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Patient body weight and response to interferon alfa 2b monotherapy
HEPATOLOGYVok 34, No. 4, Pt. 2, 2001
AASLD ABSTRACTS
421A
995 IMPAIRED CHOLESTEROL SYNTHESIS IN PATIENTS INFECTED WITH H CV-3o~. EFFECT OF ANTIVIRAL THERAPY. Harald Hofer, Dept of Internal Medicine IV, Vienna Austria; Fritz Wrba, Dept of Clinical Pathology, Vienna Austria; Petra Steindl-Munda, Christian Mueller, Alfred Gangl, Peter Ferenci, Dept of Internal Medicine IV, Vienna Austria
996 AMANTADINE AND RIMANTADINE HAVE NO SIGNIFICANT ANTIHCV ACTIVITY IN A REPLICON CELL CULTURE SYSTEM, BOTH ALONE AND IN COMBINATION WITH INTERFERON/RIBAVIRIN. Vicky C Lai, Jane W Fang, Suhaila Naim, Johnson Y kau, Weidong Zhong, ICN Pharmaceuticals, Costa Mesa, CA
Background and Significance: Recent evidence suggests that hepatoceflular fat accumulation is more common in patients chronically infected with the hepatitis C virus genotype 3a (HCV-3a) than with other genotypes. Hepatucellular fat accumulation is also associated with low serum cholesterol levels in HCV3a. The aim of this study was to investigate the influence of antiviral therapy on serum lipid parameters in patients with different HCV-genotypes. Patients and Methods: A liver biopsy was obtained from 137 de novo patients with chronic hepatitis C (CHC) (m=102, f=35, mean age: 40.8-+10.7) enrolled in two prospective clinical trials of IFN/ribavirin therapy. No patient had diabetes mellitus, was actively using drugs, was on methadone replacement therapy, or consumed more than 20g alcohol/d. Body mass index (BMI), fasting triglycerides and cholesterol levels were determined at baseline, during and after therapy. Results: Marked steatosis (defined as >20% of hepatocytes containing fat droplets) was present in 35 of 47 (74.5%) patients with HCV-3a, in i2 of 67 (17.9%) patients with HCV-1 and in 5 of 23 (21.7%) with genotype 4. In contrast to patients infected with genotypes 1 or 4, steatosis in patients with HCV-3a did not correlate with the BMI. No patient with genotype 3a had cicrhosis. Prior to initiation of therapy, serum cholesterol levels were lower in patients infected with HCV-3a as compared to HCV-I or HCV-4 (147---42 [mg/dl; mean-+SD1 vs. 188-+36.4 vs. 172-+35.2; p<0.01). At end of treatment (ET), serum cholesterol increased in responding HCV-3a patients (ET vs. baseline: 166.7-+29 vs. 146-+38 at p=0.01) but remained unchanged in patients HCV-RNA positive at ET. Six months after therapy, in HCV-3a sustained virological responders (SVR) serum cholesterol further increased (200-+34; p<0.01), but remained unchanged low m nonresponders (NR) or relapsers (136-+44). In HCV-1 serum cholesterol decreased on antiviral therapy (ET vs. baseline: responder: i70-+38 vs. 190-+44, NR: i62-+24 vs.191-+29; NS) and reached baseline levels six months after therapy irrespective of response (SVR: 201-+35, NR: 162---24; NS). Conclusion: HCV-3a appears to interfere with hepatic cholesterol synthesis and fat metabolism. This may explain the occurre_nce and extent of hepatic steatosis in these patients. After successful HCV-3a eradication by antiviral treatment serum cholesterol levels increase into the normal range. This unique property is not shared by other HCV-genotypes.
Introduction: Amantadine, a drug known to inhibit influenza A M2 protein function, was recently reported to be an effective treatment in a segment of patients with chronic hepatitis C virus (HCV) infection. The data on the combination use of amantadine and interferon-odribavirin was controversial Rimantadine is a related analogue of amantadine. Aim: To determine whether amantadine or rimantadine has any direct anti-HCV activity in a cell-based HCV replicon system. Methods: Sequence homology was performed using MacVector, version 6.5.3. The in vitro anti-HCV activity was assessed using Huh-7 cells that contain a self-replicating HCV subgenomic RNA with a luciferase reporter gene. Cells were incubated with the drugs for 72 hours after which luciferase activity was measured. Reduction of HCV RNA was calculated based on the luciferase read-out and expressed as ICso. Cytotoxicity was evaluated by MTT cell viability assay and expressed as CCs0. These drugs were also tested in combination with ribavirin (0-200/aM) and IFN-a to determine their effects on the efficacy of the combination therapy. Results: Sequence comparison showed no homology between tnfuenza M2 and any of the HCV proteins. We previously reported that amantadine and rimantadine have no inhibitory activity against HCV protease, helicase, ATPase, polymerase and IRES in biochemical assays in vitro. In the HCV subgenomic replicon cell culture system, amantadine and rimantadine showed weak anti-HCV activity, with ICso at 200 b~Mand 75/aM, respectively (Cmaxin clinical studies for amantadine: 1-3/aM). This is close to the toxicity level of these compounds, with CCsoat 500/aM and 200 bsM, respectively, giving selectivity index of <3 for both compounds. Addition of amantadine and rimantadine did not significantly" augment the anti-HCV activity observed with IFN-odribavirin combination. Conclusions: (1) Amantadine and rimantadine did not effectively inhibit HCV RNA replication in the replicon cell culture model. The observed weak activity closely paralleled with toxicity. (2) Amantadine and rimantadine did not significantly augment the anti-HCV activity of IFN-a/ribavirin.
997
998
COMBINATION ANTMRAL THERAPY IN PATIENTS W I T H CHRONIC HEPATITIS C A N D CRYOGLOBULINEMIA. Warren N Schmidt, Douglas R Labrecque, Michael D Voigt, Jack T Stapleton, Stephen C Rayhill, Feng Wen, Mary Jeanne Perino-Phillips, Judy M Swift, Jane M Hershberger, Laura A Ippolito, Deana L Geraets, Stephanie A Schmid, University of Iowa, Iowa City, IA
PATIENT BODY WEIGHT A N D RESPONSE TO INTERFERON ALFA 2B MONOTHERAPY. John G McHutchison, Scripps Clinic, LaJolla, CA; Thierry Poynard, Pitie-Salpetriere, Paris France; Keyur Patel, Scripps Clinic, La Jolla, CA; Mei-Hsiu Ling, Schering Plough Research Institute, Kenilworth, NJ;JeanJacques Garaud, Schering Plough Research Institute, Kenwilworth, NM;Janice Albrecht For The Hepatitis [nterventional Therapy Group, Schering Plough Research Institute, Kenilworth, NJ
Introduction: Although cryoprecipitate occurs in about 40% of patients with HCV and chronic hepatitis, there is little information on the efficacy of combination therapy in patients with detectable cryoglobulins. We recently found that patients with cryoprecipitate (CP+) had increased fibrosis and cirrhosis when compared to patients without cryoprecipitate (CP-), suggesting that cryoglobulins may be an important clinical prognostic parameter. The overall aim of this study was to evaluate virological response to antiviral therapy in patients with or without CP. Methods: 139 patients with chronic hepatitis C were treated with standard dosages of Interferon a-2b(3.0 x 106 U, sc, tiw), plus ribavirin 1000-1200 mg PO QD for 24-48 weeks depending on HCV genotFpe. Liver biopsies were obtained prior to therapy and graded for histologic inflammation and fibrosis by standard pathologic analysis. Results: 53 patients had detectable CP (38%) and 86 did not (62%). There were no significant differences in genotype, age, duration of disease, alcohol consumption, or risk factors for HCV transmission between the two groups. In agreement with our previous findings, histologic evaluation of pre-treatment liver biopsies showed increased bridging fibrosis and cirrhosis in the CP+ patients when compared to CP- patients (p<.03). In contrast, no difference in the inflammatory activity profiles was observed. The percentages of virological nonresponders (NR), relapsers (R), and sustained responders (SR) are listed in the table below. CP+ patients had a significantly higher incidence of SR than CPpatients (p = 0.037) while there was no difference in NR and R between the two groups. Currently, 5 CP+ and 4 CP- patients are still on treatment. Seven of the 139 patients did not complete therapy. Conclusions: In spite of the fact that CP+ patients had more advanced liver disease than those CP-, they responded more favorably to antiviral therapy. These findings suggest that cryoprecipitates may be a useful parameter in the evaluation and treatment of patients with chronic HCV infection. Group . . . . . . . #Patients
NR
R 8R Total
47 36 40 123
~By7~2analysis betweengroups
CP+(%)
CP-(%)
~P Value
14 (32) 10 (23) 20 (45) 44 (100)
33 (42) 26 (33) 20 (25) 79 (100)
0.371 0,326 0,037
Background: Interferon for 12 months is effective therapy for chronic hepatitis C, but only 15-20% of treated patients achieve a sustained response. The effect of body weight on response and efficacy has been previously noted in numerous small studies. Aim: To evaluate the effect of body weight on sustained response rates in patients receiving interferon alfa-2b (Intron A) alone for 48 weeks by performing a retrospective analysis from previous published randomized controlled trials. Methods: 1744 patients with chronic hepatitis C were enrolled in 2 randomized controlled trials comparing interferon -+ ribavirin for treatment naive patients (NEJM 1998; 339:1485; Lancet 1998; 352:1426). 503 subjects received interferon alone for 48 weeks and are the focus of this analysis. All patients received 48 weeks of therapy and were then followedfor 24 weeks post therapy. Sustained virologic response was defined as loss of serum HCV RNA (qPCR, NGI) at follow-upweek 24 (SR). Patients without follow up data or who were discontinued were included in this analysis as non-responders. Patients were divided into four categories according to their body weight at entry into the study as follows: -< 55kg; >55 to 75kg; >75 to 95kg; and > 95kg. Results: Patient characteristics: male (66%), mean age 43 years, pretreatment HCV RNA > 2 x 106 (70%), cirrhosis (4%), HCV genotype 1 (66%), 2/3 (32%). The overall sustained virologic response rate in this group of patients was 16%. Efficacy in the groups defined according to body weight categories is shown in the table below. Conclusions: Patient body weight appears to be related to sustained response rates in patients receiving 48 weeks of interferon monotherapy. Patients with |ower body weight have a higher sustained response rate. This finding appeared to be independent of HCV genotype. This retrospective data further provides the rationale for dosing interferon and peginterferon according to body weight.
SR all patients Sustained response according to HCV Genotype: Genotype 1 Genotype non 1
_<55KG (n=37) 12 (32%)8 5/24 (21%) 7/13 (54%)
>55 TO 75 KG >75 TO 95 KG (n=191) (n=209) 37 (19%)~ 27 (13%)~
> 95 KG _(.n=66) 6 (9%)~
12/122(10%) 10/136(7%} 3/48 (6%) 25i69 (36%1 17/73(23%) 3/18 {17%) a versus b, p = 0.07: b versus c, p = 0.07; c versus d, p= 0,46; a versus s, p = 0,003; a versus d, p = 0,003;, b versus d, p = 0,054; b versus a, p = 0,08; c versus a, p = 0,03
AASLD ABSTRACTS
421A
995 IMPAIRED CHOLESTEROL SYNTHESIS IN PATIENTS INFECTED WITH H CV-3o~. EFFECT OF ANTIVIRAL THERAPY. Harald Hofer, Dept of Internal Medicine IV, Vienna Austria; Fritz Wrba, Dept of Clinical Pathology, Vienna Austria; Petra Steindl-Munda, Christian Mueller, Alfred Gangl, Peter Ferenci, Dept of Internal Medicine IV, Vienna Austria
996 AMANTADINE AND RIMANTADINE HAVE NO SIGNIFICANT ANTIHCV ACTIVITY IN A REPLICON CELL CULTURE SYSTEM, BOTH ALONE AND IN COMBINATION WITH INTERFERON/RIBAVIRIN. Vicky C Lai, Jane W Fang, Suhaila Naim, Johnson Y kau, Weidong Zhong, ICN Pharmaceuticals, Costa Mesa, CA
Background and Significance: Recent evidence suggests that hepatoceflular fat accumulation is more common in patients chronically infected with the hepatitis C virus genotype 3a (HCV-3a) than with other genotypes. Hepatucellular fat accumulation is also associated with low serum cholesterol levels in HCV3a. The aim of this study was to investigate the influence of antiviral therapy on serum lipid parameters in patients with different HCV-genotypes. Patients and Methods: A liver biopsy was obtained from 137 de novo patients with chronic hepatitis C (CHC) (m=102, f=35, mean age: 40.8-+10.7) enrolled in two prospective clinical trials of IFN/ribavirin therapy. No patient had diabetes mellitus, was actively using drugs, was on methadone replacement therapy, or consumed more than 20g alcohol/d. Body mass index (BMI), fasting triglycerides and cholesterol levels were determined at baseline, during and after therapy. Results: Marked steatosis (defined as >20% of hepatocytes containing fat droplets) was present in 35 of 47 (74.5%) patients with HCV-3a, in i2 of 67 (17.9%) patients with HCV-1 and in 5 of 23 (21.7%) with genotype 4. In contrast to patients infected with genotypes 1 or 4, steatosis in patients with HCV-3a did not correlate with the BMI. No patient with genotype 3a had cicrhosis. Prior to initiation of therapy, serum cholesterol levels were lower in patients infected with HCV-3a as compared to HCV-I or HCV-4 (147---42 [mg/dl; mean-+SD1 vs. 188-+36.4 vs. 172-+35.2; p<0.01). At end of treatment (ET), serum cholesterol increased in responding HCV-3a patients (ET vs. baseline: 166.7-+29 vs. 146-+38 at p=0.01) but remained unchanged in patients HCV-RNA positive at ET. Six months after therapy, in HCV-3a sustained virological responders (SVR) serum cholesterol further increased (200-+34; p<0.01), but remained unchanged low m nonresponders (NR) or relapsers (136-+44). In HCV-1 serum cholesterol decreased on antiviral therapy (ET vs. baseline: responder: i70-+38 vs. 190-+44, NR: i62-+24 vs.191-+29; NS) and reached baseline levels six months after therapy irrespective of response (SVR: 201-+35, NR: 162---24; NS). Conclusion: HCV-3a appears to interfere with hepatic cholesterol synthesis and fat metabolism. This may explain the occurre_nce and extent of hepatic steatosis in these patients. After successful HCV-3a eradication by antiviral treatment serum cholesterol levels increase into the normal range. This unique property is not shared by other HCV-genotypes.
Introduction: Amantadine, a drug known to inhibit influenza A M2 protein function, was recently reported to be an effective treatment in a segment of patients with chronic hepatitis C virus (HCV) infection. The data on the combination use of amantadine and interferon-odribavirin was controversial Rimantadine is a related analogue of amantadine. Aim: To determine whether amantadine or rimantadine has any direct anti-HCV activity in a cell-based HCV replicon system. Methods: Sequence homology was performed using MacVector, version 6.5.3. The in vitro anti-HCV activity was assessed using Huh-7 cells that contain a self-replicating HCV subgenomic RNA with a luciferase reporter gene. Cells were incubated with the drugs for 72 hours after which luciferase activity was measured. Reduction of HCV RNA was calculated based on the luciferase read-out and expressed as ICso. Cytotoxicity was evaluated by MTT cell viability assay and expressed as CCs0. These drugs were also tested in combination with ribavirin (0-200/aM) and IFN-a to determine their effects on the efficacy of the combination therapy. Results: Sequence comparison showed no homology between tnfuenza M2 and any of the HCV proteins. We previously reported that amantadine and rimantadine have no inhibitory activity against HCV protease, helicase, ATPase, polymerase and IRES in biochemical assays in vitro. In the HCV subgenomic replicon cell culture system, amantadine and rimantadine showed weak anti-HCV activity, with ICso at 200 b~Mand 75/aM, respectively (Cmaxin clinical studies for amantadine: 1-3/aM). This is close to the toxicity level of these compounds, with CCsoat 500/aM and 200 bsM, respectively, giving selectivity index of <3 for both compounds. Addition of amantadine and rimantadine did not significantly" augment the anti-HCV activity observed with IFN-odribavirin combination. Conclusions: (1) Amantadine and rimantadine did not effectively inhibit HCV RNA replication in the replicon cell culture model. The observed weak activity closely paralleled with toxicity. (2) Amantadine and rimantadine did not significantly augment the anti-HCV activity of IFN-a/ribavirin.
997
998
COMBINATION ANTMRAL THERAPY IN PATIENTS W I T H CHRONIC HEPATITIS C A N D CRYOGLOBULINEMIA. Warren N Schmidt, Douglas R Labrecque, Michael D Voigt, Jack T Stapleton, Stephen C Rayhill, Feng Wen, Mary Jeanne Perino-Phillips, Judy M Swift, Jane M Hershberger, Laura A Ippolito, Deana L Geraets, Stephanie A Schmid, University of Iowa, Iowa City, IA
PATIENT BODY WEIGHT A N D RESPONSE TO INTERFERON ALFA 2B MONOTHERAPY. John G McHutchison, Scripps Clinic, LaJolla, CA; Thierry Poynard, Pitie-Salpetriere, Paris France; Keyur Patel, Scripps Clinic, La Jolla, CA; Mei-Hsiu Ling, Schering Plough Research Institute, Kenilworth, NJ;JeanJacques Garaud, Schering Plough Research Institute, Kenwilworth, NM;Janice Albrecht For The Hepatitis [nterventional Therapy Group, Schering Plough Research Institute, Kenilworth, NJ
Introduction: Although cryoprecipitate occurs in about 40% of patients with HCV and chronic hepatitis, there is little information on the efficacy of combination therapy in patients with detectable cryoglobulins. We recently found that patients with cryoprecipitate (CP+) had increased fibrosis and cirrhosis when compared to patients without cryoprecipitate (CP-), suggesting that cryoglobulins may be an important clinical prognostic parameter. The overall aim of this study was to evaluate virological response to antiviral therapy in patients with or without CP. Methods: 139 patients with chronic hepatitis C were treated with standard dosages of Interferon a-2b(3.0 x 106 U, sc, tiw), plus ribavirin 1000-1200 mg PO QD for 24-48 weeks depending on HCV genotFpe. Liver biopsies were obtained prior to therapy and graded for histologic inflammation and fibrosis by standard pathologic analysis. Results: 53 patients had detectable CP (38%) and 86 did not (62%). There were no significant differences in genotype, age, duration of disease, alcohol consumption, or risk factors for HCV transmission between the two groups. In agreement with our previous findings, histologic evaluation of pre-treatment liver biopsies showed increased bridging fibrosis and cirrhosis in the CP+ patients when compared to CP- patients (p<.03). In contrast, no difference in the inflammatory activity profiles was observed. The percentages of virological nonresponders (NR), relapsers (R), and sustained responders (SR) are listed in the table below. CP+ patients had a significantly higher incidence of SR than CPpatients (p = 0.037) while there was no difference in NR and R between the two groups. Currently, 5 CP+ and 4 CP- patients are still on treatment. Seven of the 139 patients did not complete therapy. Conclusions: In spite of the fact that CP+ patients had more advanced liver disease than those CP-, they responded more favorably to antiviral therapy. These findings suggest that cryoprecipitates may be a useful parameter in the evaluation and treatment of patients with chronic HCV infection. Group . . . . . . . #Patients
NR
R 8R Total
47 36 40 123
~By7~2analysis betweengroups
CP+(%)
CP-(%)
~P Value
14 (32) 10 (23) 20 (45) 44 (100)
33 (42) 26 (33) 20 (25) 79 (100)
0.371 0,326 0,037
Background: Interferon for 12 months is effective therapy for chronic hepatitis C, but only 15-20% of treated patients achieve a sustained response. The effect of body weight on response and efficacy has been previously noted in numerous small studies. Aim: To evaluate the effect of body weight on sustained response rates in patients receiving interferon alfa-2b (Intron A) alone for 48 weeks by performing a retrospective analysis from previous published randomized controlled trials. Methods: 1744 patients with chronic hepatitis C were enrolled in 2 randomized controlled trials comparing interferon -+ ribavirin for treatment naive patients (NEJM 1998; 339:1485; Lancet 1998; 352:1426). 503 subjects received interferon alone for 48 weeks and are the focus of this analysis. All patients received 48 weeks of therapy and were then followedfor 24 weeks post therapy. Sustained virologic response was defined as loss of serum HCV RNA (qPCR, NGI) at follow-upweek 24 (SR). Patients without follow up data or who were discontinued were included in this analysis as non-responders. Patients were divided into four categories according to their body weight at entry into the study as follows: -< 55kg; >55 to 75kg; >75 to 95kg; and > 95kg. Results: Patient characteristics: male (66%), mean age 43 years, pretreatment HCV RNA > 2 x 106 (70%), cirrhosis (4%), HCV genotype 1 (66%), 2/3 (32%). The overall sustained virologic response rate in this group of patients was 16%. Efficacy in the groups defined according to body weight categories is shown in the table below. Conclusions: Patient body weight appears to be related to sustained response rates in patients receiving 48 weeks of interferon monotherapy. Patients with |ower body weight have a higher sustained response rate. This finding appeared to be independent of HCV genotype. This retrospective data further provides the rationale for dosing interferon and peginterferon according to body weight.
SR all patients Sustained response according to HCV Genotype: Genotype 1 Genotype non 1
_<55KG (n=37) 12 (32%)8 5/24 (21%) 7/13 (54%)
>55 TO 75 KG >75 TO 95 KG (n=191) (n=209) 37 (19%)~ 27 (13%)~
> 95 KG _(.n=66) 6 (9%)~
12/122(10%) 10/136(7%} 3/48 (6%) 25i69 (36%1 17/73(23%) 3/18 {17%) a versus b, p = 0.07: b versus c, p = 0.07; c versus d, p= 0,46; a versus s, p = 0,003; a versus d, p = 0,003;, b versus d, p = 0,054; b versus a, p = 0,08; c versus a, p = 0,03