based on a one-sided 95%confidence interval with a difference of 15% in SVR among group A and B with a power of 80%. Results: 19 pts (8.4%) discontinued treatment before wk 24, 3/226 individuals are still under follow-up. EOT response was 96/103 patients in group A (93%) and 94/95 pts in group B (99%). SVR rates were 83/97 pts (85%) in group A versus 69/95 pts (73%) in group B. Relapse rates were 8% vs 21% in group A and B (p < 0.005). Conclusion: Shortened RBV treatment (group B) seems to be non inferior referring to EOT response (group A vs B: 93% vs 99%) concerning our defined statistical criteria. However, there is a trend of higher SVR in the 24 wk combination arm (group A vs B: 85% vs 73%) explained by a higher relapse rate of 21% in the shortened ribavirin treatment group B. A shortened ribavirin treatment of 12 weeks compromises SVR rates in HCV infected patients with genotype 2 and 3, confirming the results ofthe Accelerate Study. SVR data stratified for low and high virological load, RVR and genotype will be presented at EASL.
16051 THERAPEUTIC PEPTIDE VACCINATION AGAINST CHRONIC HEPATITIS C VIRUS INFECTION C.S. Klade', H. Wedemeyeg, C. Sarrazin3, C. Firbas4, B. Jilma4, E. Tauber'. Intercell AG, Vienna, Austria; 2Departnient of' Gastroenterology, Hepatology and Endocrinology, Medical School of Hannooel; Hunnooer; 'Innere Medizin IT, Saurbnd Unioersity Hospitul, Hontliurg, Germany; Depurtnzent of C h i d Pharnzucology, Medical Uniuersity Vienna, Vienna, Austria E-mail: [email protected]
'
Novel treatments of chronic HCV infection are urgently needed and therapeutic vaccination aiming at restoring HCV specific CD8 and CD4 T cell immunity is a promising approach. We have identifed disease relevant epitopes by comprehensive analysis of overlapping synthetic peptides covering conserved regions of HCV using PBMC from therapy responders and spontaneous resolvers. 1C41 is a prototypic peptide vaccine containing 5 HLA-A*0201 CTL, several promiscuous T-helper epitopes and poly-Larginine as synthetic adjuvant. Safety, immunogenicity and > I log RNA declines in several chronic HCV patients refractory to standard therapy have been reported previously. Here we show correlation of individual immune and RNA responses: CD4 responses (proliferation or IFN-gamma secretion) were not sufficient for RNA response, but a prerequisite for IFN secreting CD8 T cells. Tetramer specific CD8 T cells and a partial shift from a CCR7+ central memory (chronic HCV) towards a CCR7- effector memory phenotype (acute HCV) were also not associated with >1 log RNA declines. The single parameter correlating with RNA response was an increase of HCV specific TFN-gamma secreting CD8+ CTL above a critical threshold of 50 SFUimio PBMC. This was only occasionally reached, typically in patients with pre-existing immunity to vaccine epitopes, and responses were dominated by a single well known epitope (NS3-1073). Analysis of viral sequences revealed broad cross reactivity of NS3-1073 CTL with naturally occurring sequences. Importantly, a single amino acid exchange at an anchor positon, leading to significantly reduced recognition of this epitope was observed during vaccination further corroborating the causal relationship of CD8+ CTL induction and HCVRNA decline.
S229
Consequently, a clinical trial aiming at intensifying T cell responses was performed: 50 healthy volunteers received either one of 5 regimes: 8 vaccinations biweekly, 16 vaccinations biweekly or weekly (all s.c.), 8 vaccinations hi-weekly i.d. with or without topic application of the TLR7 agonist imiquimod. The optimal schedule resulted in increased responder rates, 5-fold stronger CD8 responses sustained for at least 20 weeks and broader induction of CTL responses (median 3 instead previously 1 epitopes per individual). The optimized schedule is now applied in a trial in chronic HCV patients naive to standard therapy.
16061 COMPARISON OF PEGINTERFERON a-2a AND RIBAVIRIN FOR 12 OR 24 WEEKS IN PATIENTS WITH HCV GENOTYPE 2/3:THE NORDYNAMIC TRIAL M. Lagging', C. Pedersen', M. Rauning Buh13, M. Farkkila4, N. Langeland5, K. Morch5, G. Norlcrans' . 'Dept. gfInf2ctious Disemes, Gothenburg lJnioersity, Sweden; 2Dept. of Infhctious Diseuses, Syddansk Uniuer~xit?,;'Dept. of l n f d i o u s Diseuses, Aurhus Uniuersih~,Denmurk; Helsinki Uniuer~xity,Finlund; 'Dept. of 4Dept. of Gustrornterolog~~, Infictious Diseuses, Bergen Uniuer~xi&Norwuy E-mail: [email protected]
Background and Aims: Prior trials investigating the efficacy of shorter treatment duration than 24 weeks for HCV genotype 2/3 infected patients have yielded differing results. The aim of this study was to compare the efficacy of 12 versus 24 weeks of combination therapy, as well as to attempt to identify patients achieving SVR using liver biopsy evaluation, TP-l 0 levels, a-interferon concentrations, ribavirin concentrations, and HCVRNA measurement using Roche COBAS TaqMan at baseline, day 3, day 7, day 8, week 4, and week 8. Methods: 392 genotype 213 infected patients at 31 centers in Denmark, Finland, Norway, and Sweden were randomized at baseline to peginterferon a-2a 180~g/weekplus ribavirin 800mgiday for 12 or 24 weeks. All patients have completed 24 weeks of follow-up as of October 2006, and at the time of the meeting final results will be available. Results: Preliminary analysis of 340 patients reveals SVR rates of 56% (29 of 52) vs. 87% (39 of 45) for genotype 2 and 65% (82 of 127) vs. 83% (96 of 116) for genotype 3 for 12 and 24 weeks of treatment respectively. Younger patients were statistically more likely to achieve SVR (p i 0.0001, Mann-Whitney U-test). For patients below 40 years of age, 85% (63 of 74) achieved SVR with 12 weeks of therapy as compared to 92% (58 of 63) with 24 weeks. For patients with age 3 40 years, the SVR rate was 46% (48 of 105) and 79% (77 of 98) for 12 and 24 weeks of therapy respectively. Conclusion: Our preliminary analysis suggests that approximately 6 of 10 genotype 2/3 patients achieve SVR with as little as 12 weeks of combination therapy and that younger patients are more likely to benefit from shorter treatment duration, but that higher SVR rates are noted in patients receiving 24 weeks of therapy.