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506 Antiviral therapy (AT) decreases hepatic venous pressure gradient (HVPG) in patients with chronic hepatitis C (CHC) and fibrotic stage (FS) 3 or 4
Category 5d: Viral Hepatitis: Hepatitis C – Clinical 505 THE INFLUENCE OF CUMULATIVE EXPOSURE TO COMBINATION PEGINTERFERON ALFA-2A (40 KD) (PEGASYS) AND RIBAVIRIN ON SUSTAINED VIROLOGICAL RESPONSE (SVR) RATES IN PATIENTS WITH GENOTYPE 1 CHRONIC HEPATITIS C
K.R. Reddy 1 , M.W. Fried 2 , M.L. Shiffman 3 , S.J. Hadziyannis 4 , H. Sette 5 , T.R. Morgan 6 , S. Schaefer 7 , M. Popescu 8 . 1 University of Pennsylvania, Philadelphia PA, USA; 2 University of North Carolina, Chapel Hill NC, USA; 3 VCU Health System, Richmond VA, USA; 4 Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece; 5 Instituto De Infectologia Emilio Ribas, Sao Paulo, Brazil; 6 VA Medical Center, Long Beach, USA; 7 IST GmbH, Gunzburg, Germany; 8 Roche, Basel, Switzerland Patients who receive full doses and durations of peginterferon/ribavirin combination therapy have higher SVR rates. It is, however, unclear if one drug is more important than the other. We investigated the relationship between cumulative drug exposure to Pegasys and ribavirin, and SVR rates. Methods: Pooled data from 569 patients randomized to 48wks of Pegasys 180mcg/wk+ribavirin 1000/1200mg/day in two phase III trials were analyzed. Duration=interval between initiation and discontinuation (>80%=treatment for ≥269days). Exposure=total drug administered (recorded at clinic visits, validated against diaries). The following exposure categories were used: 100%, 90-99.9%, 80-89.9% and <80%. Results: 63% and 20% of patients had 100% Pegasys and ribavirin exposure, respectively. 81% and 71% had cumulative Pegasys and ribavirin exposure of ≥90%, respectively. The overall SVR rate was 49.2%; 61.9% in patients treated for ≥80% and 11.8% in those treated for <80% of the prescribed duration. Patients receiving treatment for ≥80% of the prescribed duration who were exposed to ≥80% of both Pegasys+ribavirin had an SVR of 65%. SVR rates according to exposure in 425 patients with genotype 1 by ITT analysis. Exposure (%) 100
P*
90-99.9 80-89.9 <80
Patient exposure to PEGASYS: SVR-% 65 56 57 59 0.259 (independent of TBV dose) (172/266) (42/75) (20/49) (29/49) Patient exposure to RBV: SVR-% 72 64 57 49 <0.001 (independent of PEGASYS dose) (60/83) (139/217) (20/35) (44/90) *Two-sided Cochrain-Armitage test for trend.
Conclusions: 1) Dose reductions occurred more frequently with ribavirin 2) Exposure to Pegasys was greater than ribavirin; 3) Treatment success correlated with exposure. Ribavirin exposure and SVR rates were significantly correlated. 4) Decreasing exposure to Pegasys had less impact on SVR rates compared with ribavirin.
506 ANTIVIRAL THERAPY (AT) DECREASES HEPATIC VENOUS PRESSURE GRADIENT (HVPG) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) AND FIBROTIC STAGE (FS) 3 OR 4
D. Rincon, R. Banares, M. Salcedo, S. Alonso, C. Ripoll, M.V. Catalina, E. Alvarez, G. Clemente. Department of Gastroenterology and Hepatology, Hospital ‘Gregorio Maranon’, Madrid, Spain Introduction: Major complications of liver cirrhosis are due to portal hypertension. Because AT improves liver histology, portal pressure could be reduced after treatment in post-hepatitis C liver cirrhosis. Aims: To study the evolution of HVPG in patients with CHC and FS 3/4 after AT and its relationship with histological changes caused by AT. Patiens and Methods: 12 patients with CHC and FS 3/4 with PHT received PEG-Interferon α2b plus ribavirin for 24/48 weeks. Every patient underwent transjugular liver biopsy and hepatic hemodynamic evaluation (HHE) immediately before and after treatment. A single pathologist estimated hepatic inflammation and fibrosis by a semiquantitative method. In order to compare hemodynamic changes, a control group of 30 patients
149
with compensated CHC, without treatment with interferon or β-blocker, FS 3/4, who received two HHE separated by a period of 12-36 months, was considered. Results: Both groups were comparable at baseline. AT reduced HVPG in all but one patient. Mean reduction was 30.4 (10.5) % [13.3 (4.7) vs 9.2 (3) mmHg, p<0.0001]. In contrast, HVPG increased in control group [14.2 (5.9) vs 17.3 (5.7) mmHg, p<0.0001]. HVPG was not related to initial ALT, previous courses and duration of AT, dose modification, and biochemical/virological response. Liver inflammation was significantly reduced [1.88 (0.6) vs 0.55 (0.5), p<0.0001]. No changes occurred in fibrosis. The HVPG reduction and the decrease of inflammation were significantly correlated (r=0.756, p=0.018). Conclusions: 1) AT reduces HVPG in patients with CHC and FS 3/4. 2) This reduction may be related to decrease of inflammation.
507 EARLY PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE (SVR) DURING TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS ) PLUS RIBAVIRIN (RBV) (COPEGUS ) IN PATIENTS WITH HCV/HIV CO-INFECTION: RESULTS FROM THE AIDS PEGASYS RIBAVIRIN INTERNATIONAL CO-INFECTIO (ABSTRACT WITHDRAWN )
M. Rodriguez-Torres 1 , F.J. Torriani 2 , E. Lissen 3 , N. Brau 4 , M. Sulkowski 5 , R. Sola 6 , B. Clotet 7 , N. Clumeck 8 , D. Cooper 9 , D. Dieterich 10 . 1 Fundacion De Investigacion De Diego, Santurce, Puerto Rico; 2 Department of Medicine, University of California, San Diego CA, USA; 3 Virgen Del Rocio University Hospital, Sevile, Spain; 4 Bronx VA Medical Center, Bronx NY, USA; 5 Johns Hopkins University School of Medicine, Baltimore MD, USA; 6 Rovira I Virgili University, Reus, Spain; 7 Germans Trias I Pujol University Hospital, Barcelona, Spain; 8 CHU Saint-Pierre, Brussels, Belgium; 9 University of New South Wales, Sydney, Australia; 10 Mt. Sinai School of Medicine, New York NY, USA The absence of an early virological response (EVR) at week 12 of combination peginterferon alfa-2a (40KD) (PEGASYS)/RBV (COPEGUS) therapy has a high negative predictive value (NPV, 97%) for the probability of achieving an SVR in HCV monoinfected patients (Fried et al. NEJM 2002;347:975). We determined whether this also applies to HCV/HIV coinfected patients. Methods: We analysed data from 289 HCV/HIV-co-infected patients randomized to 48 weeks of peginterferon alfa-2a (40KD) 180 µg/wk + RBV 800 mg/d in the APRICOT study. Patients had compensated liver disease, a CD4+ count >100 cells/mL, and stable HIV disease. SVR was defined as undetectable HCV RNA (<50 IU/mL) after 24 weeks of treatment-free follow-up (COBAS AMPLICOR HCV Test, v2.0). EVR was defined as undetectable HCV RNA or a ≥2-log10 decline in HCV RNA by week 12 or 24. Results (table): Overall, 204 patients (71%) had an EVR, of whom 114 (56%) achieved an SVR. 45% of the 110 genotype 1 patients who had an EVR also achieved an SVR. N All* 289 Geno 1 176 Geno 2,3 95
Pts with an SVR (%) 116 (40) 51 (29) 59 (62)
Pts with an EVR (%) PPV-% NPV-% Wk 12 Wk 24 Wk 12 Wk 24 Wk 12 Wk 24 204 (71) 216 (75) 110 (63) 120 (68) 84 (88) 85 (89)
56 45 70
53 43 69
98 98 100
99 100 100
PPV (positive predictive value) - probability of achieving an SVR in patients who achieve an EVR. *Includes 16 patients with genotype 4 and 2 with unknown genotypes - specific dat not shown.
Conclusions: The results are consistent with those in patients with HCV monoinfection. Treatment with PEGASYS/COPEGUS may be discontinued at week 12 in co-infected patients without an EVR because they are highly unlikely to develop an SVR. This will decrease adverse events and save healthcare resources. Patients with an EVR have a good chance of achieving an SVR.
K.R. Reddy 1 , M.W. Fried 2 , M.L. Shiffman 3 , S.J. Hadziyannis 4 , H. Sette 5 , T.R. Morgan 6 , S. Schaefer 7 , M. Popescu 8 . 1 University of Pennsylvania, Philadelphia PA, USA; 2 University of North Carolina, Chapel Hill NC, USA; 3 VCU Health System, Richmond VA, USA; 4 Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece; 5 Instituto De Infectologia Emilio Ribas, Sao Paulo, Brazil; 6 VA Medical Center, Long Beach, USA; 7 IST GmbH, Gunzburg, Germany; 8 Roche, Basel, Switzerland Patients who receive full doses and durations of peginterferon/ribavirin combination therapy have higher SVR rates. It is, however, unclear if one drug is more important than the other. We investigated the relationship between cumulative drug exposure to Pegasys and ribavirin, and SVR rates. Methods: Pooled data from 569 patients randomized to 48wks of Pegasys 180mcg/wk+ribavirin 1000/1200mg/day in two phase III trials were analyzed. Duration=interval between initiation and discontinuation (>80%=treatment for ≥269days). Exposure=total drug administered (recorded at clinic visits, validated against diaries). The following exposure categories were used: 100%, 90-99.9%, 80-89.9% and <80%. Results: 63% and 20% of patients had 100% Pegasys and ribavirin exposure, respectively. 81% and 71% had cumulative Pegasys and ribavirin exposure of ≥90%, respectively. The overall SVR rate was 49.2%; 61.9% in patients treated for ≥80% and 11.8% in those treated for <80% of the prescribed duration. Patients receiving treatment for ≥80% of the prescribed duration who were exposed to ≥80% of both Pegasys+ribavirin had an SVR of 65%. SVR rates according to exposure in 425 patients with genotype 1 by ITT analysis. Exposure (%) 100
P*
90-99.9 80-89.9 <80
Patient exposure to PEGASYS: SVR-% 65 56 57 59 0.259 (independent of TBV dose) (172/266) (42/75) (20/49) (29/49) Patient exposure to RBV: SVR-% 72 64 57 49 <0.001 (independent of PEGASYS dose) (60/83) (139/217) (20/35) (44/90) *Two-sided Cochrain-Armitage test for trend.
Conclusions: 1) Dose reductions occurred more frequently with ribavirin 2) Exposure to Pegasys was greater than ribavirin; 3) Treatment success correlated with exposure. Ribavirin exposure and SVR rates were significantly correlated. 4) Decreasing exposure to Pegasys had less impact on SVR rates compared with ribavirin.
506 ANTIVIRAL THERAPY (AT) DECREASES HEPATIC VENOUS PRESSURE GRADIENT (HVPG) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) AND FIBROTIC STAGE (FS) 3 OR 4
D. Rincon, R. Banares, M. Salcedo, S. Alonso, C. Ripoll, M.V. Catalina, E. Alvarez, G. Clemente. Department of Gastroenterology and Hepatology, Hospital ‘Gregorio Maranon’, Madrid, Spain Introduction: Major complications of liver cirrhosis are due to portal hypertension. Because AT improves liver histology, portal pressure could be reduced after treatment in post-hepatitis C liver cirrhosis. Aims: To study the evolution of HVPG in patients with CHC and FS 3/4 after AT and its relationship with histological changes caused by AT. Patiens and Methods: 12 patients with CHC and FS 3/4 with PHT received PEG-Interferon α2b plus ribavirin for 24/48 weeks. Every patient underwent transjugular liver biopsy and hepatic hemodynamic evaluation (HHE) immediately before and after treatment. A single pathologist estimated hepatic inflammation and fibrosis by a semiquantitative method. In order to compare hemodynamic changes, a control group of 30 patients
149
with compensated CHC, without treatment with interferon or β-blocker, FS 3/4, who received two HHE separated by a period of 12-36 months, was considered. Results: Both groups were comparable at baseline. AT reduced HVPG in all but one patient. Mean reduction was 30.4 (10.5) % [13.3 (4.7) vs 9.2 (3) mmHg, p<0.0001]. In contrast, HVPG increased in control group [14.2 (5.9) vs 17.3 (5.7) mmHg, p<0.0001]. HVPG was not related to initial ALT, previous courses and duration of AT, dose modification, and biochemical/virological response. Liver inflammation was significantly reduced [1.88 (0.6) vs 0.55 (0.5), p<0.0001]. No changes occurred in fibrosis. The HVPG reduction and the decrease of inflammation were significantly correlated (r=0.756, p=0.018). Conclusions: 1) AT reduces HVPG in patients with CHC and FS 3/4. 2) This reduction may be related to decrease of inflammation.
507 EARLY PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE (SVR) DURING TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS ) PLUS RIBAVIRIN (RBV) (COPEGUS ) IN PATIENTS WITH HCV/HIV CO-INFECTION: RESULTS FROM THE AIDS PEGASYS RIBAVIRIN INTERNATIONAL CO-INFECTIO (ABSTRACT WITHDRAWN )
M. Rodriguez-Torres 1 , F.J. Torriani 2 , E. Lissen 3 , N. Brau 4 , M. Sulkowski 5 , R. Sola 6 , B. Clotet 7 , N. Clumeck 8 , D. Cooper 9 , D. Dieterich 10 . 1 Fundacion De Investigacion De Diego, Santurce, Puerto Rico; 2 Department of Medicine, University of California, San Diego CA, USA; 3 Virgen Del Rocio University Hospital, Sevile, Spain; 4 Bronx VA Medical Center, Bronx NY, USA; 5 Johns Hopkins University School of Medicine, Baltimore MD, USA; 6 Rovira I Virgili University, Reus, Spain; 7 Germans Trias I Pujol University Hospital, Barcelona, Spain; 8 CHU Saint-Pierre, Brussels, Belgium; 9 University of New South Wales, Sydney, Australia; 10 Mt. Sinai School of Medicine, New York NY, USA The absence of an early virological response (EVR) at week 12 of combination peginterferon alfa-2a (40KD) (PEGASYS)/RBV (COPEGUS) therapy has a high negative predictive value (NPV, 97%) for the probability of achieving an SVR in HCV monoinfected patients (Fried et al. NEJM 2002;347:975). We determined whether this also applies to HCV/HIV coinfected patients. Methods: We analysed data from 289 HCV/HIV-co-infected patients randomized to 48 weeks of peginterferon alfa-2a (40KD) 180 µg/wk + RBV 800 mg/d in the APRICOT study. Patients had compensated liver disease, a CD4+ count >100 cells/mL, and stable HIV disease. SVR was defined as undetectable HCV RNA (<50 IU/mL) after 24 weeks of treatment-free follow-up (COBAS AMPLICOR HCV Test, v2.0). EVR was defined as undetectable HCV RNA or a ≥2-log10 decline in HCV RNA by week 12 or 24. Results (table): Overall, 204 patients (71%) had an EVR, of whom 114 (56%) achieved an SVR. 45% of the 110 genotype 1 patients who had an EVR also achieved an SVR. N All* 289 Geno 1 176 Geno 2,3 95
Pts with an SVR (%) 116 (40) 51 (29) 59 (62)
Pts with an EVR (%) PPV-% NPV-% Wk 12 Wk 24 Wk 12 Wk 24 Wk 12 Wk 24 204 (71) 216 (75) 110 (63) 120 (68) 84 (88) 85 (89)
56 45 70
53 43 69
98 98 100
99 100 100
PPV (positive predictive value) - probability of achieving an SVR in patients who achieve an EVR. *Includes 16 patients with genotype 4 and 2 with unknown genotypes - specific dat not shown.
Conclusions: The results are consistent with those in patients with HCV monoinfection. Treatment with PEGASYS/COPEGUS may be discontinued at week 12 in co-infected patients without an EVR because they are highly unlikely to develop an SVR. This will decrease adverse events and save healthcare resources. Patients with an EVR have a good chance of achieving an SVR.