- Email: [email protected]
449 INCREASED IL28B PLASMA LEVEL IS ASSOCIATED WITH REDUCED IP-10, KLRD1 AND INCREASED MX1 EXPRESSION DURING CHRONICALLY EVOLVING ACUTE HCV INFECTION
POSTERS Results: In the Cases ALT was 1,063±1,038 IU/dL and total bilirubin 15.87±7.15 mg/dL. IL-28B CC genotype was more frequent in the Cases than the Controls (40.2% vs. 24.4%; p < 0.05). Sixty-nine Cases and 73 Controls were followed up for at least 2 years. In the Cases, 43.5% of patients showed a steady ALT increase ≥2-fold baseline values and 56.5% returned to their values before ae-CHC. Twenty-three Cases and 31 Controls, all naïve to anti-HCV therapy, had two liver biopsies, one before enrolment and one during the follow up [at a 5.85- (IQR 4.2–7.1) and 5.05- (IQR 4.18–6.89) year interval, respectively]. In these patients, deterioration in liver fibrosis ≥2 scores (Ishak) was observed in 18 (78.3%) Cases and in 11 (35.5%) Controls (p < 0.005); deterioration in necroinflammation ≥2 scores occurred in 14 (60.9%) Cases and 3 (9.6%) Controls (p < 0.005). Thirty-two (46.4%) Cases and 38 (52%) Controls received pegylated interferon plus ribavirin and a sustained viral response was achieved in 26 (81.2%) Cases and 23 (60.5%) Controls. Conclusion: ae-CHC is a clinical event frequently responsible for an unfavourable outcome; however, a clear tendency to achieve a SVR to antiviral therapy was observed. 447 CANNABINOID RECEPTOR 2 (CB2) 63 QQ VARIANT IS ASSOCIATED WITH A SEVERE HISTOLOGICAL ACTIVITY INDEX IN PATIENTS WITH CHRONIC HEPATITIS C N. Coppola, R. Zampino, G. Bellini, M. Macera, A. Marrone, M. Pisaturo, A. Boemio, B. Nobili, S. Maione, L.E. Adinolfi, E. Sagnelli, E. Miraglia del Giudice, F. Rossi. Second University of Naples, Naples, Italy E-mail: [email protected] Aims: To evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 SNP of the CNR2 gene leading to substitution of Arg (R) of codon 63 of cannabinoid receptor 2 (CB2) with Gln (Q). Patients and Methods: 169 consecutive anti-HCV/HCV-RNA positive patients (HCV group) were enrolled at the time of their first liver biopsy: males 59.1%; median age 53 years (range 18–80), median serum HCV-RNA 9x10E5 IU/ml (range 200–6.5x10E7), 70.4% with genotype 1. A control group of 51 consecutive patients with chronic hepatitis B (HBV group) who underwent their first liver biopsy was established: males 68.6%; median age 47 years (range 27–69); median serum HBV-DNA 1.5x10E5 IU/ml (range 150–1.1x10E7); all anti-HBe positive, all but two with HBV genotype D. All patients in the study were naive to antiviral therapy and were screened for the CNR2 rs357661398 SNP by direct sequencing. Results: The prevalence of patients with CB2–63 QQ variant was similar in the two groups (10.7% and 9.8%). CB2–63 RR variant was less frequently identified in HCV group than in HBV group (27.2% vs 47.1%, p < 0.05). Regarding HCV group, patients with CB2–63 QQ variant showed higher aminotransferase serum levels and higher score of Histological Activity Index (HAI) (Table 1); the logistic regression analysis identified CB2–63 QQ variant and fibrosis score as the only independent predictors of a more severe HAI (>8) (p < 0.0001). Table 1. HCV group
No. of patients Males, n (%) Median age, years (range) ALT (M ± SD), n.v.x HAI (M ± SD) Fibrosis scores* (M ± SD) Steatosis scores (M ± SD)
HBV group
CB2 RR
CB2 QR
CB2 QQ
CB2 RR
CB2 QR
CB2 QQ
46 27 (58.7) 51 (22–74) 2.1±1.3 A 5.3±3.6 C 2.3±1.4 1.4±1.3
105 62 (59) 52 (18–69) 2.3±1.8 5.8±3.3 D 2.3±1.4 1.2±1.2
18 12 (66.7) 50 (25–73) 3±2.2 B 8.6±3.8 E 2.7±1.7 1.3±1.3
24 17 (70.8) 46.5 (27–61) 4.4±7.5 6.8±3.1 2.8±1.7 1.0±1.1
22 15 (68.2) 46.5 (35–69) 3.2±2.4 5.8±3.6 2.7±1.6 1.0±1.0
5 4 (80) 47 (37–61) 3.5±1.0 6±1.7 2.8±1.3 1.6±1.8
*By Ishak. A vs. B: p < 0.05; C vs. E: p < 0.005; D vs. E: p < 0.001.
Discussion: The CB2 63 QQ variant in HCV patients was associated with more severe inflammation and hepatocellular necrosis.
448 IL28B GENOTYPE IS NOT ASSOCIATED WITH INSULIN RESISTANCE IN CHRONIC HEPATITIS C PATIENTS E. Degasperi1 , L. Valenti2 , A. Aghemo1 , R. De Francesco3 , R. Soffredini1 , R. D’Ambrosio1 , M. Rumi4 , L. Donnici3 , C. Cheroni3 , V. Zanoni3 , E. Orsi5 , M. Colombo1 . 1 First Division of Gastroenterology, 2 Division of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a degli Studi di Milano, 3 INGM – Istituto Nazionale Genetica Molecolare Milano, 4 Division of Hepatology, Ospedale San Giuseppe IRCCS Multimedica, Universit` a degli Studi di Milano, 5 Division of Endocrinology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a degli Studi di Milano, Milan, Italy E-mail: [email protected] Background: Recently, an association between IL28B genotype and insulin-resistance (IR), known predictors of outcome to PegInterferon (PegIFN) and Ribavirin (Rbv) treatment for chronic hepatitis C, has been hypothesized. Aim: To investigate the association of IR and IL28B genotype in two cohorts of well-characterized HCV patients. Methods: A total of 480 non-diabetic HCV patients were analyzed: 391 non-diabetic patients from the MIST study, and 89 from a previous study conducted at the Metabolic Center of Liver Diseases. All patients were tested for IL28B rs12979860 SNP by RT-PCR and had IR measured by HOMA-IR. Staging of liver disease through liver biopsy was available for all patients. Results: Of the 480 patients included in the study, 164 (34%) were IL28B CC, 316 (66%) were CT/TT. Mean HOMA-IR values did not differ according to IL28B genotype, being respectively 1.14±0.78 in CC vs 1.14±0.78 in CT/TT in the first cohort and 2.4±1.0 vs 2.5±1.0 in the second cohort. HOMA-IR >2 was not associated with IL28B genotype, as it was found in 18/132 CC vs 37/259 CT/TT (p = 1.0) in the first cohort, and 17/32 vs 40/57 (p = 0.12) in the second. In the MIST cohort HOMA-IR >2 did not influence treatment outcome, as sustained virological response (SVR) rates were 28/47 (60%) in HOMA-IR>2 vs 214/344 (62%) in HOMA-IR <2 (p = 0.8). On the contrary, IL28B genotype was a strong predictor of SVR: 84% (111/132) in CC vs 51% (131/259) in CT/TT patients (p < 0.0001). Conclusions: In two large cohorts of non-diabetic HCV patients where IL28B genotype predicted treatment outcome, we found no association between IL28B genotype and HOMA-IR. 449 INCREASED IL28B PLASMA LEVEL IS ASSOCIATED WITH REDUCED IP-10, KLRD1 AND INCREASED MX1 EXPRESSION DURING CHRONICALLY EVOLVING ACUTE HCV INFECTION M. Depla1 , C. Brunaud1,2 , J. Bruneau1,3 , N. Shoukry1,4 . 1 Centre de Recherche du CHUM, CRCHUM St Luc, 2 Immunologie et Microbiologie, Universit´e de Montr´eal, 3 D´epartement de M´edecine Familiale, 4 D´epartement de M´edecine, Facult´e de M´edecine, Universit´e de Montr´eal, Montr´eal, QC, Canada E-mail: [email protected] Background: Polymorphisms in the IL28B gene, encoding IFN-l3, can predict spontaneous resolution of HCV. This predictive feature may be enhanced when combined with polymorphisms in the killer cell immunoglobulin-like receptor (KIR) genes controlling the function of natural killer (NK) cells. We have previously demonstrated that NK cells are activated during acute HCV infection irrespective of its outcome and that their activity correlated with the magnitude of adaptive T cell responses, essential for viral clearance. This suggests that cross-talk between the two components of the immune system is an important determinant of infectious outcome. Here, we hypothesized that IL28B polymorphisms modulate the expression of IL28B during acute HCV and, consequently, the induction and cross-talk between innate and adaptive immunity including the induction of innate
Journal of Hepatology 2013 vol. 58 | S63–S227
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POSTERS immune genes, activation and recruitment of NK cells and T cells to the liver. Methods: We performed longitudinal quantification of the levels of IL28B by ELISA on plasma samples collected from a cohort of injection drug users (n = 30) during acute HCV infection with different outcomes. In addition, we used qRT-PCR to monitor expression of seven genes previously associated with response to interferon following HCV infection in in vitro models (IFI6, IFIT1, Mx1, USP18, IP-10) and NK cell activity (NCR3, KLRD1). Results: We observed that patients homozygous for the favourable IL28B rs12979860 C allele (CC) expressed higher levels of IL28B during early acute infection as compared to patients bearing the non-favourable T allele (*/T) (p = 0.0205). This observation became more significant when only acute infected patients with chronic evolution were analysed (p = 0.0047). IL28B plasma levels did not correlate with induction of genes examined in PBMCs except for IP-10, KLRD1 and Mx1. Higher IL28B plasma levels correlated with decreased expression of IP-10 (p = 0.0016) and KLRD1 (CD94) (p = 0.0002) and increased expression of Mx1 (p = 0.0283) only in patients with chronic evolution despite having the favourable genotype. Conclusions: Our results suggest that IL28B polymorphism may modulate the recruitment of immune cells to the liver and the NK cell activity by affecting the expression of the interferonstimulated chemokine IP-10 and antiviral protein Mx1, and the NK cell inhibitory receptor KLRD1. 450 A NOVEL PREDICTION MODEL FOR LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS USING FIBROSCAN AND ROUTINE LABORATORY DATA M. El Raziky1 , A.B. Awad2 , M. Youssef1 , A. Awad2 , A. Elsharkawi1 , G. Esmat1 , M. Mustafa1 , M. Mabrouk1 . 1 Faculty of Medicine Cairo University, 2 Computer Science, Faculty of Computers and Information, Cairo University, Cairo, Egypt E-mail: [email protected] Background: Data mining analysis explores data to discover hidden patterns, trends and enables the development of model to assess liver fibrosis utilizing liver stiffness measured by fibro-scan and simple laboratory data. Aim: To develop a novel model to predict the stage of fibrosis in chronic HCV patients using fibro-scan and routine clinical and laboratory data. Methods: Decision tree learning algorithm was applied to routine laboratory data of 296 chronic HCV Egyptian patients for model building using 20 attributes. Internal cross-validation was performed with 10-folds, and confidence (0.01). Liver histopathology (Metavir scoring) was used to assess accuracy for the model. Transient elastography measurement was used. Results: Fibrosis was classified into three groups F0–F1 (minimal), F2–F3 (moderate), and F4 (severe). The correctly classified instances were 218/296 (74%). Decision tree was able to diagnose F0–F1, F2–F3, and F4 with sensitivity 59% and specificity 36% using only routine data, and with sensitivity 70% and specificity 68.5% using fibroscan. At stiffness 7.25 fibroscan was able to diagnose liver fibrosis F0–F1with sensitivity 84% and specificity 85% and F2 F3 F4 with sensitivity 78% and specificity 76%. Out of 20 attributes the decision tree models showed that liver stiffness was selected as the variable of initial split (most decisive), with optimal cut-off value of <7.1 the possibility of being F0–F1 167/18 was 89.2%. At liver stiffness from 7.1–13.6 the possibility of being F2–F3 76/33 was 56.7%. Patients with liver stiffness >13.6, hepatic texture was the second important splitting attribute, other attributes as albumin, and AFP have less decisive role for prediction of fibrosis. as shown in fig (1). These results were confirmed statistically using univariate logistic regression analysis with P value <0.01. The reproducibility S184
of the model was confirmed by external validation set on 249 at cut off value <7.1 patients with correctly classified instances 90/15 (83.3%). Liver stiffness from 7.1–13.6 correctly classified instances is 76/20 (73.6). Conclusion: The model tree using fibro-scan and routine clinical and laboratory data can predict degree of hepatic fibrosis in chronic HCV patients with high accuracy and reproducibility. 451 EVALUATION OF PHARMACOKINETIC DRUG–DRUG INTERACTION (DDI) BETWEEN BMS-791325, AN NS5B NON-NUCLEOTIDE POLYMERASE INHIBITOR, DACLATASVIR AND ASUNAPREVIR IN TRIPLE COMBINATION IN HCV GENOTYPE 1-INFECTED PATIENTS X. Wang, W. Li, S.-P. Huang, B. He, E. Chung, A. Griffies, E. Cooney, E. Hughes, H. Kandoussi, K. Sims, D. Gardiner, R. Bertz, T. Eley. Bristol-Myers Squibb, Princeton, NJ, USA E-mail: [email protected] Background and Aims: Interferon and ribavirin free treatments for HCV may be achieved by combinations of direct-acting antivirals. Daclatasvir (DCV), an NS5A replication complex inhibitor, and asunaprevir (ASV), an NS3 protease inhibitor were combined with BMS-791325, a potent, selective non-nucleoside inhibitor of the NS5B polymerase, to treat HCV genotype (GT) 1-infected patients. All three drugs are P-glycoprotein substrates, CYP3A4 substrates, OATP1B1 inhibitors and P-glycoprotein inhibitors in vitro and/or in vivo. ASV induces CYP3A4, and is an OATP1B1 substrate. BMS791325 appears to induce CYP3A4. BMS-794712 is the active metabolite of BMS-791325. No clinically meaningful DDI occurred previously between DCV and ASV. In this study, potential DDIs of the triple combination were assessed in a subset of patients. Methods: Study AI443014 is a phase 2a open-label, multipledose study combining DCV (60 mg QD), ASV (200 mg BID, tablet), and BMS-791325 at two doses (75 mg BID or 150 mg BID) in 32 treatment-naive, HCV GT 1-infected, non-cirrhotic patients for 12 or 24 weeks. Non-compartmental pharmacokinetic parameters were derived on Day 14. The pharmacokinetics of all analytes in each regimen (N = 12 for 75 mg BID and N = 18 for 150 mg BID), including BMS-794712, were explored versus historical data graphically and using descriptive statistics. Results: See Table. Day 14 exposures: DCV and BMS-791325 were comparable to historical data. ASV exposures appeared to be reduced by ~30%; variability was high. Metabolic ratio for BMS794712 was ~25%. Conclusion: No clinically meaningful interaction was observed by addition of BMS-791325 to DCV and ASV. Additional study of both doses of BMS-791325 in this triple combination is warranted to confirm the most appropriate dose in broader patient populations. Table: AUC(TAU) (ng*h/mL), Geometric Mean (CV%) on Day 14
Daclatasvir Asunaprevir BMS-791325 BMS-794712
This study
Historical values
11248 (36)* 1065 (78)* 9554 (65)‡ 2364 (48)‡
10700 (30.7) (N = 11)† 1528 (106) (N = 12)† 9170 (34)§ 2150 (35)§
*DCV 60 mg QD+ASV 200 mg BID+BMS-791325 150 mg BID; † DCV 60 mg QD+ASV 200 mg BID in HCV-1 patients; ‡ DCV 60 mg QD+ASV 200 mg BID+BMS-791325 75 mg BID; § BMS-791325 75 mg BID+peginterferon alfa2a+ribavirin in HCV-1 patients (N = 12).
Journal of Hepatology 2013 vol. 58 | S63–S227
No. of patients Males, n (%) Median age, years (range) ALT (M ± SD), n.v.x HAI (M ± SD) Fibrosis scores* (M ± SD) Steatosis scores (M ± SD)
HBV group
CB2 RR
CB2 QR
CB2 QQ
CB2 RR
CB2 QR
CB2 QQ
46 27 (58.7) 51 (22–74) 2.1±1.3 A 5.3±3.6 C 2.3±1.4 1.4±1.3
105 62 (59) 52 (18–69) 2.3±1.8 5.8±3.3 D 2.3±1.4 1.2±1.2
18 12 (66.7) 50 (25–73) 3±2.2 B 8.6±3.8 E 2.7±1.7 1.3±1.3
24 17 (70.8) 46.5 (27–61) 4.4±7.5 6.8±3.1 2.8±1.7 1.0±1.1
22 15 (68.2) 46.5 (35–69) 3.2±2.4 5.8±3.6 2.7±1.6 1.0±1.0
5 4 (80) 47 (37–61) 3.5±1.0 6±1.7 2.8±1.3 1.6±1.8
*By Ishak. A vs. B: p < 0.05; C vs. E: p < 0.005; D vs. E: p < 0.001.
Discussion: The CB2 63 QQ variant in HCV patients was associated with more severe inflammation and hepatocellular necrosis.
448 IL28B GENOTYPE IS NOT ASSOCIATED WITH INSULIN RESISTANCE IN CHRONIC HEPATITIS C PATIENTS E. Degasperi1 , L. Valenti2 , A. Aghemo1 , R. De Francesco3 , R. Soffredini1 , R. D’Ambrosio1 , M. Rumi4 , L. Donnici3 , C. Cheroni3 , V. Zanoni3 , E. Orsi5 , M. Colombo1 . 1 First Division of Gastroenterology, 2 Division of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a degli Studi di Milano, 3 INGM – Istituto Nazionale Genetica Molecolare Milano, 4 Division of Hepatology, Ospedale San Giuseppe IRCCS Multimedica, Universit` a degli Studi di Milano, 5 Division of Endocrinology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a degli Studi di Milano, Milan, Italy E-mail: [email protected] Background: Recently, an association between IL28B genotype and insulin-resistance (IR), known predictors of outcome to PegInterferon (PegIFN) and Ribavirin (Rbv) treatment for chronic hepatitis C, has been hypothesized. Aim: To investigate the association of IR and IL28B genotype in two cohorts of well-characterized HCV patients. Methods: A total of 480 non-diabetic HCV patients were analyzed: 391 non-diabetic patients from the MIST study, and 89 from a previous study conducted at the Metabolic Center of Liver Diseases. All patients were tested for IL28B rs12979860 SNP by RT-PCR and had IR measured by HOMA-IR. Staging of liver disease through liver biopsy was available for all patients. Results: Of the 480 patients included in the study, 164 (34%) were IL28B CC, 316 (66%) were CT/TT. Mean HOMA-IR values did not differ according to IL28B genotype, being respectively 1.14±0.78 in CC vs 1.14±0.78 in CT/TT in the first cohort and 2.4±1.0 vs 2.5±1.0 in the second cohort. HOMA-IR >2 was not associated with IL28B genotype, as it was found in 18/132 CC vs 37/259 CT/TT (p = 1.0) in the first cohort, and 17/32 vs 40/57 (p = 0.12) in the second. In the MIST cohort HOMA-IR >2 did not influence treatment outcome, as sustained virological response (SVR) rates were 28/47 (60%) in HOMA-IR>2 vs 214/344 (62%) in HOMA-IR <2 (p = 0.8). On the contrary, IL28B genotype was a strong predictor of SVR: 84% (111/132) in CC vs 51% (131/259) in CT/TT patients (p < 0.0001). Conclusions: In two large cohorts of non-diabetic HCV patients where IL28B genotype predicted treatment outcome, we found no association between IL28B genotype and HOMA-IR. 449 INCREASED IL28B PLASMA LEVEL IS ASSOCIATED WITH REDUCED IP-10, KLRD1 AND INCREASED MX1 EXPRESSION DURING CHRONICALLY EVOLVING ACUTE HCV INFECTION M. Depla1 , C. Brunaud1,2 , J. Bruneau1,3 , N. Shoukry1,4 . 1 Centre de Recherche du CHUM, CRCHUM St Luc, 2 Immunologie et Microbiologie, Universit´e de Montr´eal, 3 D´epartement de M´edecine Familiale, 4 D´epartement de M´edecine, Facult´e de M´edecine, Universit´e de Montr´eal, Montr´eal, QC, Canada E-mail: [email protected] Background: Polymorphisms in the IL28B gene, encoding IFN-l3, can predict spontaneous resolution of HCV. This predictive feature may be enhanced when combined with polymorphisms in the killer cell immunoglobulin-like receptor (KIR) genes controlling the function of natural killer (NK) cells. We have previously demonstrated that NK cells are activated during acute HCV infection irrespective of its outcome and that their activity correlated with the magnitude of adaptive T cell responses, essential for viral clearance. This suggests that cross-talk between the two components of the immune system is an important determinant of infectious outcome. Here, we hypothesized that IL28B polymorphisms modulate the expression of IL28B during acute HCV and, consequently, the induction and cross-talk between innate and adaptive immunity including the induction of innate
Journal of Hepatology 2013 vol. 58 | S63–S227
S183
POSTERS immune genes, activation and recruitment of NK cells and T cells to the liver. Methods: We performed longitudinal quantification of the levels of IL28B by ELISA on plasma samples collected from a cohort of injection drug users (n = 30) during acute HCV infection with different outcomes. In addition, we used qRT-PCR to monitor expression of seven genes previously associated with response to interferon following HCV infection in in vitro models (IFI6, IFIT1, Mx1, USP18, IP-10) and NK cell activity (NCR3, KLRD1). Results: We observed that patients homozygous for the favourable IL28B rs12979860 C allele (CC) expressed higher levels of IL28B during early acute infection as compared to patients bearing the non-favourable T allele (*/T) (p = 0.0205). This observation became more significant when only acute infected patients with chronic evolution were analysed (p = 0.0047). IL28B plasma levels did not correlate with induction of genes examined in PBMCs except for IP-10, KLRD1 and Mx1. Higher IL28B plasma levels correlated with decreased expression of IP-10 (p = 0.0016) and KLRD1 (CD94) (p = 0.0002) and increased expression of Mx1 (p = 0.0283) only in patients with chronic evolution despite having the favourable genotype. Conclusions: Our results suggest that IL28B polymorphism may modulate the recruitment of immune cells to the liver and the NK cell activity by affecting the expression of the interferonstimulated chemokine IP-10 and antiviral protein Mx1, and the NK cell inhibitory receptor KLRD1. 450 A NOVEL PREDICTION MODEL FOR LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS USING FIBROSCAN AND ROUTINE LABORATORY DATA M. El Raziky1 , A.B. Awad2 , M. Youssef1 , A. Awad2 , A. Elsharkawi1 , G. Esmat1 , M. Mustafa1 , M. Mabrouk1 . 1 Faculty of Medicine Cairo University, 2 Computer Science, Faculty of Computers and Information, Cairo University, Cairo, Egypt E-mail: [email protected] Background: Data mining analysis explores data to discover hidden patterns, trends and enables the development of model to assess liver fibrosis utilizing liver stiffness measured by fibro-scan and simple laboratory data. Aim: To develop a novel model to predict the stage of fibrosis in chronic HCV patients using fibro-scan and routine clinical and laboratory data. Methods: Decision tree learning algorithm was applied to routine laboratory data of 296 chronic HCV Egyptian patients for model building using 20 attributes. Internal cross-validation was performed with 10-folds, and confidence (0.01). Liver histopathology (Metavir scoring) was used to assess accuracy for the model. Transient elastography measurement was used. Results: Fibrosis was classified into three groups F0–F1 (minimal), F2–F3 (moderate), and F4 (severe). The correctly classified instances were 218/296 (74%). Decision tree was able to diagnose F0–F1, F2–F3, and F4 with sensitivity 59% and specificity 36% using only routine data, and with sensitivity 70% and specificity 68.5% using fibroscan. At stiffness 7.25 fibroscan was able to diagnose liver fibrosis F0–F1with sensitivity 84% and specificity 85% and F2 F3 F4 with sensitivity 78% and specificity 76%. Out of 20 attributes the decision tree models showed that liver stiffness was selected as the variable of initial split (most decisive), with optimal cut-off value of <7.1 the possibility of being F0–F1 167/18 was 89.2%. At liver stiffness from 7.1–13.6 the possibility of being F2–F3 76/33 was 56.7%. Patients with liver stiffness >13.6, hepatic texture was the second important splitting attribute, other attributes as albumin, and AFP have less decisive role for prediction of fibrosis. as shown in fig (1). These results were confirmed statistically using univariate logistic regression analysis with P value <0.01. The reproducibility S184
of the model was confirmed by external validation set on 249 at cut off value <7.1 patients with correctly classified instances 90/15 (83.3%). Liver stiffness from 7.1–13.6 correctly classified instances is 76/20 (73.6). Conclusion: The model tree using fibro-scan and routine clinical and laboratory data can predict degree of hepatic fibrosis in chronic HCV patients with high accuracy and reproducibility. 451 EVALUATION OF PHARMACOKINETIC DRUG–DRUG INTERACTION (DDI) BETWEEN BMS-791325, AN NS5B NON-NUCLEOTIDE POLYMERASE INHIBITOR, DACLATASVIR AND ASUNAPREVIR IN TRIPLE COMBINATION IN HCV GENOTYPE 1-INFECTED PATIENTS X. Wang, W. Li, S.-P. Huang, B. He, E. Chung, A. Griffies, E. Cooney, E. Hughes, H. Kandoussi, K. Sims, D. Gardiner, R. Bertz, T. Eley. Bristol-Myers Squibb, Princeton, NJ, USA E-mail: [email protected] Background and Aims: Interferon and ribavirin free treatments for HCV may be achieved by combinations of direct-acting antivirals. Daclatasvir (DCV), an NS5A replication complex inhibitor, and asunaprevir (ASV), an NS3 protease inhibitor were combined with BMS-791325, a potent, selective non-nucleoside inhibitor of the NS5B polymerase, to treat HCV genotype (GT) 1-infected patients. All three drugs are P-glycoprotein substrates, CYP3A4 substrates, OATP1B1 inhibitors and P-glycoprotein inhibitors in vitro and/or in vivo. ASV induces CYP3A4, and is an OATP1B1 substrate. BMS791325 appears to induce CYP3A4. BMS-794712 is the active metabolite of BMS-791325. No clinically meaningful DDI occurred previously between DCV and ASV. In this study, potential DDIs of the triple combination were assessed in a subset of patients. Methods: Study AI443014 is a phase 2a open-label, multipledose study combining DCV (60 mg QD), ASV (200 mg BID, tablet), and BMS-791325 at two doses (75 mg BID or 150 mg BID) in 32 treatment-naive, HCV GT 1-infected, non-cirrhotic patients for 12 or 24 weeks. Non-compartmental pharmacokinetic parameters were derived on Day 14. The pharmacokinetics of all analytes in each regimen (N = 12 for 75 mg BID and N = 18 for 150 mg BID), including BMS-794712, were explored versus historical data graphically and using descriptive statistics. Results: See Table. Day 14 exposures: DCV and BMS-791325 were comparable to historical data. ASV exposures appeared to be reduced by ~30%; variability was high. Metabolic ratio for BMS794712 was ~25%. Conclusion: No clinically meaningful interaction was observed by addition of BMS-791325 to DCV and ASV. Additional study of both doses of BMS-791325 in this triple combination is warranted to confirm the most appropriate dose in broader patient populations. Table: AUC(TAU) (ng*h/mL), Geometric Mean (CV%) on Day 14
Daclatasvir Asunaprevir BMS-791325 BMS-794712
This study
Historical values
11248 (36)* 1065 (78)* 9554 (65)‡ 2364 (48)‡
10700 (30.7) (N = 11)† 1528 (106) (N = 12)† 9170 (34)§ 2150 (35)§
*DCV 60 mg QD+ASV 200 mg BID+BMS-791325 150 mg BID; † DCV 60 mg QD+ASV 200 mg BID in HCV-1 patients; ‡ DCV 60 mg QD+ASV 200 mg BID+BMS-791325 75 mg BID; § BMS-791325 75 mg BID+peginterferon alfa2a+ribavirin in HCV-1 patients (N = 12).
Journal of Hepatology 2013 vol. 58 | S63–S227