- Email: [email protected]
P0909 : Analysis of natural resistance profile to NS5A replication complex inhibitors in different Hepatitis C genotypes
POSTERS was rapid, and RG-101 was rapidly and efficiently cleaved to unconjugated oligo in the liver. Half-life of the unconjugated oligo in the liver was 8–14 days in mouse and monkey. Measurement of an endogenous miR-122 target mRNA, aldoa, in the liver revealed rapid onset of action with 80% maximal activity within 24 h and greater than 60 days duration of action. Pro-inflammatory effects in mouse and rat were minimal at high doses. In single and repeat dose studies, typical PS oligo class effects, including complement activation and prolonged APTT, were observed in monkeys, but were not considered adverse. No renal toxicity occurred, which reflects the biased distribution of GalNAc-conjugated oligo to the liver. Delayed dose-related increases in liver enzymes, including alanine aminotransferase (ALT), were observed after the first dose with no further increases seen after subsequent doses. None of these findings were associated with adverse clinical signs and completeto-partial recovery occurred 3 months after last dose. No Observed Adverse Effect Levels (NOAELs) of 450 mg/kg and 45 mg/kg in mouse and monkey, respectively, were declared for RG-101, producing a 30–100 fold therapeutic index. Conclusions: Taken together, the PK/PD/Tox profile of RG-101 suggests that conjugation of oligos to GalNAc produces significant advantages that are likely to translate to more effective and safer clinical outcomes.
or placebo (Table). In the 3D+RBV arms, 5 patients had adherence <80% to one or more study drug; none of the 5 experienced virologic failure. In SAPPHIRE-I, patients with ontreatment virologic breakthrough (n = 1; 0.2%) or post-treatment relapse (n = 7; 1.5%) had ≥95% adherence to all 3 study drugs. In SAPPHIRE-II, all patients with post-treatment relapse (n = 7; 2.4%) had >98% adherence to 3D; 5 of 7 had >98% adherence to RBV, and 2 had missing RBV pill count data. In both trials, most adverse events were mild, and those leading to treatment discontinuation were infrequent: 0.8% (6/770.)
P0908 ADHERENCE TO OMBITASVIR/PARITAPREVIR/R, DASABUVIR, AND RIBAVIRIN IS >98% IN THE SAPPHIRE-I AND SAPPHIRE-II TRIALS T. Hassanein1 , S. Roberts2 , S.D. Shafran3 , M. Makara4 , M. Bennett5 , 6 B. Mullhaupt ¨ , F. Poordad7 , S. Ryder8 , A.M. Di Bisceglie9 , B. Fu10 , E. Coakley10 , B.H. McGovern10 , G.R. Foster11 . 1 Southern California Liver Centers and Southern California Research Center, Coronado, United States; 2 The Alfred Hospital, Melbourne, Australia; 3 University of Alberta Hospital, Edmonton, Canada; 4 Saint Laszlo Hospital, Budapest, Hungary; 5 San Diego Digestive Diseases, San Diego, United States; 6 University Hospital, Zurich, Switzerland; 7 The Texas Liver Institute/University of Texas Health Science Center, San Antonio, United States; 8 Nottingham Digestive Diseases Centre and Biomedical Research Unit, Nottingham, United Kingdom; 9 Saint Louis University Liver Center, Saint Louis University, Saint Louis, 10 AbbVie Inc., North Chicago, United States; 11 Queen Marys University of London, Barts Health, London, United Kingdom E-mail: [email protected]
a Adherence reflects days on study drug for all patients with pill count data available, including patients who discontinued or interrupted study drug for adverse events or other reasons. b Adherence data for each type of pill not available for all patients. c Treatment-experienced patients had a prior relapse, partial, or null response to pegIFN/ribavirin therapy.
Background and Aims: Scant data are available on adherence with direct-acting antiviral (DAA) regimens or the impact of poor adherence on virologic outcomes. Ombitasvir is a NS5A inhibitor and dasabuvir is an NS5B RNA polymerase inhibitor. Paritaprevir (formerly ABT-450) is a HCV NS3/4A protease inhibitor identified by AbbVie and Enanta and co-dosed with the pharmacokinetic enhancer ritonavir (r), to improve peak, trough and overall drug concentrations. We report adherence rates in the 3DAA + ribavirin (3D+RBV) and placebo arms in the phase 3 double-blind, placebo-controlled SAPPHIRE trials among 1025 HCV genotype (GT) 1-infected patients in 20 countries. Methods: Treatment-naïve (n = 631; SAPPHIRE-I) and treatmentexperienced patients (n = 394; SAPPHIRE-II) were randomized to 12 weeks of active treatment (3D+RBV: co-formulated ombitasvir/paritaprevir/r [25 mg/150 mg/100 mg QD] and dasabuvir [250 mg BID] with weight-based RBV [1000 or 1200 mg]), or placebo. For all patients with pill count data available during double-blind treatment, adherence was calculated as: (pills dispensed minus pills returned)/(total pills expected to be taken for days on study drug). Results: Of 1025 patients, 56% were male, 90% were white, mean (SD) age was 50.9 (10.6) years, and mean (SD) BMI was 26.0 (4.2) kg/m2 . Intent-to-treat SVR12 rates were 96.4% (SAPPHIRE-I) and 96.3% (SAPPHIRE-II). Mean adherence to each study drug in both trials was >98.8% for patients on 3D+RBV
Table: Summary of adherence to study drugs during double-blind treatment Adherence a , Mean % (SD), n b
Ombitasvir/Paritaprevir/r Dasabuvir RBV
SAPPHIRE-I HCV GT1 (treatment-naïve)
SAPPHIRE-II HCV GT1 (treatment-experienced c )
3D+RBV
Placebo
3D+RBV
Placebo
99.71 (1.75) n = 444 99.22 (3.07) n = 444 98.85 (3.96) n = 427
99.79 (1.81) n = 152 99.34 (2.13) n = 152 98.93 (2.18) n = 152
99.81 (1.00) n = 289 99.49 (1.10) n = 289 99.46 (5.66) n = 272
99.62 (0.84) n = 92 99.25 (0.84) n = 92 99.25 (2.42) n = 92
Conclusions: In this analysis, the multi-targeted IFN-free regimen of ombitasvir/paritaprevir/r and dasabuvir with RBV was well tolerated, with high rates of adherence (>98%) to all study drugs, including RBV at 1000 or 1200 mg. Low adherence rates were infrequent and did not lead to virologic failure. P0909 ANALYSIS OF NATURAL RESISTANCE PROFILE TO NS5A REPLICATION COMPLEX INHIBITORS IN DIFFERENT HEPATITIS C GENOTYPES S. Bagaglio1,2 , E. Messina1 , M. Merli1 , H. Hasson1 , A. Lazzarin1,2 , C. Uberti-Foppa1 , G. Morsica1 . 1 Infectious Diseases Department, Ospedale San Raffaele Scientific Institute, 2 Vita Salute University, Milan, Italy E-mail: [email protected] Background and Aims: Recent progress in the understanding of hepatitis C virus (HCV) biology has facilitated the development of direct-acting antiviral agents (DAAs) that target specific steps in the viral replication cycle. Several compounds thought to bind directly with NS5A are now in various clinical trial phases, including the most advanced, daclatasvir, ledipasvir and ABT-267. Resistance mutations have been mapped to the N-terminal region of NS5A (the first 100 amino acids within domain 1). Analysis from daclatasvir clinical trials showed that treatment failure was related to preexisting variants exhibiting resistance to NS5A inhibitors (NS5A-I) in patients infected by genotype (G) 1a and 1b. We aimed to evaluate the frequency of natural resistant variants to NS5A-I in different HCV genotypes. Methods: Changes reported to be associated with NS5A-I resistance (positions 28, 30, 31, 54, 58, 93) were examined. A total of 2831 (domain 1: aa 1–100) NS5A sequences deposited at Los Alamos HCV database were analysed: 1209 sequences belonged to G1a, 1552 to G1b, 48 to G3a and 22 to G4 (17 subtype 4a and 5 subtype 4d). Results: Overall, resistance associated mutations (RAM) were detected in 641 of 2831 (22.5%) isolates. In G1a sequences, 117 (10%) RAM has been detected: 37 sequences showed aa change
Journal of Hepatology 2015 vol. 62 | S263–S864
S685
POSTERS at position M28, 16 at Q30, 6 at L31, 37 at H58, 7 at Y93 and 14 sequences harboured 2 aa changes at least. In G1b sequences, 519 (33%) RAM has been detected: 78 isolates showed mutation at aa L31, 364 at Q54, 12 at Y93 and 65 strains harboured 2 aa changes at least. None of 48 G3a sequences showed RAM, 2 of 22 (9%) G4 sequences harboured P58T resistance mutation; both these isolates belonged to subtype 4d. The presence of natural RAM was more frequently reported in G1b than in G1a isolates (33% vs 10%; p < 0.0001). The frequency of variants harbouring more than one RAM was significantly different between G1a and G1b (1% vs 4%; p < 0.0001). Comparison among different genotype showed a significant difference (p < 0.0001). Conclusions: Natural polymorphisms in NS5A at positions that may influence susceptibility to NS5A-I were less frequently observed in genotypes 3a and 4. Surprisingly, G1a isolates showed a lower prevalence of natural RAM respect to G1b, both considering single RAM or variants with more than one resistance mutation. This information may provide further insights in evaluate the right interferon free regimen including DAAs combination. P0910 NO EVIDENCE OF PHARMACOKINETIC DRUG–DRUG INTERACTION IN HEALTHY SUBJECTS BETWEEN COADMINISTERED GRAZOPREVIR (MK-5172)/ELBASVIR (MK-8742) AND SOFOSBUVIR W.L. Marshall1 , W.W. Yeh1 , D. Stypinski2 , P. Auger2 , C. BethelBrown2 , L. Caro1,2 , P. Jumes1 , X. Huang1 , Z. Guo1 , M. Martinho1 , H-P Feng1 , D. Armas2 , J. Brejda2 , M. Iwamoto1 , J.R. Butterton1 . 1 Merck and Co., Inc., Whitehouse Station, NJ, 2 Celerion, Tempe, AZ, United States E-mail: [email protected] Background and Aims: Grazoprevir (MK-5172) is a potent, oncedaily inhibitor of the hepatitis C virus (HCV) NS3/4A protease, and elbasvir (MK-8742) is a potent, once-daily inhibitor of the HCV NS5A replication complex that are being developed as a fixed-dose combination therapy for the treatment of chronic HCV infection. This study evaluated the effect of grazoprevir and elbasvir on the pharmacokinetics of sofosbuvir (SOF), an HCV NS5B inhibitor, when coadministered in healthy subjects. Methods: This was an open-label, 2-period, fixed-sequence study to assess the effect of multiple oral doses of grazoprevir and elbasvir on the pharmacokinetics of a single oral dose of SOF. Sixteen healthy adult male and female subjects were enrolled. In Period 1, subjects received a single oral 400 mg dose of SOF. Following an 8 day washout period, in Period 2 multiple oral doses of 200 mg grazoprevir and 50 mg elbasvir were co-administered once daily from Days 1 to 15, inclusive. On Day 11, a single oral dose of SOF was co-administered with the dose of grazoprevir and elbasvir. Plasma pharmacokinetic parameters of SOF and its principal nucleoside metabolite (GS-331007) were measured in Period 1 and following Day 11 in Period 2. Results: SOF + grazoprevir + elbasvir/SOF alone geometric mean ratios (GMRs) [90% confidence intervals (90%CIs)] for plasma SOF AUC0–∞ and Cmax were 2.43 [2.12, 2.79] and 2.27 [1.72, 2.99], respectively. These changes in SOF are not considered to be clinically meaningful based on the safety margins of SOF. The GMRs [90% CIs] for plasma GS-331007 AUC0–infty; and Cmax for the same comparison were 1.13 [1.05, 1.21] and 0.87 [0.78, 0.96], respectively. These changes in GS-331007 are not considered to be clinically meaningful. Coadministration of SOF, grazoprevir, and elbasvir was generally well tolerated. Conclusions: Multiple dose administration of 200 mg grazoprevir and 50 mg elbasvir daily with a single dose of SOF was generally well tolerated by healthy subjects in this study. Co-administration of elbasvir and grazoprevir with SOF had no clinically meaningful effect on the PK of SOF and its metabolite GS-331007. Taken S686
together with the lack of potential for SOF to perpetrate a drug– drug interaction on grazoprevir or elbasvir, these results suggest that SOF, grazoprevir, and elbasvir may be coadministered without dose adjustment. P0911 CHARACTERIZATION OF CLINICAL PREDICTORS OF NATURALLY OCCURRING NS3/NS4A PROTEASE POLYMORPHISM IN GENOTYPE 1 HEPATITIS C VIRUS INFECTED PATIENTS G. Lisboa Neto1 , C. Noble2 , J.R.R. Pinho2 , F.M. Malta2 , M.S. GomesGouvˆea2 , M.V. Alvarado-Mora2 , M.H. Silva3 , A.G. Leite4 , L.Z. Piccoli4 , F.J. Carrilho2 , M.C. Mendes-Correa1 . 1 Department of Infectious Diseases, 2 LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of S˜ ao Paulo School of Medicine, 3 Centro de Referˆencia e Treinamento em DST/AIDS, S˜ ao Paulo, 4 Centro Especializado em Sa´ ude, Caxias do Sul, Brazil E-mail: [email protected] Background and Aims: Chronic hepatitis C is a major cause of liver disease worldwide. Its high replication rate and lack of proofreading activity lead to a great diversity in viral population (polymorphisms) that may emerge as dominant strains in a DAA’s therapy set. Spontaneously occurring resistance may impair the rate of success in some macrocyclic NS3 protease inhibitors (PI) based regimens. This study aimed to evaluate potential associations between the frequency of amino acid variations in NS3/NS4A protease of hepatitis C virus (HCV) and demographic/clinical features in chronic HCV infected patients. Methods: Clinical and epidemiological data were retrieved from medical records of 247 HCV chronically infected patients consecutively evaluated in 5 tertiary centers in Brazil. HCV NS3 analysis was performed by direct sequencing with Sanger-based technology. Results: 156 subjects (63.1%) were male and the mean age was 44.9(±9.6) years. Sixty-seven individuals (27.1%) had history of ethanol use. One hundred and twelve patients (45.3%) were coinfected with HIV. Overall, 21.9% of analyzed subjects had at least one amino acid substitution in HCV NS3 region [95% CI: 15.0–53.9]. Fourteen HCV samples (5.6%) harbored at least one NS3 PI resistance mutation (T54S, V55A or Q80R) [95% CI: 3.1–9.3]. Variables independently associated with NS3 amino acids substitutions were HCV subtype 1b (OR: 5.68, 95% CI: 2.61–12.35), total bilirubin level >1.5 ULN (OR: 5.25, 95% CI: 1.19–23.16) and albumin level <3.5 g/dL (OR: 3.88, 95% CI: 1.19–23.16). Conclusions: The frequency of HCV NS3 polymorphism in patients with laboratory markers of advanced liver disease was high, indicating a possible relation between length of hepatopathy and accumulation of such amino acid substitutions. HCV protease in subtype 1b appears to be highly variable in our country. P0912 EARLY-PHASE HCV KINETICS AND ROLE OF PRE-EXISTING RESISTANCE IN CIRRHOTIC OR INTERFERON-INSENSITIVE PATIENTS ON DACLATASVIR PLUS ASUNAPREVIR V. Cento1 , V. Calvaruso2 , S. Marenco3 , R. Alfieri4 , M. Aragri1 , F.P. Antonucci1 , V.C. Di Maio1 , S. Petta2 , A. Mazzola2 , L. Milanesi4 , A. Picciotto3 , F. Ceccherini-Silberstein1 , A. Craxì2 , C.F. Perno1 . 1 Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, 2 Gastroenterology, “P. Giaccone” University Hospital, Palermo, 3 Gastroenterology, “S. Martino” Hospital, Genova, 4 Institute for Biomedical Technologies, National Research Council, Segrate (Mi), Italy E-mail: [email protected] Background and Aims: The combination of daclatasvir (DCV) and asunaprevir (ASV) obtains HCV clearance in up to 90% of patients infected with HCV Gt-1, but treatment response is slower in subjects with a previous non-response to pegIFN+ribavirin (P/R).
Journal of Hepatology 2015 vol. 62 | S263–S864
or placebo (Table). In the 3D+RBV arms, 5 patients had adherence <80% to one or more study drug; none of the 5 experienced virologic failure. In SAPPHIRE-I, patients with ontreatment virologic breakthrough (n = 1; 0.2%) or post-treatment relapse (n = 7; 1.5%) had ≥95% adherence to all 3 study drugs. In SAPPHIRE-II, all patients with post-treatment relapse (n = 7; 2.4%) had >98% adherence to 3D; 5 of 7 had >98% adherence to RBV, and 2 had missing RBV pill count data. In both trials, most adverse events were mild, and those leading to treatment discontinuation were infrequent: 0.8% (6/770.)
P0908 ADHERENCE TO OMBITASVIR/PARITAPREVIR/R, DASABUVIR, AND RIBAVIRIN IS >98% IN THE SAPPHIRE-I AND SAPPHIRE-II TRIALS T. Hassanein1 , S. Roberts2 , S.D. Shafran3 , M. Makara4 , M. Bennett5 , 6 B. Mullhaupt ¨ , F. Poordad7 , S. Ryder8 , A.M. Di Bisceglie9 , B. Fu10 , E. Coakley10 , B.H. McGovern10 , G.R. Foster11 . 1 Southern California Liver Centers and Southern California Research Center, Coronado, United States; 2 The Alfred Hospital, Melbourne, Australia; 3 University of Alberta Hospital, Edmonton, Canada; 4 Saint Laszlo Hospital, Budapest, Hungary; 5 San Diego Digestive Diseases, San Diego, United States; 6 University Hospital, Zurich, Switzerland; 7 The Texas Liver Institute/University of Texas Health Science Center, San Antonio, United States; 8 Nottingham Digestive Diseases Centre and Biomedical Research Unit, Nottingham, United Kingdom; 9 Saint Louis University Liver Center, Saint Louis University, Saint Louis, 10 AbbVie Inc., North Chicago, United States; 11 Queen Marys University of London, Barts Health, London, United Kingdom E-mail: [email protected]
a Adherence reflects days on study drug for all patients with pill count data available, including patients who discontinued or interrupted study drug for adverse events or other reasons. b Adherence data for each type of pill not available for all patients. c Treatment-experienced patients had a prior relapse, partial, or null response to pegIFN/ribavirin therapy.
Background and Aims: Scant data are available on adherence with direct-acting antiviral (DAA) regimens or the impact of poor adherence on virologic outcomes. Ombitasvir is a NS5A inhibitor and dasabuvir is an NS5B RNA polymerase inhibitor. Paritaprevir (formerly ABT-450) is a HCV NS3/4A protease inhibitor identified by AbbVie and Enanta and co-dosed with the pharmacokinetic enhancer ritonavir (r), to improve peak, trough and overall drug concentrations. We report adherence rates in the 3DAA + ribavirin (3D+RBV) and placebo arms in the phase 3 double-blind, placebo-controlled SAPPHIRE trials among 1025 HCV genotype (GT) 1-infected patients in 20 countries. Methods: Treatment-naïve (n = 631; SAPPHIRE-I) and treatmentexperienced patients (n = 394; SAPPHIRE-II) were randomized to 12 weeks of active treatment (3D+RBV: co-formulated ombitasvir/paritaprevir/r [25 mg/150 mg/100 mg QD] and dasabuvir [250 mg BID] with weight-based RBV [1000 or 1200 mg]), or placebo. For all patients with pill count data available during double-blind treatment, adherence was calculated as: (pills dispensed minus pills returned)/(total pills expected to be taken for days on study drug). Results: Of 1025 patients, 56% were male, 90% were white, mean (SD) age was 50.9 (10.6) years, and mean (SD) BMI was 26.0 (4.2) kg/m2 . Intent-to-treat SVR12 rates were 96.4% (SAPPHIRE-I) and 96.3% (SAPPHIRE-II). Mean adherence to each study drug in both trials was >98.8% for patients on 3D+RBV
Table: Summary of adherence to study drugs during double-blind treatment Adherence a , Mean % (SD), n b
Ombitasvir/Paritaprevir/r Dasabuvir RBV
SAPPHIRE-I HCV GT1 (treatment-naïve)
SAPPHIRE-II HCV GT1 (treatment-experienced c )
3D+RBV
Placebo
3D+RBV
Placebo
99.71 (1.75) n = 444 99.22 (3.07) n = 444 98.85 (3.96) n = 427
99.79 (1.81) n = 152 99.34 (2.13) n = 152 98.93 (2.18) n = 152
99.81 (1.00) n = 289 99.49 (1.10) n = 289 99.46 (5.66) n = 272
99.62 (0.84) n = 92 99.25 (0.84) n = 92 99.25 (2.42) n = 92
Conclusions: In this analysis, the multi-targeted IFN-free regimen of ombitasvir/paritaprevir/r and dasabuvir with RBV was well tolerated, with high rates of adherence (>98%) to all study drugs, including RBV at 1000 or 1200 mg. Low adherence rates were infrequent and did not lead to virologic failure. P0909 ANALYSIS OF NATURAL RESISTANCE PROFILE TO NS5A REPLICATION COMPLEX INHIBITORS IN DIFFERENT HEPATITIS C GENOTYPES S. Bagaglio1,2 , E. Messina1 , M. Merli1 , H. Hasson1 , A. Lazzarin1,2 , C. Uberti-Foppa1 , G. Morsica1 . 1 Infectious Diseases Department, Ospedale San Raffaele Scientific Institute, 2 Vita Salute University, Milan, Italy E-mail: [email protected] Background and Aims: Recent progress in the understanding of hepatitis C virus (HCV) biology has facilitated the development of direct-acting antiviral agents (DAAs) that target specific steps in the viral replication cycle. Several compounds thought to bind directly with NS5A are now in various clinical trial phases, including the most advanced, daclatasvir, ledipasvir and ABT-267. Resistance mutations have been mapped to the N-terminal region of NS5A (the first 100 amino acids within domain 1). Analysis from daclatasvir clinical trials showed that treatment failure was related to preexisting variants exhibiting resistance to NS5A inhibitors (NS5A-I) in patients infected by genotype (G) 1a and 1b. We aimed to evaluate the frequency of natural resistant variants to NS5A-I in different HCV genotypes. Methods: Changes reported to be associated with NS5A-I resistance (positions 28, 30, 31, 54, 58, 93) were examined. A total of 2831 (domain 1: aa 1–100) NS5A sequences deposited at Los Alamos HCV database were analysed: 1209 sequences belonged to G1a, 1552 to G1b, 48 to G3a and 22 to G4 (17 subtype 4a and 5 subtype 4d). Results: Overall, resistance associated mutations (RAM) were detected in 641 of 2831 (22.5%) isolates. In G1a sequences, 117 (10%) RAM has been detected: 37 sequences showed aa change
Journal of Hepatology 2015 vol. 62 | S263–S864
S685
POSTERS at position M28, 16 at Q30, 6 at L31, 37 at H58, 7 at Y93 and 14 sequences harboured 2 aa changes at least. In G1b sequences, 519 (33%) RAM has been detected: 78 isolates showed mutation at aa L31, 364 at Q54, 12 at Y93 and 65 strains harboured 2 aa changes at least. None of 48 G3a sequences showed RAM, 2 of 22 (9%) G4 sequences harboured P58T resistance mutation; both these isolates belonged to subtype 4d. The presence of natural RAM was more frequently reported in G1b than in G1a isolates (33% vs 10%; p < 0.0001). The frequency of variants harbouring more than one RAM was significantly different between G1a and G1b (1% vs 4%; p < 0.0001). Comparison among different genotype showed a significant difference (p < 0.0001). Conclusions: Natural polymorphisms in NS5A at positions that may influence susceptibility to NS5A-I were less frequently observed in genotypes 3a and 4. Surprisingly, G1a isolates showed a lower prevalence of natural RAM respect to G1b, both considering single RAM or variants with more than one resistance mutation. This information may provide further insights in evaluate the right interferon free regimen including DAAs combination. P0910 NO EVIDENCE OF PHARMACOKINETIC DRUG–DRUG INTERACTION IN HEALTHY SUBJECTS BETWEEN COADMINISTERED GRAZOPREVIR (MK-5172)/ELBASVIR (MK-8742) AND SOFOSBUVIR W.L. Marshall1 , W.W. Yeh1 , D. Stypinski2 , P. Auger2 , C. BethelBrown2 , L. Caro1,2 , P. Jumes1 , X. Huang1 , Z. Guo1 , M. Martinho1 , H-P Feng1 , D. Armas2 , J. Brejda2 , M. Iwamoto1 , J.R. Butterton1 . 1 Merck and Co., Inc., Whitehouse Station, NJ, 2 Celerion, Tempe, AZ, United States E-mail: [email protected] Background and Aims: Grazoprevir (MK-5172) is a potent, oncedaily inhibitor of the hepatitis C virus (HCV) NS3/4A protease, and elbasvir (MK-8742) is a potent, once-daily inhibitor of the HCV NS5A replication complex that are being developed as a fixed-dose combination therapy for the treatment of chronic HCV infection. This study evaluated the effect of grazoprevir and elbasvir on the pharmacokinetics of sofosbuvir (SOF), an HCV NS5B inhibitor, when coadministered in healthy subjects. Methods: This was an open-label, 2-period, fixed-sequence study to assess the effect of multiple oral doses of grazoprevir and elbasvir on the pharmacokinetics of a single oral dose of SOF. Sixteen healthy adult male and female subjects were enrolled. In Period 1, subjects received a single oral 400 mg dose of SOF. Following an 8 day washout period, in Period 2 multiple oral doses of 200 mg grazoprevir and 50 mg elbasvir were co-administered once daily from Days 1 to 15, inclusive. On Day 11, a single oral dose of SOF was co-administered with the dose of grazoprevir and elbasvir. Plasma pharmacokinetic parameters of SOF and its principal nucleoside metabolite (GS-331007) were measured in Period 1 and following Day 11 in Period 2. Results: SOF + grazoprevir + elbasvir/SOF alone geometric mean ratios (GMRs) [90% confidence intervals (90%CIs)] for plasma SOF AUC0–∞ and Cmax were 2.43 [2.12, 2.79] and 2.27 [1.72, 2.99], respectively. These changes in SOF are not considered to be clinically meaningful based on the safety margins of SOF. The GMRs [90% CIs] for plasma GS-331007 AUC0–infty; and Cmax for the same comparison were 1.13 [1.05, 1.21] and 0.87 [0.78, 0.96], respectively. These changes in GS-331007 are not considered to be clinically meaningful. Coadministration of SOF, grazoprevir, and elbasvir was generally well tolerated. Conclusions: Multiple dose administration of 200 mg grazoprevir and 50 mg elbasvir daily with a single dose of SOF was generally well tolerated by healthy subjects in this study. Co-administration of elbasvir and grazoprevir with SOF had no clinically meaningful effect on the PK of SOF and its metabolite GS-331007. Taken S686
together with the lack of potential for SOF to perpetrate a drug– drug interaction on grazoprevir or elbasvir, these results suggest that SOF, grazoprevir, and elbasvir may be coadministered without dose adjustment. P0911 CHARACTERIZATION OF CLINICAL PREDICTORS OF NATURALLY OCCURRING NS3/NS4A PROTEASE POLYMORPHISM IN GENOTYPE 1 HEPATITIS C VIRUS INFECTED PATIENTS G. Lisboa Neto1 , C. Noble2 , J.R.R. Pinho2 , F.M. Malta2 , M.S. GomesGouvˆea2 , M.V. Alvarado-Mora2 , M.H. Silva3 , A.G. Leite4 , L.Z. Piccoli4 , F.J. Carrilho2 , M.C. Mendes-Correa1 . 1 Department of Infectious Diseases, 2 LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of S˜ ao Paulo School of Medicine, 3 Centro de Referˆencia e Treinamento em DST/AIDS, S˜ ao Paulo, 4 Centro Especializado em Sa´ ude, Caxias do Sul, Brazil E-mail: [email protected] Background and Aims: Chronic hepatitis C is a major cause of liver disease worldwide. Its high replication rate and lack of proofreading activity lead to a great diversity in viral population (polymorphisms) that may emerge as dominant strains in a DAA’s therapy set. Spontaneously occurring resistance may impair the rate of success in some macrocyclic NS3 protease inhibitors (PI) based regimens. This study aimed to evaluate potential associations between the frequency of amino acid variations in NS3/NS4A protease of hepatitis C virus (HCV) and demographic/clinical features in chronic HCV infected patients. Methods: Clinical and epidemiological data were retrieved from medical records of 247 HCV chronically infected patients consecutively evaluated in 5 tertiary centers in Brazil. HCV NS3 analysis was performed by direct sequencing with Sanger-based technology. Results: 156 subjects (63.1%) were male and the mean age was 44.9(±9.6) years. Sixty-seven individuals (27.1%) had history of ethanol use. One hundred and twelve patients (45.3%) were coinfected with HIV. Overall, 21.9% of analyzed subjects had at least one amino acid substitution in HCV NS3 region [95% CI: 15.0–53.9]. Fourteen HCV samples (5.6%) harbored at least one NS3 PI resistance mutation (T54S, V55A or Q80R) [95% CI: 3.1–9.3]. Variables independently associated with NS3 amino acids substitutions were HCV subtype 1b (OR: 5.68, 95% CI: 2.61–12.35), total bilirubin level >1.5 ULN (OR: 5.25, 95% CI: 1.19–23.16) and albumin level <3.5 g/dL (OR: 3.88, 95% CI: 1.19–23.16). Conclusions: The frequency of HCV NS3 polymorphism in patients with laboratory markers of advanced liver disease was high, indicating a possible relation between length of hepatopathy and accumulation of such amino acid substitutions. HCV protease in subtype 1b appears to be highly variable in our country. P0912 EARLY-PHASE HCV KINETICS AND ROLE OF PRE-EXISTING RESISTANCE IN CIRRHOTIC OR INTERFERON-INSENSITIVE PATIENTS ON DACLATASVIR PLUS ASUNAPREVIR V. Cento1 , V. Calvaruso2 , S. Marenco3 , R. Alfieri4 , M. Aragri1 , F.P. Antonucci1 , V.C. Di Maio1 , S. Petta2 , A. Mazzola2 , L. Milanesi4 , A. Picciotto3 , F. Ceccherini-Silberstein1 , A. Craxì2 , C.F. Perno1 . 1 Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, 2 Gastroenterology, “P. Giaccone” University Hospital, Palermo, 3 Gastroenterology, “S. Martino” Hospital, Genova, 4 Institute for Biomedical Technologies, National Research Council, Segrate (Mi), Italy E-mail: [email protected] Background and Aims: The combination of daclatasvir (DCV) and asunaprevir (ASV) obtains HCV clearance in up to 90% of patients infected with HCV Gt-1, but treatment response is slower in subjects with a previous non-response to pegIFN+ribavirin (P/R).
Journal of Hepatology 2015 vol. 62 | S263–S864