- Email: [email protected]
pH responsive Janus polymeric nanosheets
ORAL PRESENTATIONS Conclusions: TSU-68 combined with repeated cTACE did not improve OS. However, favourable TTTF was observed in patients with low VEGF-C and those with BCLC-B HCC receiving TSU68. Further study is needed to confirm the potential of VEGF-C as a predictive marker. TSU-68 treatment was tolerable in HCC patients receiving repeated TACE with a high safety profile and long treatment duration of 1 year.
Viral hepatitis C: Therapy
O001 C-SALVAGE: GRAZOPREVIR (GZR; MK-5172), ELBASVIR (EBR; MK-8742) AND RIBAVIRIN (RBV) FOR CHRONIC HCV-GENOTYPE 1 (GT1) INFECTION AFTER FAILURE OF DIRECT-ACTING ANTIVIRAL (DAA) THERAPY 1
2
3
4
5
X. Forns , S. Gordon , E. Zuckerman , E. Lawitz , M. Buti , J. Calleja Panero6 , H. Hofer7 , C. Gilbert8 , J. Palcza8 , A. Howe8 , M. DiNubile8 , M. Robertson8 , J. Wahl8 , E. Barr8 , J. Sullivan-Bolyai8 . 1 IDIBAPS and CIBEREHD, Barcelona, Spain; 2 Henry Ford Health System, Detroit, United States; 3 Carmel Medical Center, Haifa, Israel; 4 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, United States; 5 Hospital Universitario Valle Hebron and Ciberehd, Barcelona, 6 Hospital University Puerta de Hierro Majadahonda, Madrid, Spain; 7 Medical University of Vienna, Vienna, Austria; 8 Merck & Co., Inc., Whitehouse Station, United States E-mail: [email protected] Background and Aims: Treatment options are needed for patients who do not achieve SVR on regimens containing DAAs. The Phase-2 C-SALVAGE study investigated the safety and efficacy of an interferon-free combination of GZR [NS3/4A protease inhibitor (PI)] and EBR [NS5A inhibitor] with RBV for patients with chronic HCV GT1 infection who had failed licensed DAA-containing therapy. Methods: C-SALVAGE is an international open-label study of GZR 100 mg QD, EBV 50 mg QD, and weight-based RBV BID for 12 weeks in patients with chronic HCV GT1 infection who had failed ≥4 weeks of peginterferon and RBV combined with boceprevir, telaprevir, simeprevir, or sofosbuvir. Per protocol, ~80% of the enrolled subjects were to have experienced virologic failure. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, HIV or HBV co-infection, thrombocytopenia <50×103 /mL, or hypoalbuminemia <3.0 g/dL. HCV RNA levels were measured by COBAS TaqMan v2.0 assay. Resistance-associated variants (RAVs) were identified at baseline by population sequencing. The primary efficacy outcome was a HCV RNA level below the limit of quantification (15 IU/mL) 12 weeks after the end of treatment (SVR12 ). Results: 79 patients were treated with ≥1 dose of study drug (Table): 33 (42%) were women, 2 (3%) were non-white, 34 (43%) had cirrhosis (including 8 diagnosed by biopsy), 30 (38%) had GT1a infection, and 66 (84%) had a history of virologic failure on a prior DAA-containing regimen [13 (16%) had failed for other reasons]. All had received a PI; none had received sofosbuvir. At entry, 30 (41%) of the 73 patients with available NS3 sequencing data harbored RAVs. 78 (99%) patients completed therapy with 1 early discontinuation due to an AE. At the end of therapy, RNA levels were <15 IU/mL in all 79 (100%) patients. 5 serious AEs (bacterial pharyngitis, laryngeal squamous cell carcinoma, asthma, appendicitis, and urinary tract infection) were reported, all of which were considered unrelated to study drugs. Conclusions: In the ongoing C-SALVAGE trial, 79 HCV GT1-infected patients who had failed PI-based regimens were treated with S190
GZR/EBR/RBV, including 43% with cirrhosis and 84% with prior virologic failure. HCV RNA levels <15 IU/mL were achieved in all patients at the end of treatment despite a high prevalence of NS3 RAVs at baseline. Study medications were well tolerated in this population. SVR12 rates, full safety data, and expanded resistance results will be presented. Table: Baseline characteristics of 79 patients treated with ≥1 dose of study drug. Age, yrs Mean (Median) Mean BMI, kg/m2 (SD) HCV Genotype, n (%) 1a 1b Fibrosis Stage, n (%) F4 (cirrhosis) F3 F0–2 Screening HCV RNA Mean, log10 IU/mL (SD) DAA Experience, n (%) Boceprevir Telaprevir Simeprevir Virologic Failure, n (%) Nonresponse to P-R + DAA Breakthrough on P-R + DAA Breakthrough on P-R tail after DAA Relapse after P-R + DAA
54.4 (55) 28.0 (4.6) 30 (38.0) 49 (62.0) 34 (43.0) 8 (10.1) 37 (46.8) 6.1 (0.5) 28 (35.4) 43 (54.4) 8 (10.1) 66 (83.5) 15 (19.0) 9 (11.4) 16 (20.2) 26 (32.9)
O002 TREATMENT OF DECOMPENSATED HCV CIRRHOSIS IN PATIENTS WITH DIVERSE GENOTYPES: 12 WEEKS SOFOSBUVIR AND NS5A INHIBITORS WITH/WITHOUT RIBAVIRIN IS EFFECTIVE IN HCV GENOTYPES 1 AND 3 G.R. Foster1 , J. McLauchlan2 , W. Irving3 , M. Cheung4 , B. Hudson5 , S. Verma6 , K. Agarwal6 , and HCV Research UK EAP Group. 1 The Blizard Institute, Queen Marys University of London, London, 2 Centre for Virus Research, MRC University of Glasgow, Glasgow, 3 Virology, University of Nottingham, Nottingham, 4 Queen Marys University of London, London, 5 University of Nottingham, Nottingham, 6 Kings College Hospital, London, United Kingdom E-mail: [email protected] Introduction: All oral antiviral therapy for patients with HCV induced decompensated cirrhosis is now possible. The optimal regimen is unclear, particularly for Genotype 3, and debate continues on which patients benefit. The NHS England Early Access Program (EAP) provided 12 weeks of therapy with sofosbuvir, with or without ribavirin and an NS5A inhibitor to a cohort of ~500 patients with decompensated cirrhosis. Here we evaluate viral clearance and safety in the initial 465 patients. This is the first analysis of a large cohort of patients with decompensated cirrhosis due to genotype 3 HCV receiving sofosbuvir plus NS5A inhibitors. Material and Methods: The EAP allowed physicians to treat patients with decompensated cirrhosis with sofosbuvir combined with either daclatasvir or ledipasvir +/− ribavirin (NS5A inhibitors kindly provided prior to license by Gilead and BMS). Choice of therapy was at the clinicians’ discretion. Data and samples were collected by HCV Research UK and we present data on those patients due to have reached 4 weeks post therapy by abstract submission; all were enrolled when daclatasvir was freely available. Results: 17 centres enrolled 465 patients between July and October 2014, 23 were co-infected with HIV. The Table shows the results and indicates response rates of >80% in patients receiving ribavirin in addition to sofosbuvir and an NS5A inhibitor. For Genotype 3 HCV with decompensated cirrhosis both daclatasvir and ledipasvir
Journal of Hepatology 2015 vol. 62 | S187–S212
ORAL PRESENTATIONS were effective with a numerical increase in patients achieving SVR4 with daclatasvir, although this was not statistically significant. 91 patients required reduction in ribavirin dosing. 19 patients (4%) died during the study (11 on therapy), 16 (3.4%) required transplantation and 181 (39%) had an SAE, which was related to therapy in 143 patients (31%). In 19 patients (4%) liver function deteriorated (worsening ascites/encephalopathy/new variceal bleed) but in 215 patients (46%) ascites/encephalopathy improved. Conclusions: In decompensated cirrhosis 12 weeks therapy with sofosbuvir plus an NS5A inhibitor is effective with most patients achieving SVR4. Patients infected with Genotype 1 HCV respond well with >80% achieving SVR4, response rates were slightly reduced in patients with G3. In this fragile population with end stage liver disease deaths and progression of liver disease were not uncommon but nearly half the patients had improvements in liver function. Table: SVR4 rates in patients with decompensated cirrhosis receiving 12 weeks therapy with different treatment regimes
Overall Genotype 1 Genotype 3 Other genotypes
SOF/LDV
SOF/LDV/Riba
SOF/DCV
SOF/DCV/Riba
21/28 (75%) 17/21 (81%) 4/7 (57%) 0
212/251 (84%) 144/163 (88%) 44/61 (72%) 24/27 (89%)
12/15 (80%) 4/5 (80%) 5/7 (71%) 3/3 (100%)
142/171 (83%) 40/45 (89%) 92/113 (81%) 10/13 (77%)
Numbers are SVR4/total available for analysis (%).
O003 CAN HEPATITIS C TREATMENT BE SAFELY DELAYED? EVIDENCE FROM THE VETERANS ADMINISTRATION HEALTHCARE SYSTEM J.S. McCombs1 , I. Tonnu-MiHara2 , T. Matsuda1 , J. McGinnis1 , S. Fox3 . 1 Schaeffer Center for Health Policy and Economics, Los Angeles, 2 Veterans Administration Healthcare System, Long Beach, 3 Keck School of Medicine, University of Southern California, Los Angeles, United States E-mail: [email protected] Background and Aims: The cost of new HCV treatments leads payers and insurance providers to question if delaying treatment for low risk patients can be accomplished without adversely impacting the patient. Retrospective patient data from the Veterans Administration [VA] were used to estimate the impact on patient risk of treatment initiation before and after the patient’s FIB4 levels became elevated. Methods: VA HCV patients with one or more reported FIB-4 values were selected. Primary outcome measures were time to death and time to the first occurrence of a composite of liver-related clinical events. The impact of time to treatment initiation and time to three different definitions of an elevated FIB4 level were estimated using a time-dependent Cox proportional hazards models. Results: 187,860 patients met study requirements. Initiating treatment before FIB4 >1.00 reduced morbidity by 41% and death by 36%. Initiating treatment after FIB4 >1.00 remained effective but diminished in the morbidity risk reduction achieved [30%]. This is not the case if treatment initiation is delayed until after FIB4 >3.25. The risk reductions associated with treatment initiation before FIB4 >3.25 were 34% for the composite event and 45% for death but if initiated after FIB4 >3.25 were only 11% and 25%, respectively. These detrimental effects of delaying treatment until FIB4 >3.25 were due to a reduction in the likelihood that treated patients would achieve viral load suppression and a reduced impact of viral load suppression on morbidity. Conclusions: Delaying treatment until after a patient’s FIB4 level exceeds 3.25 has a clear detrimental effect on treatment effectiveness
O004 ON-TREATMENT VIROLOGIC RESPONSE AND TOLERABILITY OF SIMEPREVIR, DACLATASVIR AND RIBAVIRIN IN PATIENTS WITH RECURRENT HEPATITIS C VIRUS GENOTYPE 1b INFECTION AFTER ORTHOTOPIC LIVER TRANSPLANTATION (OLT): INTERIM DATA FROM THE PHASE II SATURN STUDY X. Forns1 , M. Berenguer2 , K. Herzer3 , M. Sterneck4 , M.F. Donato5 , P. Andreone6 , S. Fagiuoli7 , T. Cieciura8 , M. Durlik8 , J.L. Calleja9 , Z. Marino ˜ 1 , A. Simion10 , U. Shukla11 , T. Verbinnen10 , O. Lenz10 , S. Ouwerkerk-Mahadevan12 , M. Peeters10 , R. Kalmeijer11 , J. Witek11 . 1 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, 2 Department of Digestive Diseases, Hepatology and Liver Transplantation Unit, La Fe University Hospital and CIBEREHD, Valencia, Spain; 3 Department for Gastroenterology and Hepatology, University Hospital Essen, Essen, 4 Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5 Division of Digestive Diseases, IRCCS Maggiore Hospital, Milan, 6 Department of Medical and Surgical Sciences, University of Bologna, Bologna, 7 Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy; 8 Department of Immunology, Transplant Medicine and Internal Diseases, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland; 9 Department of Gastroenterology and Hepatology, University Hospital Puerta de Hierro Mahadahonda, Madrid, Spain; 10 Janssen Infectious Diseases BVBA, Beerse, Belgium; 11 Janssen Research & Development LLC, Titusville, NJ, United States; 12 Janssen Research and Development, Beerse, Belgium E-mail: [email protected] Background and Aims: Simeprevir (SMV) and daclatasvir (DCV) are approved for the treatment of hepatitis C virus (HCV) infection in the non-transplant setting. SMV is a NS3/4A protease inhibitor and DCV is a NS5A replication complex inhibitor. The combination of SMV+DCV±ribavirin (RBV) has been previously evaluated in treatment-naïve and prior null responder patients (pts; LEAGUE-1). SATURN is an ongoing open-label Phase II study, investigating SMV+DCV+RBV in pts with recurrent HCV genotype 1b infection after orthotopic liver transplantation (OLT). Virologic response and tolerability results are presented from a pre-planned interim analysis. Methods: Post-OLT treatment-naïve or -experienced (prior relapser, partial or null responder to peginterferon±RBV) adults on stable immunosuppressive therapy following OLT were included. Part 1 (P1) included pts with METAVIR score F1–F2 on cyclosporine (CsA) or tacrolimus (TAC). Part 2 (P2) included F1–F4 pts on TAC. Pts received SMV (150 mg once daily [QD]), DCV (60 mg QD) and RBV (1–1.2 g/day) for 24 weeks. At the time of analysis, all P1 pts had reached end of treatment (EOT) and in P2, Week 4 of treatment (or early discontinuation). Analyses were based on the intent-to-treat population. Results: A total of 21 (P1) and 14 (P2) pts were included (P1/P2: female, 33%/43%; median age, 63.0 years [y]/59.5 y; mean time since transplantation, 3.98 y/5.36 y; median baseline HCV RNA 6.9 log10 /6.9 log10 IU/mL; METAVIR F3/F4, 0%/57%). P1 CsA pts had ~6-fold higher SMV plasma concentrations leading to SMV dose adjustment and exclusion of CsA pts from P2. On-treatment virologic response is shown in the Table. In P1, 91% of pts had HCV RNA <25 IU/mL undetectable at EOT. In P2, 93% had HCV RNA <25 IU/mL detectable/undetectable at Week 4. The most common adverse events (AEs) were anaemia (P1/P2: 62%[CsA: 70%/TAC: 55%]/21%) and asthenia (P1: 38%). Grade 3/4 AEs were reported in 19% (P1) and 36% (P2) of pts. Serious AEs were reported in 24% and 14% of pts, while 2 P1 and 0 P2 pts discontinued at least one study drug due to an AE. RBV dose reductions occurred in 3 P1 and 2 P2 pts. Grade 3/4 haemoglobin decreases and hyperbilirubinemia were observed in 5% and 33% of P1 and 7% and 36% of P2 pts.
Journal of Hepatology 2015 vol. 62 | S187–S212
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Viral hepatitis C: Therapy
O001 C-SALVAGE: GRAZOPREVIR (GZR; MK-5172), ELBASVIR (EBR; MK-8742) AND RIBAVIRIN (RBV) FOR CHRONIC HCV-GENOTYPE 1 (GT1) INFECTION AFTER FAILURE OF DIRECT-ACTING ANTIVIRAL (DAA) THERAPY 1
2
3
4
5
X. Forns , S. Gordon , E. Zuckerman , E. Lawitz , M. Buti , J. Calleja Panero6 , H. Hofer7 , C. Gilbert8 , J. Palcza8 , A. Howe8 , M. DiNubile8 , M. Robertson8 , J. Wahl8 , E. Barr8 , J. Sullivan-Bolyai8 . 1 IDIBAPS and CIBEREHD, Barcelona, Spain; 2 Henry Ford Health System, Detroit, United States; 3 Carmel Medical Center, Haifa, Israel; 4 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, United States; 5 Hospital Universitario Valle Hebron and Ciberehd, Barcelona, 6 Hospital University Puerta de Hierro Majadahonda, Madrid, Spain; 7 Medical University of Vienna, Vienna, Austria; 8 Merck & Co., Inc., Whitehouse Station, United States E-mail: [email protected] Background and Aims: Treatment options are needed for patients who do not achieve SVR on regimens containing DAAs. The Phase-2 C-SALVAGE study investigated the safety and efficacy of an interferon-free combination of GZR [NS3/4A protease inhibitor (PI)] and EBR [NS5A inhibitor] with RBV for patients with chronic HCV GT1 infection who had failed licensed DAA-containing therapy. Methods: C-SALVAGE is an international open-label study of GZR 100 mg QD, EBV 50 mg QD, and weight-based RBV BID for 12 weeks in patients with chronic HCV GT1 infection who had failed ≥4 weeks of peginterferon and RBV combined with boceprevir, telaprevir, simeprevir, or sofosbuvir. Per protocol, ~80% of the enrolled subjects were to have experienced virologic failure. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, HIV or HBV co-infection, thrombocytopenia <50×103 /mL, or hypoalbuminemia <3.0 g/dL. HCV RNA levels were measured by COBAS TaqMan v2.0 assay. Resistance-associated variants (RAVs) were identified at baseline by population sequencing. The primary efficacy outcome was a HCV RNA level below the limit of quantification (15 IU/mL) 12 weeks after the end of treatment (SVR12 ). Results: 79 patients were treated with ≥1 dose of study drug (Table): 33 (42%) were women, 2 (3%) were non-white, 34 (43%) had cirrhosis (including 8 diagnosed by biopsy), 30 (38%) had GT1a infection, and 66 (84%) had a history of virologic failure on a prior DAA-containing regimen [13 (16%) had failed for other reasons]. All had received a PI; none had received sofosbuvir. At entry, 30 (41%) of the 73 patients with available NS3 sequencing data harbored RAVs. 78 (99%) patients completed therapy with 1 early discontinuation due to an AE. At the end of therapy, RNA levels were <15 IU/mL in all 79 (100%) patients. 5 serious AEs (bacterial pharyngitis, laryngeal squamous cell carcinoma, asthma, appendicitis, and urinary tract infection) were reported, all of which were considered unrelated to study drugs. Conclusions: In the ongoing C-SALVAGE trial, 79 HCV GT1-infected patients who had failed PI-based regimens were treated with S190
GZR/EBR/RBV, including 43% with cirrhosis and 84% with prior virologic failure. HCV RNA levels <15 IU/mL were achieved in all patients at the end of treatment despite a high prevalence of NS3 RAVs at baseline. Study medications were well tolerated in this population. SVR12 rates, full safety data, and expanded resistance results will be presented. Table: Baseline characteristics of 79 patients treated with ≥1 dose of study drug. Age, yrs Mean (Median) Mean BMI, kg/m2 (SD) HCV Genotype, n (%) 1a 1b Fibrosis Stage, n (%) F4 (cirrhosis) F3 F0–2 Screening HCV RNA Mean, log10 IU/mL (SD) DAA Experience, n (%) Boceprevir Telaprevir Simeprevir Virologic Failure, n (%) Nonresponse to P-R + DAA Breakthrough on P-R + DAA Breakthrough on P-R tail after DAA Relapse after P-R + DAA
54.4 (55) 28.0 (4.6) 30 (38.0) 49 (62.0) 34 (43.0) 8 (10.1) 37 (46.8) 6.1 (0.5) 28 (35.4) 43 (54.4) 8 (10.1) 66 (83.5) 15 (19.0) 9 (11.4) 16 (20.2) 26 (32.9)
O002 TREATMENT OF DECOMPENSATED HCV CIRRHOSIS IN PATIENTS WITH DIVERSE GENOTYPES: 12 WEEKS SOFOSBUVIR AND NS5A INHIBITORS WITH/WITHOUT RIBAVIRIN IS EFFECTIVE IN HCV GENOTYPES 1 AND 3 G.R. Foster1 , J. McLauchlan2 , W. Irving3 , M. Cheung4 , B. Hudson5 , S. Verma6 , K. Agarwal6 , and HCV Research UK EAP Group. 1 The Blizard Institute, Queen Marys University of London, London, 2 Centre for Virus Research, MRC University of Glasgow, Glasgow, 3 Virology, University of Nottingham, Nottingham, 4 Queen Marys University of London, London, 5 University of Nottingham, Nottingham, 6 Kings College Hospital, London, United Kingdom E-mail: [email protected] Introduction: All oral antiviral therapy for patients with HCV induced decompensated cirrhosis is now possible. The optimal regimen is unclear, particularly for Genotype 3, and debate continues on which patients benefit. The NHS England Early Access Program (EAP) provided 12 weeks of therapy with sofosbuvir, with or without ribavirin and an NS5A inhibitor to a cohort of ~500 patients with decompensated cirrhosis. Here we evaluate viral clearance and safety in the initial 465 patients. This is the first analysis of a large cohort of patients with decompensated cirrhosis due to genotype 3 HCV receiving sofosbuvir plus NS5A inhibitors. Material and Methods: The EAP allowed physicians to treat patients with decompensated cirrhosis with sofosbuvir combined with either daclatasvir or ledipasvir +/− ribavirin (NS5A inhibitors kindly provided prior to license by Gilead and BMS). Choice of therapy was at the clinicians’ discretion. Data and samples were collected by HCV Research UK and we present data on those patients due to have reached 4 weeks post therapy by abstract submission; all were enrolled when daclatasvir was freely available. Results: 17 centres enrolled 465 patients between July and October 2014, 23 were co-infected with HIV. The Table shows the results and indicates response rates of >80% in patients receiving ribavirin in addition to sofosbuvir and an NS5A inhibitor. For Genotype 3 HCV with decompensated cirrhosis both daclatasvir and ledipasvir
Journal of Hepatology 2015 vol. 62 | S187–S212
ORAL PRESENTATIONS were effective with a numerical increase in patients achieving SVR4 with daclatasvir, although this was not statistically significant. 91 patients required reduction in ribavirin dosing. 19 patients (4%) died during the study (11 on therapy), 16 (3.4%) required transplantation and 181 (39%) had an SAE, which was related to therapy in 143 patients (31%). In 19 patients (4%) liver function deteriorated (worsening ascites/encephalopathy/new variceal bleed) but in 215 patients (46%) ascites/encephalopathy improved. Conclusions: In decompensated cirrhosis 12 weeks therapy with sofosbuvir plus an NS5A inhibitor is effective with most patients achieving SVR4. Patients infected with Genotype 1 HCV respond well with >80% achieving SVR4, response rates were slightly reduced in patients with G3. In this fragile population with end stage liver disease deaths and progression of liver disease were not uncommon but nearly half the patients had improvements in liver function. Table: SVR4 rates in patients with decompensated cirrhosis receiving 12 weeks therapy with different treatment regimes
Overall Genotype 1 Genotype 3 Other genotypes
SOF/LDV
SOF/LDV/Riba
SOF/DCV
SOF/DCV/Riba
21/28 (75%) 17/21 (81%) 4/7 (57%) 0
212/251 (84%) 144/163 (88%) 44/61 (72%) 24/27 (89%)
12/15 (80%) 4/5 (80%) 5/7 (71%) 3/3 (100%)
142/171 (83%) 40/45 (89%) 92/113 (81%) 10/13 (77%)
Numbers are SVR4/total available for analysis (%).
O003 CAN HEPATITIS C TREATMENT BE SAFELY DELAYED? EVIDENCE FROM THE VETERANS ADMINISTRATION HEALTHCARE SYSTEM J.S. McCombs1 , I. Tonnu-MiHara2 , T. Matsuda1 , J. McGinnis1 , S. Fox3 . 1 Schaeffer Center for Health Policy and Economics, Los Angeles, 2 Veterans Administration Healthcare System, Long Beach, 3 Keck School of Medicine, University of Southern California, Los Angeles, United States E-mail: [email protected] Background and Aims: The cost of new HCV treatments leads payers and insurance providers to question if delaying treatment for low risk patients can be accomplished without adversely impacting the patient. Retrospective patient data from the Veterans Administration [VA] were used to estimate the impact on patient risk of treatment initiation before and after the patient’s FIB4 levels became elevated. Methods: VA HCV patients with one or more reported FIB-4 values were selected. Primary outcome measures were time to death and time to the first occurrence of a composite of liver-related clinical events. The impact of time to treatment initiation and time to three different definitions of an elevated FIB4 level were estimated using a time-dependent Cox proportional hazards models. Results: 187,860 patients met study requirements. Initiating treatment before FIB4 >1.00 reduced morbidity by 41% and death by 36%. Initiating treatment after FIB4 >1.00 remained effective but diminished in the morbidity risk reduction achieved [30%]. This is not the case if treatment initiation is delayed until after FIB4 >3.25. The risk reductions associated with treatment initiation before FIB4 >3.25 were 34% for the composite event and 45% for death but if initiated after FIB4 >3.25 were only 11% and 25%, respectively. These detrimental effects of delaying treatment until FIB4 >3.25 were due to a reduction in the likelihood that treated patients would achieve viral load suppression and a reduced impact of viral load suppression on morbidity. Conclusions: Delaying treatment until after a patient’s FIB4 level exceeds 3.25 has a clear detrimental effect on treatment effectiveness
O004 ON-TREATMENT VIROLOGIC RESPONSE AND TOLERABILITY OF SIMEPREVIR, DACLATASVIR AND RIBAVIRIN IN PATIENTS WITH RECURRENT HEPATITIS C VIRUS GENOTYPE 1b INFECTION AFTER ORTHOTOPIC LIVER TRANSPLANTATION (OLT): INTERIM DATA FROM THE PHASE II SATURN STUDY X. Forns1 , M. Berenguer2 , K. Herzer3 , M. Sterneck4 , M.F. Donato5 , P. Andreone6 , S. Fagiuoli7 , T. Cieciura8 , M. Durlik8 , J.L. Calleja9 , Z. Marino ˜ 1 , A. Simion10 , U. Shukla11 , T. Verbinnen10 , O. Lenz10 , S. Ouwerkerk-Mahadevan12 , M. Peeters10 , R. Kalmeijer11 , J. Witek11 . 1 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, 2 Department of Digestive Diseases, Hepatology and Liver Transplantation Unit, La Fe University Hospital and CIBEREHD, Valencia, Spain; 3 Department for Gastroenterology and Hepatology, University Hospital Essen, Essen, 4 Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5 Division of Digestive Diseases, IRCCS Maggiore Hospital, Milan, 6 Department of Medical and Surgical Sciences, University of Bologna, Bologna, 7 Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy; 8 Department of Immunology, Transplant Medicine and Internal Diseases, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland; 9 Department of Gastroenterology and Hepatology, University Hospital Puerta de Hierro Mahadahonda, Madrid, Spain; 10 Janssen Infectious Diseases BVBA, Beerse, Belgium; 11 Janssen Research & Development LLC, Titusville, NJ, United States; 12 Janssen Research and Development, Beerse, Belgium E-mail: [email protected] Background and Aims: Simeprevir (SMV) and daclatasvir (DCV) are approved for the treatment of hepatitis C virus (HCV) infection in the non-transplant setting. SMV is a NS3/4A protease inhibitor and DCV is a NS5A replication complex inhibitor. The combination of SMV+DCV±ribavirin (RBV) has been previously evaluated in treatment-naïve and prior null responder patients (pts; LEAGUE-1). SATURN is an ongoing open-label Phase II study, investigating SMV+DCV+RBV in pts with recurrent HCV genotype 1b infection after orthotopic liver transplantation (OLT). Virologic response and tolerability results are presented from a pre-planned interim analysis. Methods: Post-OLT treatment-naïve or -experienced (prior relapser, partial or null responder to peginterferon±RBV) adults on stable immunosuppressive therapy following OLT were included. Part 1 (P1) included pts with METAVIR score F1–F2 on cyclosporine (CsA) or tacrolimus (TAC). Part 2 (P2) included F1–F4 pts on TAC. Pts received SMV (150 mg once daily [QD]), DCV (60 mg QD) and RBV (1–1.2 g/day) for 24 weeks. At the time of analysis, all P1 pts had reached end of treatment (EOT) and in P2, Week 4 of treatment (or early discontinuation). Analyses were based on the intent-to-treat population. Results: A total of 21 (P1) and 14 (P2) pts were included (P1/P2: female, 33%/43%; median age, 63.0 years [y]/59.5 y; mean time since transplantation, 3.98 y/5.36 y; median baseline HCV RNA 6.9 log10 /6.9 log10 IU/mL; METAVIR F3/F4, 0%/57%). P1 CsA pts had ~6-fold higher SMV plasma concentrations leading to SMV dose adjustment and exclusion of CsA pts from P2. On-treatment virologic response is shown in the Table. In P1, 91% of pts had HCV RNA <25 IU/mL undetectable at EOT. In P2, 93% had HCV RNA <25 IU/mL detectable/undetectable at Week 4. The most common adverse events (AEs) were anaemia (P1/P2: 62%[CsA: 70%/TAC: 55%]/21%) and asthenia (P1: 38%). Grade 3/4 AEs were reported in 19% (P1) and 36% (P2) of pts. Serious AEs were reported in 24% and 14% of pts, while 2 P1 and 0 P2 pts discontinued at least one study drug due to an AE. RBV dose reductions occurred in 3 P1 and 2 P2 pts. Grade 3/4 haemoglobin decreases and hyperbilirubinemia were observed in 5% and 33% of P1 and 7% and 36% of P2 pts.
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