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A randomized trial of high dose interferon alfa-2b with or without ribavirin for chronic hepatitis C in non-responders to standard dose interferon
GASTROENTEROLOGY Vol. 118, No.4
A1488 AASLD ABSTRACTS
6734
6736
RAPID TURNOVER RATE OF HEPATITIS C VIRUS CLEARANCE BY THE TWICE-A-DAY TREATMENT REGIMEN USING INTERFERON-BETA. Yasushi Shiratori, As Perelson, L. Weinberger, F. Imazeki, O. Yokosuka, R. Nakata, M. Ornata, Univ of Tokyo, Tokyo, Japan; Los Alamos, Nm, NM; Chiba Univ, Chiba, Japan; Japanese Red Cross Med Ctr, Tokyo, Japan. (Background!Aim) Since patients with high viral load and HCV subtype Ib are known to respond poorly to interferon therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. (Methods) 22 patients with chronic hepatitis C confirmed by liver biopsy and with> I Meq/ml of HCV RNA and HCV subtype Ib were randomly assigned to two different IFN administration regimens (6 million unit of IFN once a day or 3 million unit of IFN twice a day), and the serum HCV RNA level was serially measured every 8-12 hrs within 3 days, and every week thereafter. (Results) Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall «72 hrs), followed by a slower clearance phase(>72 hrs). Fitting the data to a model for a HCV decay proposed by Neumann et al. (Science 1998; 282: 103-107) showed that the treatment efficacy was significantly higher (96%) with twice daily administration as compared with that (89%) with a once-a day treatment (P<0.05). Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1,2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively with the once-a-day administration regimen (P
PERCUTANEOUS LIVER BIOPSY FRAGMENTATION: DOES IT CORRELATE WITH THE EXTENT OF FIBROSIS? K. Shiva Kumar, Peter F. Malet, Rajeev Jain, Priyajit Prasad, Arshad H. Malik, Kimberly Persley, George Ostapowicz, Univ of Texas Southwestern Med Ctr, Dallas, TX. Fragmentation of liver biopsy specimens is not uncommon and extensive fragmentation has been said to correlate with the presence of cirrhosis. Aims: To determine if fragmentation of percutaneous liver biopsy specimens correlates with the degree of fibrosis. Methods: 145 consecutive patients undergoing percutaneous liver biopsy at the Univ of Texas Southwestern Med Ctr were enrolled prospectively. Clinical and lab data were collected and pre-biopsy judgement of cirrhosis was made based on these parameters. All biopsies were performed using a Klatskin-type needle and suction technique. The specimens were then measured for the number of fragments. Histological exam was subsequently done and the extent of fibrosis scored by a pathologist who was blinded to the fragmentation data, using the METAVIR system. The stages were reported from stage 0 (no fibrosis) to stage IV (cirrhosis). Fragmentation data was then compared among the different stages. Results: The biopsy specimens were distributed as follows: St 0 -16 (II %), St I - 45 (31%), St II - 47 (32%), St III - 17 (12%), St IV or cirrhosis - 20 (14%). The mean fragment number was 5.3 ± 4.14 of the 145 biopsies were predicted to be cirrhotic and 7 of these actually had cirrhosis on biopsy (p=0.0006). The median number of fragments among the various stages were(ranges in brackets): St 0 - 4.5 (1-12), St I - 3.0 (1-9), St II - 4.0 (1-11), St III - 7.0 (1-20), St IV - 8.0 (2-25). The fragment number increased significantly from non-cirrhotic to cirrhotic specimens (p=0.OO3) and also with increasing stages of fibrosis from stage O-IV (p
6735 A RANDOMIZED TRIAL OF HIGH DOSE INTERFERON ALFA-2B WITH OR WITHOUT RIBAVIRIN FOR CHRONIC HEPATITIS C IN NON-RESPONDERS TO STANDARD DOSE INTERFERON. K. Shiva Kumar, Arshad H. Malik, Peter F. Malet, George Ostapowicz, Megan Wood, Ann Jones, William M. Lee, Univ of Texas Southwestern, Dallas, TX. There is no optimal therapy for patients with chronic hepatitis C who do not respond to standard interferon treatment. Induction regimens utilizing higher interferon doses may improve response rates in these non-responders. Aim: To assess in a group of interferon treated non-responders, the response to re-treatment with an induction regimen of high dose interferon alfa-2b (IFN), with or without ribavirin (RIB). Methods: Previous nonresponders to standard dose IFN (3-5 MU TIW x ~ 20 weeks), were randomized to receive, unblinded, either: Group A: 10 MU IFN daily x 10 days, then 5 MU daily x 74 days, then 5 MU TIW x 24 weeks (total 36 weeks) or Group B: The above regimen, with addition of RIB 1000 mg/d at day 11. Patients who did not respond by week 12 were discontinued. Primary outcome measures were negative serum HCV RNA « 100 copiesl ml;NGI Superquant)at the end of treatment and 24 weeks of follow up. Results: 25 patients were included in the study: 10 were randomized to group A and 15 to group B. Genotype was 1a in 14 and Ib in 9 (2 unknown). 6 patients in group A and 7 in group B discontinued therapy for failure to respond by week 12. Only 2 patients discontinued treatment due to side effects. 8 patients required dose reductions. Intention to treat analysis was performed. End of treatment response (ETR) was noted in I of 10 (10%) patients in group A and 8 of 15 (54%)in group B (p = 0.04). The sole ETR in group A and 3 in group B relapsed on follow up. A sustained response (Negative HCV RNA at follow up week 24) was seen in no patient in group A and 5 of 15 (33%) in group B (p = 0.06). Conclusions: Induction monotherapy with IFN showed little efficacy in previous non-responders to standard dose IFN. However, an induction regimen with RIB yielded a 33% sustained response rate. Treatment was well tolerated, despite the higher doses of IFN used. Hence, high dose IFN with RIB appears to be a therapeutic option for non-responders to conventional IFN monotherapy. (Research support: Schering Plough Inc.).
Loss ofserum HCV RNA
Group A (n=10) Group B (n=15)
1W12
1W24
1W36
FW12
FW24
3/10 8/15
1/10 8/15
1/10 8/15
0/10 6/15
0/10 5/15
::I~:::':::::I 10
12 14 16 Fr,gments
18
20
22
24
26
6737 EFFICACY OF BETA-BLOCKERS AS SECONDARY PROPHYLAXIS IN VARICEAL BLEEDING AFTER TIPS THERAPY. Pankaj Singh, David Siegel, Veena Channamsetty, Neera Yadav, Vernu Visvalingam, Ronald Greenberg, Simrny Bank, Long Island Jewish Hosp, New Hyde Park, NY; State Univ of New York, Brooklyn, NY. AIM: To evaluate the additive effect of beta blockers in preventing rebleeding in patients who have undergone TIPS therapy for variceal hemorrhage. BACKGROUND: Hepatic venous-portal pressure gradient is an important predictor of variceal hemmorhage. TIPS effectively lowers the pressure gradient to a normal level, resulting in control of acute bleeding and reduction in episodes of re-bleeding. However, 16-40% of patients with TIPS re-bleed in 6 months to I year. One of the underlying mechanisms is re-occlusion of the shunt, which leads to restoration of the pressure gradient. This group of patients may benefit from therapeutic maneuvers to lower this gradient. The role of beta-blockers for secondary prophylaxis is well established. However, the efficacy of beta-blockers to prevent rebleeding in patients previously treated with TIPS has not been well reported in the literature. METHOD: This study included 15 patients who presented with variceal hemmorhage and were treated with TIPS. Patients were divided into two treatment arms: with and without beta-blockers. Both groups were comparable with respect to age, sex, etiology of cirrhosis, Child's classification and pre- and post- TIPS hepatic venous pressure gradient. Follow up evaluation was done for re-bleeding, worsening in encephalopathy and shunt patency. Evaluation included upper endoscopy and Doppler ultrasound. Treatment failure was defined as uncontrolled bleeding or 3 episodes of re-bleeding within 6 months after initiation of therapy. RESULTS: Median observation time was 12 months. Rates of re-bleeding were 12.5% in both the beta-blocker and non-beta-blocker groups. Treatment failure was not seen in either of the groups. Rates of worsening encephalopathy were 37% in both the beta-blocker and nonbeta-blocker group. Cummulative rates of shunt dysfunction after I year was 28% in both groups. Survival in the beta-blocker group was 67% and in the non-beta-blocker group was 75%, but there was no statistical significance between the two groups (p>0.05). CONCLUSION: Recurrence of variceal bleeding after TIPS therapy was the same in patients with or without beta-blockers. Similarly, there was no significant difference in the mortality due to progressive liver dysfunction between the two groups. In conclusion, it appears that use of beta-blockers after TIPS therapy offers no advantage.
A1488 AASLD ABSTRACTS
6734
6736
RAPID TURNOVER RATE OF HEPATITIS C VIRUS CLEARANCE BY THE TWICE-A-DAY TREATMENT REGIMEN USING INTERFERON-BETA. Yasushi Shiratori, As Perelson, L. Weinberger, F. Imazeki, O. Yokosuka, R. Nakata, M. Ornata, Univ of Tokyo, Tokyo, Japan; Los Alamos, Nm, NM; Chiba Univ, Chiba, Japan; Japanese Red Cross Med Ctr, Tokyo, Japan. (Background!Aim) Since patients with high viral load and HCV subtype Ib are known to respond poorly to interferon therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. (Methods) 22 patients with chronic hepatitis C confirmed by liver biopsy and with> I Meq/ml of HCV RNA and HCV subtype Ib were randomly assigned to two different IFN administration regimens (6 million unit of IFN once a day or 3 million unit of IFN twice a day), and the serum HCV RNA level was serially measured every 8-12 hrs within 3 days, and every week thereafter. (Results) Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall «72 hrs), followed by a slower clearance phase(>72 hrs). Fitting the data to a model for a HCV decay proposed by Neumann et al. (Science 1998; 282: 103-107) showed that the treatment efficacy was significantly higher (96%) with twice daily administration as compared with that (89%) with a once-a day treatment (P<0.05). Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1,2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively with the once-a-day administration regimen (P
PERCUTANEOUS LIVER BIOPSY FRAGMENTATION: DOES IT CORRELATE WITH THE EXTENT OF FIBROSIS? K. Shiva Kumar, Peter F. Malet, Rajeev Jain, Priyajit Prasad, Arshad H. Malik, Kimberly Persley, George Ostapowicz, Univ of Texas Southwestern Med Ctr, Dallas, TX. Fragmentation of liver biopsy specimens is not uncommon and extensive fragmentation has been said to correlate with the presence of cirrhosis. Aims: To determine if fragmentation of percutaneous liver biopsy specimens correlates with the degree of fibrosis. Methods: 145 consecutive patients undergoing percutaneous liver biopsy at the Univ of Texas Southwestern Med Ctr were enrolled prospectively. Clinical and lab data were collected and pre-biopsy judgement of cirrhosis was made based on these parameters. All biopsies were performed using a Klatskin-type needle and suction technique. The specimens were then measured for the number of fragments. Histological exam was subsequently done and the extent of fibrosis scored by a pathologist who was blinded to the fragmentation data, using the METAVIR system. The stages were reported from stage 0 (no fibrosis) to stage IV (cirrhosis). Fragmentation data was then compared among the different stages. Results: The biopsy specimens were distributed as follows: St 0 -16 (II %), St I - 45 (31%), St II - 47 (32%), St III - 17 (12%), St IV or cirrhosis - 20 (14%). The mean fragment number was 5.3 ± 4.14 of the 145 biopsies were predicted to be cirrhotic and 7 of these actually had cirrhosis on biopsy (p=0.0006). The median number of fragments among the various stages were(ranges in brackets): St 0 - 4.5 (1-12), St I - 3.0 (1-9), St II - 4.0 (1-11), St III - 7.0 (1-20), St IV - 8.0 (2-25). The fragment number increased significantly from non-cirrhotic to cirrhotic specimens (p=0.OO3) and also with increasing stages of fibrosis from stage O-IV (p
6735 A RANDOMIZED TRIAL OF HIGH DOSE INTERFERON ALFA-2B WITH OR WITHOUT RIBAVIRIN FOR CHRONIC HEPATITIS C IN NON-RESPONDERS TO STANDARD DOSE INTERFERON. K. Shiva Kumar, Arshad H. Malik, Peter F. Malet, George Ostapowicz, Megan Wood, Ann Jones, William M. Lee, Univ of Texas Southwestern, Dallas, TX. There is no optimal therapy for patients with chronic hepatitis C who do not respond to standard interferon treatment. Induction regimens utilizing higher interferon doses may improve response rates in these non-responders. Aim: To assess in a group of interferon treated non-responders, the response to re-treatment with an induction regimen of high dose interferon alfa-2b (IFN), with or without ribavirin (RIB). Methods: Previous nonresponders to standard dose IFN (3-5 MU TIW x ~ 20 weeks), were randomized to receive, unblinded, either: Group A: 10 MU IFN daily x 10 days, then 5 MU daily x 74 days, then 5 MU TIW x 24 weeks (total 36 weeks) or Group B: The above regimen, with addition of RIB 1000 mg/d at day 11. Patients who did not respond by week 12 were discontinued. Primary outcome measures were negative serum HCV RNA « 100 copiesl ml;NGI Superquant)at the end of treatment and 24 weeks of follow up. Results: 25 patients were included in the study: 10 were randomized to group A and 15 to group B. Genotype was 1a in 14 and Ib in 9 (2 unknown). 6 patients in group A and 7 in group B discontinued therapy for failure to respond by week 12. Only 2 patients discontinued treatment due to side effects. 8 patients required dose reductions. Intention to treat analysis was performed. End of treatment response (ETR) was noted in I of 10 (10%) patients in group A and 8 of 15 (54%)in group B (p = 0.04). The sole ETR in group A and 3 in group B relapsed on follow up. A sustained response (Negative HCV RNA at follow up week 24) was seen in no patient in group A and 5 of 15 (33%) in group B (p = 0.06). Conclusions: Induction monotherapy with IFN showed little efficacy in previous non-responders to standard dose IFN. However, an induction regimen with RIB yielded a 33% sustained response rate. Treatment was well tolerated, despite the higher doses of IFN used. Hence, high dose IFN with RIB appears to be a therapeutic option for non-responders to conventional IFN monotherapy. (Research support: Schering Plough Inc.).
Loss ofserum HCV RNA
Group A (n=10) Group B (n=15)
1W12
1W24
1W36
FW12
FW24
3/10 8/15
1/10 8/15
1/10 8/15
0/10 6/15
0/10 5/15
::I~:::':::::I 10
12 14 16 Fr,gments
18
20
22
24
26
6737 EFFICACY OF BETA-BLOCKERS AS SECONDARY PROPHYLAXIS IN VARICEAL BLEEDING AFTER TIPS THERAPY. Pankaj Singh, David Siegel, Veena Channamsetty, Neera Yadav, Vernu Visvalingam, Ronald Greenberg, Simrny Bank, Long Island Jewish Hosp, New Hyde Park, NY; State Univ of New York, Brooklyn, NY. AIM: To evaluate the additive effect of beta blockers in preventing rebleeding in patients who have undergone TIPS therapy for variceal hemorrhage. BACKGROUND: Hepatic venous-portal pressure gradient is an important predictor of variceal hemmorhage. TIPS effectively lowers the pressure gradient to a normal level, resulting in control of acute bleeding and reduction in episodes of re-bleeding. However, 16-40% of patients with TIPS re-bleed in 6 months to I year. One of the underlying mechanisms is re-occlusion of the shunt, which leads to restoration of the pressure gradient. This group of patients may benefit from therapeutic maneuvers to lower this gradient. The role of beta-blockers for secondary prophylaxis is well established. However, the efficacy of beta-blockers to prevent rebleeding in patients previously treated with TIPS has not been well reported in the literature. METHOD: This study included 15 patients who presented with variceal hemmorhage and were treated with TIPS. Patients were divided into two treatment arms: with and without beta-blockers. Both groups were comparable with respect to age, sex, etiology of cirrhosis, Child's classification and pre- and post- TIPS hepatic venous pressure gradient. Follow up evaluation was done for re-bleeding, worsening in encephalopathy and shunt patency. Evaluation included upper endoscopy and Doppler ultrasound. Treatment failure was defined as uncontrolled bleeding or 3 episodes of re-bleeding within 6 months after initiation of therapy. RESULTS: Median observation time was 12 months. Rates of re-bleeding were 12.5% in both the beta-blocker and non-beta-blocker groups. Treatment failure was not seen in either of the groups. Rates of worsening encephalopathy were 37% in both the beta-blocker and nonbeta-blocker group. Cummulative rates of shunt dysfunction after I year was 28% in both groups. Survival in the beta-blocker group was 67% and in the non-beta-blocker group was 75%, but there was no statistical significance between the two groups (p>0.05). CONCLUSION: Recurrence of variceal bleeding after TIPS therapy was the same in patients with or without beta-blockers. Similarly, there was no significant difference in the mortality due to progressive liver dysfunction between the two groups. In conclusion, it appears that use of beta-blockers after TIPS therapy offers no advantage.