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Ribavirin plus interferon daily or thrice weekly in chronic hepatitis C genotype 4
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Abstracts
(45.5% and 21.2%; p⫽0.23), genotype and baseline HCV RNA levels (3.52 ⫾1.8 and 3.57 ⫾1.8⫻108 copies/ml. respect). Results: Twenty-two (32%) patients in the low dose group and 31 (50%) in the high dose had initial response (p⫽0.05). Twenty (29%) and 21 (34%) had end of treatment response (p⫽0.09) and 13 (19%) and 16 (26%) had sustained virological response (p⫽0.18). Seven patients relapsed at 12 months (1 low dose and 6 high dose) and nine at 18 months (6 low, 3 high). Conclusion: Re-treatment with lower doses of interferon and ribavirin results in similar rates of sustained virological response compared to standard dosing. Thus, dose reduction of these antivirals seems to have minimal effects on the probability of sustained virologic response. (Supported in part by Schering Pharm. Corp).
365 Response to combination therapy with interferon and ribavirin in hepatitis C cirrhotic patients F Pereyra, R Pena, V Kaul, A Suvannasankha, K DiGregorio, L Stein, F Gross, S Peikin, O Perez, G Benson, A Mushnick, C DeAngelo, J Goldfarb, K Rothstein, C Manazarbeitia, D Reich, N Kern, S Munoz. Center for Liver Disease, Albert Einstein Medical Center, Philadelphia, PA. Background: Only small groups of HCV patients have been reported in trials with combination antiviral therapy (interferon alpha 2b (IFN) plus Ribavirin). The response rates have generally been lower than in noncirrhotic patients. Aim: We evaluated the relationship between response to two dose schedules of therapy and pre-treatment biopsy findings. Methods: A prospective study of a cohort of non-responders (NR) and relapsers (RE) to monotherapy with IFN was randomized to receive IFN 3MU tiw plus ribavirin 600 mg qd, or IFN 5 MU tiw plus ribavirin 1,000 mg qd. Patients were stratified according to absence/presence of cirrhosis on biopsy as well as HCV RNA level and genotype. Results: Ninety patients were enrolled, 25.6% of whom had cirrhosis on biopsy as well as HCV RNA level and genotype. Results: Ninety patients were enrolled, 25.6% of whom had cirrhosis on biopsy. Demographics, viral levels and genotype distribution were similar between the cirrhotic and non-cirrhotic groups. Only 13% of cirrhotic patients exhibited a sustained virological response (SVR), whereas 21% of non-cirrhotics patients showed SVR (p⫽n.s.). Analysis including bridging fibrosis patients in the cirrhotic group, did not alter the significance level. When low and high dose groups were compared, there was a non-significant difference in SVR rates between cirrhotics and non-cirrhotic patients. Conclusion: Histological severity of chronic hepatitis C was not associated with the probability of durable response to combination antiviral therapy with IFN and ribavirin. These results suggests that cirrhotic patients should be offered this therapy regardless of their histologic diagnosis. (Supported in part by Schering Pharm. Corp).
366 Drugs induced liver damage Cvetka Pernat, M. Skalicky. General Hospital Maribor, Slovenia. Introduction: Almost every known drug has been implicated as a cause of liver damage. Toxic effect of drugs on the liver can mimic every naturally occurring liver disease in man. There are no specific tests in the diagnosis of drug liver injury. The aim of our study was to evaluate how common drugs cause liver damage. Methods: Since January 1996 to October 1999 we evaluated 38 patients with the drug liver injury. Viral hepatitis, Wilson disease, autoimmune hepatitis, metabolic and alcohol liver disease were excluded in 30 patients. Blockage of the bile ducts was excluded in 8 patients. All patients have the history of drug intake. Liver biopsy was made in all patients. Results: 21 patients have symptoms and histological features of acute liver injury, 9 patients of chronic liver injury, 8 patients have cholestasis. In 35
AJG – Vol. 95, No. 9, 2000
cases removal of the drug led to improvement. In 3 patients with cirrhosis there was no improvement after removal of the drug. Conclusions: Drugs in common use often cause toxic effect on the liver. Early suspicion of drug related hepatic reaction and exclusion of other causes of a hepatic reaction, are essential. Removal of the drug can lead to improvement even if chronic liver disease has developed. 367 Ribavirin plus interferon daily or thrice weekly in chronic hepatitis C genotype 4 Ayman Y. Abdel Rahim, M.D., Mohsen Salama, M.D., Salah El-Dirini, M.D., Baher Badawy, M.D. Faculty of Medicine, Cairo University, Egypt. Hepatitis C virus (HCV) genotype 4 infections show less favorable response to interferon-⬀ (IFN-⬀) treatment. The aim of this study was to assess the efficacy of ribavirin (RIB) combined with either thrice weekly IFN or daily IFN induction dosing in Egyptian patients with chronic hepatitis C (CHC) due to genotype 4. Methods: Fifty Egyptian patients with biopsy proven CHC due to genotype 4 were randomly assigned to: Group A (25 patients) received subcutaneous IFN-␣ 2b (Intron-A, Schering-Plough International) 5MU thrice weekly plus oral RIB (Virazole, ICN Pharmaceuticals) 1000 –1200 mg/day for 24 weeks. Group B (25 patients) received subcutaneous IFN-␣ 2b 5MU daily plus oral RIB for 4 weeks followed by IFN-␣ 2b 5MU thrice weekly plus RIB for 20 weeks. Patients were followed-up for 24 weeks after cessation of treatment. Liver biopsy was performed at the end of treatment. One patient in group A and three patients in group B discontinued treatment due to side-effects. Results: Virological end of treatment response and sustained response did not differ significantly between the two groups (41.7% and 29.2% in group A vs 45.5% and 36.4% in group B respectively). However, the virological response in group B after the 4 weeks of daily IFN-␣ induction dosing was almost 2-fold that in group A, but the difference did not reach statistical significance (54.6% vs 29.2% respectively, p ⫽ 0.08). There was a significant improvement of the Histologic Activity Index in both groups A and B (p ⫽ 0.001 and p ⫽ 0.005 respectively), in both the sustained responders and responders-relapsers (using criteria of Ishak et al., J. Hepatol. 1995; 22:696 – 699). Conclusions: There was a strong trend towards improvement of the virological response rate to IFN plus RIB when IFN was given daily; this trend however, was lost when daily IFN was switched to thrice weekly IFN. 368 Hepatic expression of endogenous IL-10 is increased in chronic hepatitis C Ravishankar Ramamoorthy, MD, Arun Samanta, MD, FACG, Lynn Schellhase, BS, Thomas Chen, MD. VA Healthcare System, East Orange and New Jersey Medical School, Newark, NJ. Endogenous liver Interleukin-10 (IL-10) inhibits Th1 cytokine mediated inflammation and macrophage effector functions. These properties of IL-10 have been shown to reduce inflammation and hepatic injury in animal models of hepatitis. Recently, treatment with IL-10 has been reported to normalize ALT, improve histology and reduce hepatic fibrosis in patients with hepatitis C. However, production of endogenous hepatic IL-10 in patients with hepatitis C is not well defined. AIM: Present study investigated the hepatic expression of endogenous IL-10 in patients with hepatitis C. Methods: Pre-treatment liver biopsies from 24 patients with chronic hepatitis C were examined immunohistochemically for IL-10. Three normal liver tissues obtained at autopsy were used as control. IL-10 expression was graded (1⫹ ⬍10%, 2⫹ 10 – 40%, 3⫹ 41– 60%, 4⫹ ⬎60% labeled cells). Histology was graded using Knodell’s Histology Activity Index (HAI). Results: In controls, ⬍10% hepatocytes expressed IL-10. In hepatitis C, expression of IL-10 was upregulated (4⫹) as compared to control (1⫹).
Abstracts
(45.5% and 21.2%; p⫽0.23), genotype and baseline HCV RNA levels (3.52 ⫾1.8 and 3.57 ⫾1.8⫻108 copies/ml. respect). Results: Twenty-two (32%) patients in the low dose group and 31 (50%) in the high dose had initial response (p⫽0.05). Twenty (29%) and 21 (34%) had end of treatment response (p⫽0.09) and 13 (19%) and 16 (26%) had sustained virological response (p⫽0.18). Seven patients relapsed at 12 months (1 low dose and 6 high dose) and nine at 18 months (6 low, 3 high). Conclusion: Re-treatment with lower doses of interferon and ribavirin results in similar rates of sustained virological response compared to standard dosing. Thus, dose reduction of these antivirals seems to have minimal effects on the probability of sustained virologic response. (Supported in part by Schering Pharm. Corp).
365 Response to combination therapy with interferon and ribavirin in hepatitis C cirrhotic patients F Pereyra, R Pena, V Kaul, A Suvannasankha, K DiGregorio, L Stein, F Gross, S Peikin, O Perez, G Benson, A Mushnick, C DeAngelo, J Goldfarb, K Rothstein, C Manazarbeitia, D Reich, N Kern, S Munoz. Center for Liver Disease, Albert Einstein Medical Center, Philadelphia, PA. Background: Only small groups of HCV patients have been reported in trials with combination antiviral therapy (interferon alpha 2b (IFN) plus Ribavirin). The response rates have generally been lower than in noncirrhotic patients. Aim: We evaluated the relationship between response to two dose schedules of therapy and pre-treatment biopsy findings. Methods: A prospective study of a cohort of non-responders (NR) and relapsers (RE) to monotherapy with IFN was randomized to receive IFN 3MU tiw plus ribavirin 600 mg qd, or IFN 5 MU tiw plus ribavirin 1,000 mg qd. Patients were stratified according to absence/presence of cirrhosis on biopsy as well as HCV RNA level and genotype. Results: Ninety patients were enrolled, 25.6% of whom had cirrhosis on biopsy as well as HCV RNA level and genotype. Results: Ninety patients were enrolled, 25.6% of whom had cirrhosis on biopsy. Demographics, viral levels and genotype distribution were similar between the cirrhotic and non-cirrhotic groups. Only 13% of cirrhotic patients exhibited a sustained virological response (SVR), whereas 21% of non-cirrhotics patients showed SVR (p⫽n.s.). Analysis including bridging fibrosis patients in the cirrhotic group, did not alter the significance level. When low and high dose groups were compared, there was a non-significant difference in SVR rates between cirrhotics and non-cirrhotic patients. Conclusion: Histological severity of chronic hepatitis C was not associated with the probability of durable response to combination antiviral therapy with IFN and ribavirin. These results suggests that cirrhotic patients should be offered this therapy regardless of their histologic diagnosis. (Supported in part by Schering Pharm. Corp).
366 Drugs induced liver damage Cvetka Pernat, M. Skalicky. General Hospital Maribor, Slovenia. Introduction: Almost every known drug has been implicated as a cause of liver damage. Toxic effect of drugs on the liver can mimic every naturally occurring liver disease in man. There are no specific tests in the diagnosis of drug liver injury. The aim of our study was to evaluate how common drugs cause liver damage. Methods: Since January 1996 to October 1999 we evaluated 38 patients with the drug liver injury. Viral hepatitis, Wilson disease, autoimmune hepatitis, metabolic and alcohol liver disease were excluded in 30 patients. Blockage of the bile ducts was excluded in 8 patients. All patients have the history of drug intake. Liver biopsy was made in all patients. Results: 21 patients have symptoms and histological features of acute liver injury, 9 patients of chronic liver injury, 8 patients have cholestasis. In 35
AJG – Vol. 95, No. 9, 2000
cases removal of the drug led to improvement. In 3 patients with cirrhosis there was no improvement after removal of the drug. Conclusions: Drugs in common use often cause toxic effect on the liver. Early suspicion of drug related hepatic reaction and exclusion of other causes of a hepatic reaction, are essential. Removal of the drug can lead to improvement even if chronic liver disease has developed. 367 Ribavirin plus interferon daily or thrice weekly in chronic hepatitis C genotype 4 Ayman Y. Abdel Rahim, M.D., Mohsen Salama, M.D., Salah El-Dirini, M.D., Baher Badawy, M.D. Faculty of Medicine, Cairo University, Egypt. Hepatitis C virus (HCV) genotype 4 infections show less favorable response to interferon-⬀ (IFN-⬀) treatment. The aim of this study was to assess the efficacy of ribavirin (RIB) combined with either thrice weekly IFN or daily IFN induction dosing in Egyptian patients with chronic hepatitis C (CHC) due to genotype 4. Methods: Fifty Egyptian patients with biopsy proven CHC due to genotype 4 were randomly assigned to: Group A (25 patients) received subcutaneous IFN-␣ 2b (Intron-A, Schering-Plough International) 5MU thrice weekly plus oral RIB (Virazole, ICN Pharmaceuticals) 1000 –1200 mg/day for 24 weeks. Group B (25 patients) received subcutaneous IFN-␣ 2b 5MU daily plus oral RIB for 4 weeks followed by IFN-␣ 2b 5MU thrice weekly plus RIB for 20 weeks. Patients were followed-up for 24 weeks after cessation of treatment. Liver biopsy was performed at the end of treatment. One patient in group A and three patients in group B discontinued treatment due to side-effects. Results: Virological end of treatment response and sustained response did not differ significantly between the two groups (41.7% and 29.2% in group A vs 45.5% and 36.4% in group B respectively). However, the virological response in group B after the 4 weeks of daily IFN-␣ induction dosing was almost 2-fold that in group A, but the difference did not reach statistical significance (54.6% vs 29.2% respectively, p ⫽ 0.08). There was a significant improvement of the Histologic Activity Index in both groups A and B (p ⫽ 0.001 and p ⫽ 0.005 respectively), in both the sustained responders and responders-relapsers (using criteria of Ishak et al., J. Hepatol. 1995; 22:696 – 699). Conclusions: There was a strong trend towards improvement of the virological response rate to IFN plus RIB when IFN was given daily; this trend however, was lost when daily IFN was switched to thrice weekly IFN. 368 Hepatic expression of endogenous IL-10 is increased in chronic hepatitis C Ravishankar Ramamoorthy, MD, Arun Samanta, MD, FACG, Lynn Schellhase, BS, Thomas Chen, MD. VA Healthcare System, East Orange and New Jersey Medical School, Newark, NJ. Endogenous liver Interleukin-10 (IL-10) inhibits Th1 cytokine mediated inflammation and macrophage effector functions. These properties of IL-10 have been shown to reduce inflammation and hepatic injury in animal models of hepatitis. Recently, treatment with IL-10 has been reported to normalize ALT, improve histology and reduce hepatic fibrosis in patients with hepatitis C. However, production of endogenous hepatic IL-10 in patients with hepatitis C is not well defined. AIM: Present study investigated the hepatic expression of endogenous IL-10 in patients with hepatitis C. Methods: Pre-treatment liver biopsies from 24 patients with chronic hepatitis C were examined immunohistochemically for IL-10. Three normal liver tissues obtained at autopsy were used as control. IL-10 expression was graded (1⫹ ⬍10%, 2⫹ 10 – 40%, 3⫹ 41– 60%, 4⫹ ⬎60% labeled cells). Histology was graded using Knodell’s Histology Activity Index (HAI). Results: In controls, ⬍10% hepatocytes expressed IL-10. In hepatitis C, expression of IL-10 was upregulated (4⫹) as compared to control (1⫹).