- Email: [email protected]
1427 THE BILE ACID RECEPTOR TGR5 PROMOTES CHOLANGIOCYTE PROLIFERATION THROUGH A cSRC–EGFR–ERK SIGNALLING PATHWAY
LATE BREAKING ABSTRACTS a working hypothesis whereby BMS-128 binds resistant NS5A causing a conformational change that is transmitted to adjacent NS5A molecules, re-sensitizing resistant NS5A to DCV inhibition. This unprecedented synergistic anti-HCV activity with two NS5Atargeting molecules enhances the resistance barrier and expands sub-genotype coverage of DCV, providing additional options for HCV combination therapy.
Table 1 Percentage of patients achieving SVR12
All patients Patients who met RGT criteria IL28B genotype CC / CT / TT HCV subtype 1a or other / 1b METAVIR score F0–F2/F3–F4
Placebo/PR
Simeprevir/PR
50% not applicable 78% / 42% / 24% 49% / 52% 60% / 28%
80% 91% 94% / 76% / 65% 71% / 90% 83% / 70%
Conclusions: Simeprevir 150 mg QD with PR was generally well tolerated, leading to a high SVR12 rate of 80%. The majority of patients (85%) receiving simeprevir was able to shorten therapy to 24 weeks. 1426 IMMUNOGENICITY AND SAFETY OF TWO DOSES OF INVESTIGATIONAL HEPLISAV™ COMPARED TO THREE DOSES OF LICENSED HEPATITIS B VACCINE (ENGERIX-B® ) IN TWO PHASE 3 TRIALS R. Janssen*, S. Bennett, H. Namini, W. Heyward, J. Martin. Dynavax Technologies Corporation, Berkeley, CA, USA E-mail: [email protected] 1425 SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NA¨IVE PATIENTS: RESULTS FROM QUEST-1, A PHASE III TRIAL I. Jacobson1 , G.J. Dore2 , G.R. Foster3 , M.W. Fried4 , M. Radu5 , V.V. Rafalskiy6 , L. Moroz7 , A. Craxì8 , M. Peeters9 , O. Lenz9 , S. Ouwerkerk-Mahadevan10 , R. Kalmeijer11 , M. Beumont-Mauviel9 . 1 Weill Cornell Medical College, New York, NY, USA; 2 Kirby Institute, University of New South Wales, Sydney, NSW, Australia; 3 Queen Mary University of London, Barts Health, London, UK; 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5 Institutul de Boli infectioase, Bucharest, Romania; 6 Smolensk Regional Clinical Hospital, Smolensk Oblast, Russia; 7 Vinnytsia National Medical University, Vinnytsia, Ukraine; 8 Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy; 9 Janssen Infectious Diseases BVBA, 10 Jansssen Research & Development, Beerse, Belgium; 11 Janssen Global Services, LLC, Titusville, NJ, USA E-mail: [email protected] Background and Aims: Simeprevir (TMC435) is a potent, once-daily, oral, investigational, HCV NS3/4A protease inhibitor. QUEST-1 (TMC435-C208; NCT01289782) is a Phase III, randomised, double-blind, placebo-controlled trial assessing simeprevir plus peginterferon a-2a/ribavirin (PR) versus placebo plus PR in treatment-naïve patients with genotype-1 infection. Safety and SVR12 results from a primary (Week 60) analysis are presented. Methods: HCV genotype-1-infected patients with METAVIR score F0–F4 (n = 394), stratified by HCV subtype and host IL28B genotype, were randomised 2:1 to receive simeprevir (150 mg QD) or placebo, plus PR for 12 weeks, followed by PR alone. Total treatment duration was 24 or 48 weeks (simeprevir group) based on responseguided therapy (RGT) criteria (HCV RNA < 25 IU/mL Week 4 and undetectable Week 12) or 48 weeks (placebo group). Results: Patient disease characteristics: 18% METAVIR F3; 12% F4; 29% CC IL28B genotype; and 56% infected with HCV genotype-1a. Simeprevir/PR was superior to placebo/PR, with SVR12 rates of 80 vs 50%, respectively (p < 0.001). The majority (85%) of patients in the simeprevir group met RGT criteria and completed treatment at Week 24. Overall, 80% of simeprevir- and 12% of placebo-treated patients achieved RVR. Treatment with simeprevir/PR led to a lower on-treatment failure rate, compared to placebo/PR (9 vs 34%), and a lower relapse rate (9 vs 21%). In the simeprevir group, AEs led to discontinuation of simeprevir in 3% of patients. The most common AEs were fatigue, pruritus and headache. The prevalence of anaemia and rash was similar between the simeprevir and placebo groups. S574
Background: Licensed hepatitis B vaccines with alum require 3 doses over 6 months in healthy adults. Vaccine adjuvants such as Toll-like receptor 9 (TLR9) agonists have the potential to induce higher rates of protection with fewer doses and be equally safe. Methods: Two multicenter, observer-blinded, randomized, phase 3 studies were conducted in 4867 persons 18–70 years of age, comparing two doses of HEPLISAV (20 mcg rHBsAg combined with 3000 mcg 1018 ISS, a TLR9 agonist) given at 0 and 1 month (placebo at 6 months) to three doses of Engerix-B (EB) (20 mcg rHBsAg combined with 500 mcg alum) given at 0, 1 and 6 months. Peak seroprotection rates (SPR = % with anti-HBs ≥ 10 mIU/mL) were compared in analyses pooling the modified intent-to-treat (mITT) populations of the two trials. The mITT population included all subjects who received a study injection and had an anti-HBs result. The safety of the vaccines was also evaluated in pooled analyses. Results: Among the 4815 subjects in the mITT population (HEPLISAV 3736; EB 1079), the mean age (HEPLISAV 47.2 years; EB 46.0 years) was similar in both groups. The peak SPR in the HEPLISAV group of 96.4% (95% CI: 95.7%, 97.0%) at month 6 was significantly higher than the peak SPR in the EB group of 76.7% (95% CI: 74.0%, 79.2%) at month 7 (p < 0.0001). The incidences of post-injection reactions, adverse events and serious adverse events were similar in both groups. The relative risks of autoimmune events (EB 0.35%; HEPLISAV 0.27%), rare serious autoimmune events (EB 0.09%; HEPLISAV 0.05%), and ANCA+ vasculitis (EB 0.09%; HEPLISAV 0.026%) were higher in the EB group than in the HEPLISAV group. An analysis of all autoimmune events adjusted for time since last vaccine dose demonstrated a significantly higher rate in the EB group (1.35 per 100 person-years) than in the HEPLISAV group (0.4 per 100 person-years; relative risk = 3.4, 95% CI 1.1, 10.9). Conclusion: HEPLISAV given as 2 doses over 1 month induced significantly higher rates of seroprotection with lower rates of autoimmune diseases than Engerix-B given as 3 doses over 6 months. 1427 THE BILE ACID RECEPTOR TGR5 PROMOTES CHOLANGIOCYTE PROLIFERATION THROUGH A cSRC–EGFR–ERK SIGNALLING PATHWAY V. Keitel*, M. Reich, A. Sommerfeld, S. Kluge, R. Kubitz, D. Haussinger. ¨ Gastroenterology, Hepatology and Infectious Diseases, University Hospital D¨ usseldorf, D¨ usseldorf, Germany E-mail: [email protected] Introduction and Aims: TGR5 (Gpbar-1) is a membrane-bound, G-protein-coupled bile acid receptor, expressed in different
Journal of Hepatology 2013 vol. 58 | S567–S577
LATE BREAKING ABSTRACTS liver cells, including cholangiocytes [1]. Bile acids can promote cholangiocyte secretion and proliferation [2], however, the function of TGR5 in cholangiocytes is largely unknown. Aim of the present study was to elucidate the role of TGR5 for cholangiocyte proliferation and to identify TGR5-dependent signalling pathways in cholangiocytes. Methods: TGR5 knockout and wildtype mice were fed a cholic acid diet (0.5%) for 7 days. Ductular proliferation was assessed by cytokeratin (CK)-19 staining. In isolated cholangiocytes proliferation was measured by BrDU incorporation after stimulation with bile acids or specific TGR5 agonists. TGR5-dependent pathways were studied with different kinase inhibitors (SU6656, PP1, PP2, AG1478, U0126). Western blotting was used to confirm the phosphorylation of the EGFR and ERK1/2. Results: While the amount of CK19-positive bile ducts was similar between TGR5 wildtype and kockout mice on chow diet, a significant increase of bile duct proliferation was observed in wildtype mice after 7 days of cholic acid diet as compared to the TGR5 knockout mice on the same diet. Treatment of isolated cholangiocytes from TGR5 wildtype and knockout mice with taurolithocholic acid (TLC 10 and 25 mM) or a TGR5 specific agonist resulted in an increased cholangiocyte proliferation exclusively in wildtype-derived cells. Preincubation of the wildtype cholangiocytes with inhibitors of ERK1/2, EGFR and cSrc abolished TLC- and TGR5 agonist-induced BrDU incorporation. Treatment with inhibitors of ROS-formation such as N-acetylcystein or apocynin also reduced TLC-mediated BrDU incorporation. In contrast inhibition of adenylate cyclase (SQ22536/dideoxyadenosine) had no effect on TLC/TGR5 agonist-dependent cholangiocyte proliferation. Stimulation of wildtype cholangiocytes with TLC and a TGR5 agonist significantly elevated tyrosine phosphorylation of the EGFR at positions 845 and 1045. Furthermore, TLC and the TGR5 agonist led to a significant increase in ERK1/2 phosphorylation exclusively in TGR5 wildtype-derived cholangiocytes. Conclusion: TGR5 mediates bile acid-induced cholangiocyte proliferation through activation of a cSrc-EGFR-ERK signalling pathway, which is independent of adenylate cyclase activation. Reference(s) [1] Keitel, V. and Haussinger, ¨ D. (2012) Clin. Res. Hepatol. Gastroenterol. 36, 412–419. [2] Xia, X et al. (2006) World J. Gastroenterol. 12, 3553–3563.
1428 INVERSE CHANGES IN HEPATIC EXPRESSION OF INTERFERON LAMBDA AND ALPHA AND IFNL4 GENOTYPE ARE ASSOCIATED WITH TREATMENT RESPONSE IN SOFOSBUVIR/RIBAVIRIN TREATED HCV GENOTYPE-1 SUBJECTS
with ribavirin for 24 weeks. Subjects had a high prevalence of negative treatment predictors including black race (83%) and unfavorable IFNL4-DG genotype (85%). Core liver biopsies were obtained in eight subjects before and at end of treatment to measure expression changes in interferons and interferon stimulated genes (ISGs). Genotyping of IFNL4 was performed with custom TaqMan assays. Viral kinetic (VK), pharmacokinetic (PK), and pharmacodynamic (PD) data for 25 subjects was fitted using a VK-PK-PD model.
Figure 1. Inverse changes in IFNL and IFNA2 hepatic gene expression during HCV serum clearance with Sofosbuvir and ribavirin. Gene expression changes in paired liver biopsies for 8 patients. End of treatment liver biopsies were obtained within 10 days of drug cessation and prior to serum HCV relapse. Delta Ct values are (Ct target gene − CtGAPDH). Graphical results show means with standard error and are displayed by treatment outcome (SVR12 = 7, relapse = 1), while statistical analysis by Wilcoxon signed-rank test is for all 8 patients combined. For IFNL4, 6 of 8 patients carry the IFNL4-DG allele and only expression of this allele as determined by allelic specific PCR is reported.
E.G. Meissner1 , D. Bon2 , A. Osinusi1,3 , W. Tang4 , E. Herrmann2 , J. McHutchison5 , W. Symonds5 , H. Masur6 , T.R. O’Brien4 , L. Prokunina-Olsson4 , S. Kottilil1 . 1 Laboratory of Immunoregulation, NIH/NIAID, Bethesda, MD, USA; 2 Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany; 3 Clinical Research Directorate/CMRP, SAICFrederick Inc, Frederick, 4 Division of Cancer Epidemiology and Genetics, NIH/NCI, Bethesda, MD, 5 Gilead Sciences, Foster City, CA, 6 Critical Care Medicine Department, NIH, Bethesda, MD, USA E-mail: [email protected] Background: Mechanisms of relapse with directly acting antiviral (DAA) therapy for HCV are unclear. The recently identified IFNL4-DG genetic variant is associated with slower HCV viral kinetic decline and poorer treatment outcome with interferon-alpha based therapy, and predicts expression of a novel interferon protein IFNL4. We explored endogenous interferon balance in the liver and effect of IFNL4 genotype on response to DAA therapy. Methods: Sixty chronic HCV genotype-1, treatment naïve subjects were treated with the NS5B RNA polymerase inhibitor Sofosbuvir
Figure 2. IFNL4-DG and response to NS5B polymerase inhibitor (Sofosbuvir) and ribavirin. Median serum HCV RNA decay of 25 patients based on IFNL4 genotype. Analyzed by fully fitted VK-PK-PD model and the Jonckheere trend test.
Journal of Hepatology 2013 vol. 58 | S567–S577
S575
Table 1 Percentage of patients achieving SVR12
All patients Patients who met RGT criteria IL28B genotype CC / CT / TT HCV subtype 1a or other / 1b METAVIR score F0–F2/F3–F4
Placebo/PR
Simeprevir/PR
50% not applicable 78% / 42% / 24% 49% / 52% 60% / 28%
80% 91% 94% / 76% / 65% 71% / 90% 83% / 70%
Conclusions: Simeprevir 150 mg QD with PR was generally well tolerated, leading to a high SVR12 rate of 80%. The majority of patients (85%) receiving simeprevir was able to shorten therapy to 24 weeks. 1426 IMMUNOGENICITY AND SAFETY OF TWO DOSES OF INVESTIGATIONAL HEPLISAV™ COMPARED TO THREE DOSES OF LICENSED HEPATITIS B VACCINE (ENGERIX-B® ) IN TWO PHASE 3 TRIALS R. Janssen*, S. Bennett, H. Namini, W. Heyward, J. Martin. Dynavax Technologies Corporation, Berkeley, CA, USA E-mail: [email protected] 1425 SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NA¨IVE PATIENTS: RESULTS FROM QUEST-1, A PHASE III TRIAL I. Jacobson1 , G.J. Dore2 , G.R. Foster3 , M.W. Fried4 , M. Radu5 , V.V. Rafalskiy6 , L. Moroz7 , A. Craxì8 , M. Peeters9 , O. Lenz9 , S. Ouwerkerk-Mahadevan10 , R. Kalmeijer11 , M. Beumont-Mauviel9 . 1 Weill Cornell Medical College, New York, NY, USA; 2 Kirby Institute, University of New South Wales, Sydney, NSW, Australia; 3 Queen Mary University of London, Barts Health, London, UK; 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5 Institutul de Boli infectioase, Bucharest, Romania; 6 Smolensk Regional Clinical Hospital, Smolensk Oblast, Russia; 7 Vinnytsia National Medical University, Vinnytsia, Ukraine; 8 Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy; 9 Janssen Infectious Diseases BVBA, 10 Jansssen Research & Development, Beerse, Belgium; 11 Janssen Global Services, LLC, Titusville, NJ, USA E-mail: [email protected] Background and Aims: Simeprevir (TMC435) is a potent, once-daily, oral, investigational, HCV NS3/4A protease inhibitor. QUEST-1 (TMC435-C208; NCT01289782) is a Phase III, randomised, double-blind, placebo-controlled trial assessing simeprevir plus peginterferon a-2a/ribavirin (PR) versus placebo plus PR in treatment-naïve patients with genotype-1 infection. Safety and SVR12 results from a primary (Week 60) analysis are presented. Methods: HCV genotype-1-infected patients with METAVIR score F0–F4 (n = 394), stratified by HCV subtype and host IL28B genotype, were randomised 2:1 to receive simeprevir (150 mg QD) or placebo, plus PR for 12 weeks, followed by PR alone. Total treatment duration was 24 or 48 weeks (simeprevir group) based on responseguided therapy (RGT) criteria (HCV RNA < 25 IU/mL Week 4 and undetectable Week 12) or 48 weeks (placebo group). Results: Patient disease characteristics: 18% METAVIR F3; 12% F4; 29% CC IL28B genotype; and 56% infected with HCV genotype-1a. Simeprevir/PR was superior to placebo/PR, with SVR12 rates of 80 vs 50%, respectively (p < 0.001). The majority (85%) of patients in the simeprevir group met RGT criteria and completed treatment at Week 24. Overall, 80% of simeprevir- and 12% of placebo-treated patients achieved RVR. Treatment with simeprevir/PR led to a lower on-treatment failure rate, compared to placebo/PR (9 vs 34%), and a lower relapse rate (9 vs 21%). In the simeprevir group, AEs led to discontinuation of simeprevir in 3% of patients. The most common AEs were fatigue, pruritus and headache. The prevalence of anaemia and rash was similar between the simeprevir and placebo groups. S574
Background: Licensed hepatitis B vaccines with alum require 3 doses over 6 months in healthy adults. Vaccine adjuvants such as Toll-like receptor 9 (TLR9) agonists have the potential to induce higher rates of protection with fewer doses and be equally safe. Methods: Two multicenter, observer-blinded, randomized, phase 3 studies were conducted in 4867 persons 18–70 years of age, comparing two doses of HEPLISAV (20 mcg rHBsAg combined with 3000 mcg 1018 ISS, a TLR9 agonist) given at 0 and 1 month (placebo at 6 months) to three doses of Engerix-B (EB) (20 mcg rHBsAg combined with 500 mcg alum) given at 0, 1 and 6 months. Peak seroprotection rates (SPR = % with anti-HBs ≥ 10 mIU/mL) were compared in analyses pooling the modified intent-to-treat (mITT) populations of the two trials. The mITT population included all subjects who received a study injection and had an anti-HBs result. The safety of the vaccines was also evaluated in pooled analyses. Results: Among the 4815 subjects in the mITT population (HEPLISAV 3736; EB 1079), the mean age (HEPLISAV 47.2 years; EB 46.0 years) was similar in both groups. The peak SPR in the HEPLISAV group of 96.4% (95% CI: 95.7%, 97.0%) at month 6 was significantly higher than the peak SPR in the EB group of 76.7% (95% CI: 74.0%, 79.2%) at month 7 (p < 0.0001). The incidences of post-injection reactions, adverse events and serious adverse events were similar in both groups. The relative risks of autoimmune events (EB 0.35%; HEPLISAV 0.27%), rare serious autoimmune events (EB 0.09%; HEPLISAV 0.05%), and ANCA+ vasculitis (EB 0.09%; HEPLISAV 0.026%) were higher in the EB group than in the HEPLISAV group. An analysis of all autoimmune events adjusted for time since last vaccine dose demonstrated a significantly higher rate in the EB group (1.35 per 100 person-years) than in the HEPLISAV group (0.4 per 100 person-years; relative risk = 3.4, 95% CI 1.1, 10.9). Conclusion: HEPLISAV given as 2 doses over 1 month induced significantly higher rates of seroprotection with lower rates of autoimmune diseases than Engerix-B given as 3 doses over 6 months. 1427 THE BILE ACID RECEPTOR TGR5 PROMOTES CHOLANGIOCYTE PROLIFERATION THROUGH A cSRC–EGFR–ERK SIGNALLING PATHWAY V. Keitel*, M. Reich, A. Sommerfeld, S. Kluge, R. Kubitz, D. Haussinger. ¨ Gastroenterology, Hepatology and Infectious Diseases, University Hospital D¨ usseldorf, D¨ usseldorf, Germany E-mail: [email protected] Introduction and Aims: TGR5 (Gpbar-1) is a membrane-bound, G-protein-coupled bile acid receptor, expressed in different
Journal of Hepatology 2013 vol. 58 | S567–S577
LATE BREAKING ABSTRACTS liver cells, including cholangiocytes [1]. Bile acids can promote cholangiocyte secretion and proliferation [2], however, the function of TGR5 in cholangiocytes is largely unknown. Aim of the present study was to elucidate the role of TGR5 for cholangiocyte proliferation and to identify TGR5-dependent signalling pathways in cholangiocytes. Methods: TGR5 knockout and wildtype mice were fed a cholic acid diet (0.5%) for 7 days. Ductular proliferation was assessed by cytokeratin (CK)-19 staining. In isolated cholangiocytes proliferation was measured by BrDU incorporation after stimulation with bile acids or specific TGR5 agonists. TGR5-dependent pathways were studied with different kinase inhibitors (SU6656, PP1, PP2, AG1478, U0126). Western blotting was used to confirm the phosphorylation of the EGFR and ERK1/2. Results: While the amount of CK19-positive bile ducts was similar between TGR5 wildtype and kockout mice on chow diet, a significant increase of bile duct proliferation was observed in wildtype mice after 7 days of cholic acid diet as compared to the TGR5 knockout mice on the same diet. Treatment of isolated cholangiocytes from TGR5 wildtype and knockout mice with taurolithocholic acid (TLC 10 and 25 mM) or a TGR5 specific agonist resulted in an increased cholangiocyte proliferation exclusively in wildtype-derived cells. Preincubation of the wildtype cholangiocytes with inhibitors of ERK1/2, EGFR and cSrc abolished TLC- and TGR5 agonist-induced BrDU incorporation. Treatment with inhibitors of ROS-formation such as N-acetylcystein or apocynin also reduced TLC-mediated BrDU incorporation. In contrast inhibition of adenylate cyclase (SQ22536/dideoxyadenosine) had no effect on TLC/TGR5 agonist-dependent cholangiocyte proliferation. Stimulation of wildtype cholangiocytes with TLC and a TGR5 agonist significantly elevated tyrosine phosphorylation of the EGFR at positions 845 and 1045. Furthermore, TLC and the TGR5 agonist led to a significant increase in ERK1/2 phosphorylation exclusively in TGR5 wildtype-derived cholangiocytes. Conclusion: TGR5 mediates bile acid-induced cholangiocyte proliferation through activation of a cSrc-EGFR-ERK signalling pathway, which is independent of adenylate cyclase activation. Reference(s) [1] Keitel, V. and Haussinger, ¨ D. (2012) Clin. Res. Hepatol. Gastroenterol. 36, 412–419. [2] Xia, X et al. (2006) World J. Gastroenterol. 12, 3553–3563.
1428 INVERSE CHANGES IN HEPATIC EXPRESSION OF INTERFERON LAMBDA AND ALPHA AND IFNL4 GENOTYPE ARE ASSOCIATED WITH TREATMENT RESPONSE IN SOFOSBUVIR/RIBAVIRIN TREATED HCV GENOTYPE-1 SUBJECTS
with ribavirin for 24 weeks. Subjects had a high prevalence of negative treatment predictors including black race (83%) and unfavorable IFNL4-DG genotype (85%). Core liver biopsies were obtained in eight subjects before and at end of treatment to measure expression changes in interferons and interferon stimulated genes (ISGs). Genotyping of IFNL4 was performed with custom TaqMan assays. Viral kinetic (VK), pharmacokinetic (PK), and pharmacodynamic (PD) data for 25 subjects was fitted using a VK-PK-PD model.
Figure 1. Inverse changes in IFNL and IFNA2 hepatic gene expression during HCV serum clearance with Sofosbuvir and ribavirin. Gene expression changes in paired liver biopsies for 8 patients. End of treatment liver biopsies were obtained within 10 days of drug cessation and prior to serum HCV relapse. Delta Ct values are (Ct target gene − CtGAPDH). Graphical results show means with standard error and are displayed by treatment outcome (SVR12 = 7, relapse = 1), while statistical analysis by Wilcoxon signed-rank test is for all 8 patients combined. For IFNL4, 6 of 8 patients carry the IFNL4-DG allele and only expression of this allele as determined by allelic specific PCR is reported.
E.G. Meissner1 , D. Bon2 , A. Osinusi1,3 , W. Tang4 , E. Herrmann2 , J. McHutchison5 , W. Symonds5 , H. Masur6 , T.R. O’Brien4 , L. Prokunina-Olsson4 , S. Kottilil1 . 1 Laboratory of Immunoregulation, NIH/NIAID, Bethesda, MD, USA; 2 Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany; 3 Clinical Research Directorate/CMRP, SAICFrederick Inc, Frederick, 4 Division of Cancer Epidemiology and Genetics, NIH/NCI, Bethesda, MD, 5 Gilead Sciences, Foster City, CA, 6 Critical Care Medicine Department, NIH, Bethesda, MD, USA E-mail: [email protected] Background: Mechanisms of relapse with directly acting antiviral (DAA) therapy for HCV are unclear. The recently identified IFNL4-DG genetic variant is associated with slower HCV viral kinetic decline and poorer treatment outcome with interferon-alpha based therapy, and predicts expression of a novel interferon protein IFNL4. We explored endogenous interferon balance in the liver and effect of IFNL4 genotype on response to DAA therapy. Methods: Sixty chronic HCV genotype-1, treatment naïve subjects were treated with the NS5B RNA polymerase inhibitor Sofosbuvir
Figure 2. IFNL4-DG and response to NS5B polymerase inhibitor (Sofosbuvir) and ribavirin. Median serum HCV RNA decay of 25 patients based on IFNL4 genotype. Analyzed by fully fitted VK-PK-PD model and the Jonckheere trend test.
Journal of Hepatology 2013 vol. 58 | S567–S577
S575