- Email: [email protected]
RIBAVIRIN RESPONSE RATE IN CHRONIC HCV INFECTION
ORAL PRESENTATIONS Conclusions: INT-747 is the first rationally developed drug for cholestatic liver disease; this study clearly shows it has efficacy in PBC and merits further evaluation. End of study changes from pretreatment means ± s.d.
D % AP
D AP – U/l
% D GTP
% D ALT
Pbo (n = 37) INT-747 10 mg (n = 38) INT-747 25 mg (n = 47) INT-747 50 mg (n = 39)
−2.6±12.5 −23.7±17.8***
−4.7±35.3 −76.9±83.7***
7±28 0±35 −48±30*** −28±27***
−24.7±17.9***
−67.4±88.1***
−63±24***
−35±22***
−21.0±27.6***
−66.1±103.6***
−57±31***
−21±49**
***: p < 0.0001; **: p < 0.0005 – vs. placebo.
3 IL28B POLYMORPHISM IS ASSOCIATED WITH INTRAHEPATIC ISG EXPRESSION AND PEGINTERFERON-A/RIBAVIRIN RESPONSE RATE IN CHRONIC HCV INFECTION A. Thompson1 , D. Schuppan2 , T. Urban3 , J. Fellay3 , K. Shianna3 , J. McHutchison1 , D. Goldstein3 , N. Afdhal2 . 1 GI / Hepatology Research Program, Duke Clinical Research Insitiute, Duke University, Durham, NC, 2 Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 3 Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA E-mail: [email protected] Background and Aims: Genetic variation of the IL28B gene region has been associated with a 2-fold increase in SVR rate in chronic hepatitis C (CHC) patients treated with peginterferon-alpha (pegIFN) and ribavirin (RBV). The underlying mechanism remains unclear. We hypothesized that IL28B polymorphism is associated with intrahepatic expression levels of IFN-stimulated genes (ISGs), known to influence treatment outcome. Methods: 74 CHC patients with consent for genetic testing and stored liver tissue were identified. 48 were treatment-naïve, 26 were non-responders (NR) to prior IFN therapy (off-treatment for ≥6 months prior to biopsy). “IL28B-type” (rs12979860: CC, CT, TT) was tested using the ABI TaqMan allelic discrimination kit. Whole-genome expression data was measured using the Illumina HumanHT-12 Expression BeadChip and differences in gene expression by IL28B-type (CC vs non-CC) were analyzed using Partek and Ingenuity Pathway Analysis, adjusting for HCV genotype, gender, age and ethnicity. To declare significance, we used a false discovery rate (FDR) threshold of 0.1. Results: Data from 61 patients were suitable for analysis: HCV-1 = 90%; male = 67%; median age = 52 yrs; ethnicity = 62% Caucasian, 20% African American, 18% other; 70% were METAVIR F0–2, none cirrhotic. In the comparison of differential intrahepatic mRNA expression, 164 genes were significant. ISGs were heavily over-represented and showed lower expression levels in CC livers (OAS 1/2/3, MX1, IFIT 1/2/3 and ISG15 all had >3 fold lower expression). IL28B and IL28A gene expression were detectable at low levels; there was no difference by IL28B-type. The IFN signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P-value <10−5 ). In 25 patients PEG/RBV response data was available (17 were NR prior to biopsy; 5/8 treated post-biopsy attained SVR). IL28B-type was strongly associated with SVR (P-value = 0.004). SVR was associated with lower intrahepatic ISG expression levels. Conclusions: The CC IL28B-type was strongly associated with reduced expression of intrahepatic ISGs. In a subset, SVR was associated with both CC IL28B-type and reduced ISG expression. This suggests that genetic variation in IL28B regulates the innate immune response to HCV in the liver, priming patients for a stronger ISG response to exogenous IFN therapy. S2
4 SVR WITH TELAPREVIR, PEGINTERFERON ALFA-2A AND RIBAVIRIN IN HCV PATIENTS WITH WELL-CHARACTERIZED PRIOR NULL RESPONSE, PARTIAL RESPONSE, VIRAL BREAKTHROUGH OR RELAPSE AFTER PR T. Berg1 , J.G. McHutchison2 , N. Adda3 , F. Poordad4 , M.L. Shiffman5 , P. Ferenci6 , J. Heathcote7 , J.-M. Pawlotsky8 , S. Zeuzem9 , H. Reesink10 , G. Dusheiko11 , E. Martin3 , D. Alexanderian3 , S. George3 , A.J. Muir2 . 1 University Clinic, Leipzig, Leipzig, Germany; 2 Duke University Medical Center, Durham, NC, 3 Vertex Pharmaceuticals Incorporated, Cambridge, MA, 4 Cedars-Sinai Medical Center, Los Angeles, CA, 5 Bon Secours Health System, Liver Institute of Virginia, Newport News, VA, USA; 6 University of Vienna, Vienna, Austria; 7 University of Toronto, Toronto, ON, Canada; 8 Hˆ opital Henri Mondor, Cr´eteil, France; 9 Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany; 10 Academisch Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 11 Royal Free and University College School of Medicine, London, UK E-mail: [email protected] Background and Aims: Study107 is an open-label rollover study of telaprevir (T) with peginterferon+ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies. Methods: Null responders (<1-log10 HCV RNA decrease at week-4 or <2-log10 at week-12), partial responders (≥2-log10 decrease at week12, detectable at week-24), patients with viral breakthrough and relapsers from PROVE1/2/3 PR arms were eligible for treatment. Initially, all patients received T 750 mg q8h plus PR at standard doses for 12 weeks, followed by 12 weeks of PR (T12/PR24). Protocol was amended to allow partial responders, viral breakthroughs and relapsers with undetectable HCV RNA at weeks 4 and 12 (eRVR) to receive T12/PR24. Partial responders, viral breakthroughs and relapsers with detectable HCV RNA at week-4 and/or week-12 and null responders received an additional 24 weeks of PR (T12/PR48). Results: Of 117 patients included in an ITT analysis, 97 (83%) had baseline HCV RNA ≥800,000IU/mL, 69 (59%) had genotype subtype 1a, 44 (38%) had cirrhosis or bridging fibrosis, and 9 (8%) were black. Viral breakthrough and relapse rates occured in 25%, 23% of prior null responders; 10%, 22% of prior partial responders; 13%, 0% of prior viral breakthroughs; and 0%, 4% of prior relapsers. Patients achieving SVR
Overall, n (%) Prior null responders, n/N (%) Prior partial responders, n/N (%) Prior relapsers, n/N (%) Prior viral breakthrough, n/N (%)
T12/PR24 N = 80
T12/PR48 N = 35
Unassigned N = 2a
47 (59) 3/23 (13) 15/25 (60) 23/25 (92) 6/7 (86)
18 (52) 16/28 (57) 0/3 (0) 2/3 (67) 0/1 (0)
2 (100) – 1/1 (100) 1/1 (100) –
a
One prior partial responder and one prior relapser who discontinued all treatment prior to reaching week 12 of dosing were designated “unassigned” to treatment group.
The most frequent AEs (≥20%) were fatigue, flu-like-syndrome, nausea, diarrhea, pruritus, rash, headache, insomnia and anemia. Grade 3 rash and Grade 3 anemia were observed in 6 (5%) and 6 (5%) patients, respectively. Ten (9%) patients discontinued due to AEs, 5 (4%) due to rash and 2 (2%) to anemia. Conclusions: Patients with prior relapse, breakthrough and partial response exhibited high SVR rates after 24 weeks of telaprevirbased regimen. High SVR rates were also observed in patients with prior null response after 48 weeks of therapy.
Journal of Hepatology 2010 vol. 52 | S1–S21
D % AP
D AP – U/l
% D GTP
% D ALT
Pbo (n = 37) INT-747 10 mg (n = 38) INT-747 25 mg (n = 47) INT-747 50 mg (n = 39)
−2.6±12.5 −23.7±17.8***
−4.7±35.3 −76.9±83.7***
7±28 0±35 −48±30*** −28±27***
−24.7±17.9***
−67.4±88.1***
−63±24***
−35±22***
−21.0±27.6***
−66.1±103.6***
−57±31***
−21±49**
***: p < 0.0001; **: p < 0.0005 – vs. placebo.
3 IL28B POLYMORPHISM IS ASSOCIATED WITH INTRAHEPATIC ISG EXPRESSION AND PEGINTERFERON-A/RIBAVIRIN RESPONSE RATE IN CHRONIC HCV INFECTION A. Thompson1 , D. Schuppan2 , T. Urban3 , J. Fellay3 , K. Shianna3 , J. McHutchison1 , D. Goldstein3 , N. Afdhal2 . 1 GI / Hepatology Research Program, Duke Clinical Research Insitiute, Duke University, Durham, NC, 2 Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 3 Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA E-mail: [email protected] Background and Aims: Genetic variation of the IL28B gene region has been associated with a 2-fold increase in SVR rate in chronic hepatitis C (CHC) patients treated with peginterferon-alpha (pegIFN) and ribavirin (RBV). The underlying mechanism remains unclear. We hypothesized that IL28B polymorphism is associated with intrahepatic expression levels of IFN-stimulated genes (ISGs), known to influence treatment outcome. Methods: 74 CHC patients with consent for genetic testing and stored liver tissue were identified. 48 were treatment-naïve, 26 were non-responders (NR) to prior IFN therapy (off-treatment for ≥6 months prior to biopsy). “IL28B-type” (rs12979860: CC, CT, TT) was tested using the ABI TaqMan allelic discrimination kit. Whole-genome expression data was measured using the Illumina HumanHT-12 Expression BeadChip and differences in gene expression by IL28B-type (CC vs non-CC) were analyzed using Partek and Ingenuity Pathway Analysis, adjusting for HCV genotype, gender, age and ethnicity. To declare significance, we used a false discovery rate (FDR) threshold of 0.1. Results: Data from 61 patients were suitable for analysis: HCV-1 = 90%; male = 67%; median age = 52 yrs; ethnicity = 62% Caucasian, 20% African American, 18% other; 70% were METAVIR F0–2, none cirrhotic. In the comparison of differential intrahepatic mRNA expression, 164 genes were significant. ISGs were heavily over-represented and showed lower expression levels in CC livers (OAS 1/2/3, MX1, IFIT 1/2/3 and ISG15 all had >3 fold lower expression). IL28B and IL28A gene expression were detectable at low levels; there was no difference by IL28B-type. The IFN signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P-value <10−5 ). In 25 patients PEG/RBV response data was available (17 were NR prior to biopsy; 5/8 treated post-biopsy attained SVR). IL28B-type was strongly associated with SVR (P-value = 0.004). SVR was associated with lower intrahepatic ISG expression levels. Conclusions: The CC IL28B-type was strongly associated with reduced expression of intrahepatic ISGs. In a subset, SVR was associated with both CC IL28B-type and reduced ISG expression. This suggests that genetic variation in IL28B regulates the innate immune response to HCV in the liver, priming patients for a stronger ISG response to exogenous IFN therapy. S2
4 SVR WITH TELAPREVIR, PEGINTERFERON ALFA-2A AND RIBAVIRIN IN HCV PATIENTS WITH WELL-CHARACTERIZED PRIOR NULL RESPONSE, PARTIAL RESPONSE, VIRAL BREAKTHROUGH OR RELAPSE AFTER PR T. Berg1 , J.G. McHutchison2 , N. Adda3 , F. Poordad4 , M.L. Shiffman5 , P. Ferenci6 , J. Heathcote7 , J.-M. Pawlotsky8 , S. Zeuzem9 , H. Reesink10 , G. Dusheiko11 , E. Martin3 , D. Alexanderian3 , S. George3 , A.J. Muir2 . 1 University Clinic, Leipzig, Leipzig, Germany; 2 Duke University Medical Center, Durham, NC, 3 Vertex Pharmaceuticals Incorporated, Cambridge, MA, 4 Cedars-Sinai Medical Center, Los Angeles, CA, 5 Bon Secours Health System, Liver Institute of Virginia, Newport News, VA, USA; 6 University of Vienna, Vienna, Austria; 7 University of Toronto, Toronto, ON, Canada; 8 Hˆ opital Henri Mondor, Cr´eteil, France; 9 Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany; 10 Academisch Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 11 Royal Free and University College School of Medicine, London, UK E-mail: [email protected] Background and Aims: Study107 is an open-label rollover study of telaprevir (T) with peginterferon+ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies. Methods: Null responders (<1-log10 HCV RNA decrease at week-4 or <2-log10 at week-12), partial responders (≥2-log10 decrease at week12, detectable at week-24), patients with viral breakthrough and relapsers from PROVE1/2/3 PR arms were eligible for treatment. Initially, all patients received T 750 mg q8h plus PR at standard doses for 12 weeks, followed by 12 weeks of PR (T12/PR24). Protocol was amended to allow partial responders, viral breakthroughs and relapsers with undetectable HCV RNA at weeks 4 and 12 (eRVR) to receive T12/PR24. Partial responders, viral breakthroughs and relapsers with detectable HCV RNA at week-4 and/or week-12 and null responders received an additional 24 weeks of PR (T12/PR48). Results: Of 117 patients included in an ITT analysis, 97 (83%) had baseline HCV RNA ≥800,000IU/mL, 69 (59%) had genotype subtype 1a, 44 (38%) had cirrhosis or bridging fibrosis, and 9 (8%) were black. Viral breakthrough and relapse rates occured in 25%, 23% of prior null responders; 10%, 22% of prior partial responders; 13%, 0% of prior viral breakthroughs; and 0%, 4% of prior relapsers. Patients achieving SVR
Overall, n (%) Prior null responders, n/N (%) Prior partial responders, n/N (%) Prior relapsers, n/N (%) Prior viral breakthrough, n/N (%)
T12/PR24 N = 80
T12/PR48 N = 35
Unassigned N = 2a
47 (59) 3/23 (13) 15/25 (60) 23/25 (92) 6/7 (86)
18 (52) 16/28 (57) 0/3 (0) 2/3 (67) 0/1 (0)
2 (100) – 1/1 (100) 1/1 (100) –
a
One prior partial responder and one prior relapser who discontinued all treatment prior to reaching week 12 of dosing were designated “unassigned” to treatment group.
The most frequent AEs (≥20%) were fatigue, flu-like-syndrome, nausea, diarrhea, pruritus, rash, headache, insomnia and anemia. Grade 3 rash and Grade 3 anemia were observed in 6 (5%) and 6 (5%) patients, respectively. Ten (9%) patients discontinued due to AEs, 5 (4%) due to rash and 2 (2%) to anemia. Conclusions: Patients with prior relapse, breakthrough and partial response exhibited high SVR rates after 24 weeks of telaprevirbased regimen. High SVR rates were also observed in patients with prior null response after 48 weeks of therapy.
Journal of Hepatology 2010 vol. 52 | S1–S21