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ribavirin therapy are associated with reduced viral clearance in patients with hepatitis C
HEPATOLOGY, Vol. 38, No. 4, Suppl. 1, 2003
AASLD ABSTRACTS
343
EFFICACY OF PEG-IFN-ALFA 2A(PEGASYS) V S P E G A S Y S A N D R B V FOR H I V / H C V COINFECTED PATIENTS THAT ARE NONRESPONDERS TO P R E V I O U S IFN T H E R A P Y .
Maribel Rodriguez-Torres, Fundacion de Invesh'gacion de Diego, Santurce, PR; Josd Rodriguez-Orengo, University of Puerto Rico School of Medicine, Rio Ih'edras, PR Background: HCV Co-infection is common among patients with HIV disease. It has been documented that HIV co-infection accelerates the course of liver disease in patients with HCV, and that liver failure is higher in co-infected patients. At this moment, there is no effective treatment for HCV non-responders to interferon therapy. Mono-therapy and interferon-ribavirin combination is only effective in 2-3% and 5-10% interferon resistant patients respectively. Treatment strategies to slow the progression to cirrhosis and to prevent fiver failure in this population are needed. Objective: This is a report of a study that examines the efficacy of Peg IFN alfa 2-a (Pegasys) vs Pegasys/RBV 800mg in co-infected HCV/HIV patients that have not responded to a previous 6-12 months course IFN-alfa. The study also examines the histological benefit of treatment in this population. Patients and Methods: 76 patients were randomized 1:1 to receive either Pegasys 180mcg weekly x 24 weeks (group 1) or Pegasys 180mcg weekly plus 800mg RBV for 24 weeks (group 2). Patients that have HCV non-detectable or 21og decrease from baseline at week 24 (group1), were added RBV 800mg. All similar responders (group 2) continue treatment for a total of 48 weeks. Baseline demographics were similar between both groups. More than 70% of patients were nonresponders to IFN monotherapy.Most patients in both groups (80%) were genotype 1. The mean HIV Baseline log was 2.92 (SD.64) group 1, vs 2.85 (SD.57) group 2 and most patients had baseline CD4 levels>400 cells, and were in stable antiretroviral therapy. The majority of patients (81%) are non cirrhotic, with mean grading group 1 6.63 (SD 3.24), group 2 7 (SD 3.64), and mean staging, group 1 3.51 (SD 2.2), and group 2 3.48 (SD 1.70). Results: Efficacy Group 1 Group 2 Total (N-33) (N-43) (N-76) Baseline HCV RNA Log 5.67 Log 5.94 (SD.86) (SD.83) 12 Weeks HCV RNA N/D 8 (24%) 17 (39%) 25 (32%) HCV RNA > 21og 9 (27%) 21 (48%) 30 (39%) 24 Weeks HCV RNA N/D 8 (24%) 17 (39%) 25 (32%) HCV RNA 21og 13 (39%) 19 (44%) 32 (42%) 48 Weeks * HCV RNA N/D 6 (18%)* 10 (23%)* 16 (21%)* HCV RNA > 21og 6 (18%)* 11 (25%)* 17 (22%)* 72 Weeks * HCV RNA N/D 1 (3%)* 3(6%)* 4 (5%)* ITrHCVRNA N/D Patients with Tx.>24weeks-4(7%) Histology Mean * Group I Group 2 Grading B1 3.63 SD 3.24 7.0 SD 3.64 Grading 72th 4.00 SD 2.13 4.18 SD 2.52 Staging B1 3.51 SD 2.20 3.48 SD 1.70 Staging 72th 2.5 SD 2.0 2.90 SD 1.50 FPR BI.37 SD.36.44 SD.45 FPR 72th.41 SD 1.2.62 SD 1.76 Histology by virological response (mean) Non Responders FPR~ (N-57).42 SD.41 (.08 - 2.4) FPR2 ( N - 8 ) 1.48 SD 1.15 (-.62 - 3.12) Relapsers FPR~ (N-4).52 SD.58 (.16 - 1.4) FPR2 ( N - 3 ) 0.0 SD 1.0 (-.62 - 1.25) Responders FPR~ (N-3).20 SD.209 (.11 -.29) FPR2 ( N - 2 ) -1.87 SD.888 (-2.5 - -1.25) Conclusions: This study is completed and pending some results, that will be available for presentation. Sustained virological response(SVR) (Intention to treat), will be of the order of 5-20%. (11 group 2 results are pending). In this study, 10 patients were discontinued because adverse events and 10 were lost to follow up, before week 24th.SVR in patients that completed at least 24
325A
weeks of therapy will be of the order of 7-26%.A significant number of end of treatment responders are relapsing at week 72th. Histology analysis show improvement in both groups of the mean grading and staging after treatment. In responders and relapsers the FPR becomes static or regressive.These results show that Pegasys /RBV therapy is effective in this population.The study also suggests that longer duration of therapy ,and higher doses of RBV should be studied in coinfected nonresponders. * - Pending results, will be available for presentation. Disclosures: Jos6 Rodriguez-Orengo - No relationships to disclose Maribel Rodriguez-Torres - Roche Laboratories: Investigator; Other: Grant to perform study.
344 DEPRESSIVE SYMPTOMS DURING IFN-ALPHA/RIBAVIRIN THERAPY ARE ASSOCIATED WITH REDUCED V I R A L CLEARANCE IN PATIENTS W I T H H E P A T I T I S C. Charles L
Raison, Sherry D Broadwell, Andrey S Borisov, Amita K Manatunga, Bobbi J Woolwine, ~ mory University, Atlanta, GA; Ira M Jacobson, Weill Medical College of Corne.ll University, New York, NY; Charles B Nemeroff, Andrew H Miller, ~ mory University, Atlanta, GA Background: Interferon (IFN)-alfa plus ribavirin is an effective treatment for chronic hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders. To determine whether increased depressive symptoms during IFN alfa/ribavirin therapy were associated with reduced clearance of HCV, a prospective cohort design was used to evaluate HCV-infected patients at baseline and after 4, 8, 12 and 24 weeks of pegylated IFN-alfa-2b/ribavirin therapy. Methods: The sample was derived from patients enrolled in a larger multi-center, randomized clinical trial of pegylated IFNalfa-2b plus fixed-dose versus weight-based ribavirin. 102 HCVinfected subjects who volunteered to participate and completed 24 weeks of IFN alfa/ribavirin treatment followed by viral load testing were included. Severity of depressive symptoms was measured by the Zung Self-Rating Depression Scale (SDS). Viral clearance was defined as polymerase chain reaction (PCR) negative (less than 29 HCV IU/ml) at 24 weeks. Findings: Increased depressive symptoms during IFN-alfa/ribavirin therapy were associated with reduced viral clearance (P-0.006). Only 34% of subjects with a 20-point or greater increase in SDS Index (N-29) were HCV PCR negative at 24 weeks, compared to 63% of patients without a 20-point increase (N-73)(crude OR, 3.2; 95% confidence interval (CI), 1.3-8.0; P-0.009). These results remained significant after adjusting for ribavirin dose assignment, viral genotype, age, antidepressant usage, IFN-alfa/ ribavirin dosage reduction and knowledge of viral load status during treatment (adjusted OR 4.1; 95%CI 1.5-11.5). Cumulative depressive symptoms over the 24 weeks of IFN-alfa/ribavirin therapy also predicted failure to clear virus (P-0.026). Interpretation: HCV patients who experience significant increases in symptoms of depression during IFN-alfa/ribavirin therapy are less likely to clear virus, highlighting the potential importance of identifying and treating depressive symptoms in this patient population. Disclosures: Andrey S Borisov - No relationships to disclose Sherry D Broadwell - No relationships to disclose Ira M Jacobson - Schering Plough: Meeting Participant/Lecturer; Scientific Study/Trial Amita K Manatunga - No relationships to disclose Andrew H Miller - Schering Plough: Meeting Participant/Lecturer; Scientific Study/Trial Charles B Nemeroff - No relationships to disclose Charles L Raison - Schering Plough: Meeting Participant/Lecturer Bobbi J Woolwine - No relationships to disclose
AASLD ABSTRACTS
343
EFFICACY OF PEG-IFN-ALFA 2A(PEGASYS) V S P E G A S Y S A N D R B V FOR H I V / H C V COINFECTED PATIENTS THAT ARE NONRESPONDERS TO P R E V I O U S IFN T H E R A P Y .
Maribel Rodriguez-Torres, Fundacion de Invesh'gacion de Diego, Santurce, PR; Josd Rodriguez-Orengo, University of Puerto Rico School of Medicine, Rio Ih'edras, PR Background: HCV Co-infection is common among patients with HIV disease. It has been documented that HIV co-infection accelerates the course of liver disease in patients with HCV, and that liver failure is higher in co-infected patients. At this moment, there is no effective treatment for HCV non-responders to interferon therapy. Mono-therapy and interferon-ribavirin combination is only effective in 2-3% and 5-10% interferon resistant patients respectively. Treatment strategies to slow the progression to cirrhosis and to prevent fiver failure in this population are needed. Objective: This is a report of a study that examines the efficacy of Peg IFN alfa 2-a (Pegasys) vs Pegasys/RBV 800mg in co-infected HCV/HIV patients that have not responded to a previous 6-12 months course IFN-alfa. The study also examines the histological benefit of treatment in this population. Patients and Methods: 76 patients were randomized 1:1 to receive either Pegasys 180mcg weekly x 24 weeks (group 1) or Pegasys 180mcg weekly plus 800mg RBV for 24 weeks (group 2). Patients that have HCV non-detectable or 21og decrease from baseline at week 24 (group1), were added RBV 800mg. All similar responders (group 2) continue treatment for a total of 48 weeks. Baseline demographics were similar between both groups. More than 70% of patients were nonresponders to IFN monotherapy.Most patients in both groups (80%) were genotype 1. The mean HIV Baseline log was 2.92 (SD.64) group 1, vs 2.85 (SD.57) group 2 and most patients had baseline CD4 levels>400 cells, and were in stable antiretroviral therapy. The majority of patients (81%) are non cirrhotic, with mean grading group 1 6.63 (SD 3.24), group 2 7 (SD 3.64), and mean staging, group 1 3.51 (SD 2.2), and group 2 3.48 (SD 1.70). Results: Efficacy Group 1 Group 2 Total (N-33) (N-43) (N-76) Baseline HCV RNA Log 5.67 Log 5.94 (SD.86) (SD.83) 12 Weeks HCV RNA N/D 8 (24%) 17 (39%) 25 (32%) HCV RNA > 21og 9 (27%) 21 (48%) 30 (39%) 24 Weeks HCV RNA N/D 8 (24%) 17 (39%) 25 (32%) HCV RNA 21og 13 (39%) 19 (44%) 32 (42%) 48 Weeks * HCV RNA N/D 6 (18%)* 10 (23%)* 16 (21%)* HCV RNA > 21og 6 (18%)* 11 (25%)* 17 (22%)* 72 Weeks * HCV RNA N/D 1 (3%)* 3(6%)* 4 (5%)* ITrHCVRNA N/D Patients with Tx.>24weeks-4(7%) Histology Mean * Group I Group 2 Grading B1 3.63 SD 3.24 7.0 SD 3.64 Grading 72th 4.00 SD 2.13 4.18 SD 2.52 Staging B1 3.51 SD 2.20 3.48 SD 1.70 Staging 72th 2.5 SD 2.0 2.90 SD 1.50 FPR BI.37 SD.36.44 SD.45 FPR 72th.41 SD 1.2.62 SD 1.76 Histology by virological response (mean) Non Responders FPR~ (N-57).42 SD.41 (.08 - 2.4) FPR2 ( N - 8 ) 1.48 SD 1.15 (-.62 - 3.12) Relapsers FPR~ (N-4).52 SD.58 (.16 - 1.4) FPR2 ( N - 3 ) 0.0 SD 1.0 (-.62 - 1.25) Responders FPR~ (N-3).20 SD.209 (.11 -.29) FPR2 ( N - 2 ) -1.87 SD.888 (-2.5 - -1.25) Conclusions: This study is completed and pending some results, that will be available for presentation. Sustained virological response(SVR) (Intention to treat), will be of the order of 5-20%. (11 group 2 results are pending). In this study, 10 patients were discontinued because adverse events and 10 were lost to follow up, before week 24th.SVR in patients that completed at least 24
325A
weeks of therapy will be of the order of 7-26%.A significant number of end of treatment responders are relapsing at week 72th. Histology analysis show improvement in both groups of the mean grading and staging after treatment. In responders and relapsers the FPR becomes static or regressive.These results show that Pegasys /RBV therapy is effective in this population.The study also suggests that longer duration of therapy ,and higher doses of RBV should be studied in coinfected nonresponders. * - Pending results, will be available for presentation. Disclosures: Jos6 Rodriguez-Orengo - No relationships to disclose Maribel Rodriguez-Torres - Roche Laboratories: Investigator; Other: Grant to perform study.
344 DEPRESSIVE SYMPTOMS DURING IFN-ALPHA/RIBAVIRIN THERAPY ARE ASSOCIATED WITH REDUCED V I R A L CLEARANCE IN PATIENTS W I T H H E P A T I T I S C. Charles L
Raison, Sherry D Broadwell, Andrey S Borisov, Amita K Manatunga, Bobbi J Woolwine, ~ mory University, Atlanta, GA; Ira M Jacobson, Weill Medical College of Corne.ll University, New York, NY; Charles B Nemeroff, Andrew H Miller, ~ mory University, Atlanta, GA Background: Interferon (IFN)-alfa plus ribavirin is an effective treatment for chronic hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders. To determine whether increased depressive symptoms during IFN alfa/ribavirin therapy were associated with reduced clearance of HCV, a prospective cohort design was used to evaluate HCV-infected patients at baseline and after 4, 8, 12 and 24 weeks of pegylated IFN-alfa-2b/ribavirin therapy. Methods: The sample was derived from patients enrolled in a larger multi-center, randomized clinical trial of pegylated IFNalfa-2b plus fixed-dose versus weight-based ribavirin. 102 HCVinfected subjects who volunteered to participate and completed 24 weeks of IFN alfa/ribavirin treatment followed by viral load testing were included. Severity of depressive symptoms was measured by the Zung Self-Rating Depression Scale (SDS). Viral clearance was defined as polymerase chain reaction (PCR) negative (less than 29 HCV IU/ml) at 24 weeks. Findings: Increased depressive symptoms during IFN-alfa/ribavirin therapy were associated with reduced viral clearance (P-0.006). Only 34% of subjects with a 20-point or greater increase in SDS Index (N-29) were HCV PCR negative at 24 weeks, compared to 63% of patients without a 20-point increase (N-73)(crude OR, 3.2; 95% confidence interval (CI), 1.3-8.0; P-0.009). These results remained significant after adjusting for ribavirin dose assignment, viral genotype, age, antidepressant usage, IFN-alfa/ ribavirin dosage reduction and knowledge of viral load status during treatment (adjusted OR 4.1; 95%CI 1.5-11.5). Cumulative depressive symptoms over the 24 weeks of IFN-alfa/ribavirin therapy also predicted failure to clear virus (P-0.026). Interpretation: HCV patients who experience significant increases in symptoms of depression during IFN-alfa/ribavirin therapy are less likely to clear virus, highlighting the potential importance of identifying and treating depressive symptoms in this patient population. Disclosures: Andrey S Borisov - No relationships to disclose Sherry D Broadwell - No relationships to disclose Ira M Jacobson - Schering Plough: Meeting Participant/Lecturer; Scientific Study/Trial Amita K Manatunga - No relationships to disclose Andrew H Miller - Schering Plough: Meeting Participant/Lecturer; Scientific Study/Trial Charles B Nemeroff - No relationships to disclose Charles L Raison - Schering Plough: Meeting Participant/Lecturer Bobbi J Woolwine - No relationships to disclose