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481 Entecavir (ETV) is superior to lamivudine and adefovir in trials of HBeAg-positive and -negative chronic hepatitis B infection: A cross-study analysis with published reports
Posters
174
in patients with pejorative outcome, 60% had HBV DNA level <7log and median bilirubin was 317 grnol/1 (IQR 68 to 570) versus 4% and 17 p.mol/1 (IQR 13 to 21), respectively, in patients with favorable outcome. Conclusion: In patients with reactivation due to lamivadine-resistant mutants, severe liver failure may progress despite virological response to adefovir therapy. Patients with low viral load or severe cholestasis should be cautiously monitored and evaluated for liver transplantation.
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LONG-TERM RESULTS OF INTERFERON ~ TREATMENT IN CHILDREN WITH CHRONIC HEPATITIS B
H. Demir, N. Saltak-Temizel, Y. Usta, H. Ozen, E Giirakan, A.L. Yiice, N. Kodak. Pediatric Gastroenterolog)~. Hepatology and Nutrition,
Haeettepe Unioersity School of Medicine, Ankara, Turkey Background and Ailn: Data on long-term effects of interferon (IFN)-~
trealment in children with chronic hepatitis B is limited. We aimed to evaluate the long-term virological response to IFN-~ therapy in patients with chronic hepatitis B. Patients: Fifty HBsAg, HBeAg,and HBV-DNA positive children (aged from 2 to 15 years, mean 7.6±3.3 years) were enrolled in a study where they received IF'N-O, subcutaneously 3 times weekly for 24 weeks. Thirty three of them were treated with an IFN-~ dosage of 10M1U/m 2 and remaining 17 received 5 MIU/rn2. Response to treatment was defined as loss of HBeAg and development of antiHBe during therapy or within 12 months after the end of therapy. The patients were followed for a range of 24 to 79 months (mean, 42.8±14.2 months) after the end of treatment. Results: Eighteen (36%) of the patients responded to treatment, 14 cases during therapy and 4 cases within 12 months after therapy withdrawal. During the follow-up period additional 17 (34%) patients had HBeAg seroconversion. Twelve of them seroconverted at 12 to 24 months' time after cessation of IKN-o,, and 5 later. All responders also cleared HBVDNA from their sera. No statistical difference was found between low and high dose IKN-c~ receivers' seroconversion rates. Total number of responders at tile end of follow up was 35 (70% of all patients). Loss of HBsAg occurred in 6 (12%) patients. All 6 were among 18 responders who cleared HBeAg during treamaent or 12 months after cessation of therapy. None of tile responders relapsed during tile follow-up period. Conclusions: IFN~ therapy in children with chronic hepatitis B seems to continue inducing HBeAg seroconversion after therapy, especially within 24 months after cessation oflFN-a. Therefore, other therapeutic regimens might be considered for non-responders, only after 2 years have passed.
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ENTECAVIR (ETV) IS S U P E R I O R TO LAMIVUDINE AND ADEFOVIR IN TRIALS OF HBeAg-POSITIVE AND -NEGATIVE CHRONIC HEPATITIS B INFECTION: A CROSS-STUDY ANALYSIS WITH PUBLISHED REPORTS
J.L. Dienstag I , L.J. Wei 2, D. Xu 3, A. Cross4, B. Kreter4, R. Wilber4.
1Massachusetts General Hospital, Boston, MA, USA,"2Harvard University, Boston, MA, USA," SBristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA Background: The oral antiviral agents LVD and ADV were approved for treatment of chronic hepatitis B based on results from placebo-controlled trials. ETV is a new oral antiviral found in clinical trials to be superior to LVD. No head-to-head comparison of all three therapies has been done, and differing virologic assays used among the trials of each agent complicate inter-study comparisons. Aim: Apply established statistical techniques using a prospectively defined analysis protocol to compare Phase III ETV data with combined data from published histologic, biochemical, serologic, and virologic trial results o f LVD, ADV and placebo. Methods: After a comprehensive search of electronic databases, abstracts, and regulatory submissions according to predefined inclusion (prospective,
randomized trials of at least one monothempy arm and a control arm or prospectively followed case series) and exclusion criteria (foreign langnage, pediatric trials, trials not performed in humans, trials of other therapies, retrospective reports, trials with inadequate description of methods, lamivudine-resistant patients or patients with viral coinfection or significant comorbidities, etc.), independent reviewers extracted Week 48/52 histologic, virologic, biochemical, and serologic endpoints, which were subjected to statistical analysis by a fixed effects model. Results: Of 612 potential publications/data sources identified, 28 satisfied inclusion/exclusion criteria. LVD, ADV, and ETV were superior to placebo for all efficacy measures (HBeAg+/-). ETV was superior to ADV for all efficacy measures in HBeAg+ patients and virologic endpoints in HBeAg- patients (other endpoints comparable). LVD was superior to ADV in HBeAg+ patients for all efficacy measures except ~>2 point histologic activity index improvement and ranked assessment of necrosis/inflammation (NI), and in HBeAg- patients for virologic endpoints (other endpoints comparable). ETV was superior to LVD for all efficacy measures except ranked assessment of NI and fibrosis (HBeAg+/-), and HBeAg+ seroconversion (other endpoints comparable). Conclusions: For virologic endpoints, ETV is superior to LVD, which is superior to ADV. Based upon controlled trials of ETV and LVD and analyses of multiple studies in which LVD and ADV were analyzed individually, ETV consistendy ranks highest among tile three drugs across multiple endpoints for both HBeAg+ and HBeAg- patients with chronic hepatitis B.
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HEPATIC FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION CAN BE PARTIALLY REVERSED BY IFN-~
S. Dooleg I , B-E. Wang 3, J-D. Jia 3, W-E Wu 4, J-Z. Xiang 4, ER. Mertens 5, W-M. Cai 2, H-L. Weng2 . 1Medical Clinic II, University-Hospital
Mannheim, University of Heidelberg, Heidelberg, Germany; 2Institute of Infectious Diseases, First Affiliated Hospital, Medical School, Zhejiang University, Hangzt~ou, China; 3Liver Research Cente~ Beijing Friendship Hospital, Capital University of Medical Science, Beijing, China," 4Eighth Hospital of Guangzhou, Guangzhou, China," 5Department of Nephrology and Immunology, University Hospital, RWTH, Aachen, Germany Background: Hepatic fibrosis clue to chronic hepatitis B virus (HBV) infection has an enormous socio-economic impact. Besides strategies aiming at virus elimination, prevention or reversal of liver fibrosis is amenible. Given the antifibrotic activity of IFN-¥, a randomized openlabeled multicenter trial was initiated to test IFN-¥ in HBV infection. Methods: HBs-antigen positive patients with biopsy proven hepatic fibrosis (n= 99, stages 2 4 according to Scheuer criterion) were treated with diammone glycyrrhizinate and potassium magnesium aspartate. Treatment with 50 mg IFN-y i.m. on a daily basis for three months and on alternate days the subsequent six months was performed in 66 randomly assigned patients. Efficacy was evaluated by liver biopsy and serologic markers. Results: 54 patients in the IFN-¥ group and 29 patients in tile control group completed the study protocol. The hepatic fibrosis score was significantly reduced in 63 percent of IFN-¥ treated patients compared to 24.1 percent in the control group as assessed by a serniquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for total fibrosis score decreased from 13.8±5.8 to 10.1±5.1 in the IFN-¥ group, whereas they were unchanged in controls (13.2±6.8 versus 12.6±4.8 after 9 months). Tile Scheuer fibrosis scoring system revealed 12 out of 54 patients improved ~>1 stage(s) in the IFN-¥ compared to 1/29 in the control group. Antffibrotic activity may be attributed to decreased TGF-[3 signaling via phospho-Smad2 and reduced number of activated, a smooth muscle actin positive hepatic stellate cells.
174
in patients with pejorative outcome, 60% had HBV DNA level <7log and median bilirubin was 317 grnol/1 (IQR 68 to 570) versus 4% and 17 p.mol/1 (IQR 13 to 21), respectively, in patients with favorable outcome. Conclusion: In patients with reactivation due to lamivadine-resistant mutants, severe liver failure may progress despite virological response to adefovir therapy. Patients with low viral load or severe cholestasis should be cautiously monitored and evaluated for liver transplantation.
I•
LONG-TERM RESULTS OF INTERFERON ~ TREATMENT IN CHILDREN WITH CHRONIC HEPATITIS B
H. Demir, N. Saltak-Temizel, Y. Usta, H. Ozen, E Giirakan, A.L. Yiice, N. Kodak. Pediatric Gastroenterolog)~. Hepatology and Nutrition,
Haeettepe Unioersity School of Medicine, Ankara, Turkey Background and Ailn: Data on long-term effects of interferon (IFN)-~
trealment in children with chronic hepatitis B is limited. We aimed to evaluate the long-term virological response to IFN-~ therapy in patients with chronic hepatitis B. Patients: Fifty HBsAg, HBeAg,and HBV-DNA positive children (aged from 2 to 15 years, mean 7.6±3.3 years) were enrolled in a study where they received IF'N-O, subcutaneously 3 times weekly for 24 weeks. Thirty three of them were treated with an IFN-~ dosage of 10M1U/m 2 and remaining 17 received 5 MIU/rn2. Response to treatment was defined as loss of HBeAg and development of antiHBe during therapy or within 12 months after the end of therapy. The patients were followed for a range of 24 to 79 months (mean, 42.8±14.2 months) after the end of treatment. Results: Eighteen (36%) of the patients responded to treatment, 14 cases during therapy and 4 cases within 12 months after therapy withdrawal. During the follow-up period additional 17 (34%) patients had HBeAg seroconversion. Twelve of them seroconverted at 12 to 24 months' time after cessation of IKN-o,, and 5 later. All responders also cleared HBVDNA from their sera. No statistical difference was found between low and high dose IKN-c~ receivers' seroconversion rates. Total number of responders at tile end of follow up was 35 (70% of all patients). Loss of HBsAg occurred in 6 (12%) patients. All 6 were among 18 responders who cleared HBeAg during treamaent or 12 months after cessation of therapy. None of tile responders relapsed during tile follow-up period. Conclusions: IFN~ therapy in children with chronic hepatitis B seems to continue inducing HBeAg seroconversion after therapy, especially within 24 months after cessation oflFN-a. Therefore, other therapeutic regimens might be considered for non-responders, only after 2 years have passed.
l
•
ENTECAVIR (ETV) IS S U P E R I O R TO LAMIVUDINE AND ADEFOVIR IN TRIALS OF HBeAg-POSITIVE AND -NEGATIVE CHRONIC HEPATITIS B INFECTION: A CROSS-STUDY ANALYSIS WITH PUBLISHED REPORTS
J.L. Dienstag I , L.J. Wei 2, D. Xu 3, A. Cross4, B. Kreter4, R. Wilber4.
1Massachusetts General Hospital, Boston, MA, USA,"2Harvard University, Boston, MA, USA," SBristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA Background: The oral antiviral agents LVD and ADV were approved for treatment of chronic hepatitis B based on results from placebo-controlled trials. ETV is a new oral antiviral found in clinical trials to be superior to LVD. No head-to-head comparison of all three therapies has been done, and differing virologic assays used among the trials of each agent complicate inter-study comparisons. Aim: Apply established statistical techniques using a prospectively defined analysis protocol to compare Phase III ETV data with combined data from published histologic, biochemical, serologic, and virologic trial results o f LVD, ADV and placebo. Methods: After a comprehensive search of electronic databases, abstracts, and regulatory submissions according to predefined inclusion (prospective,
randomized trials of at least one monothempy arm and a control arm or prospectively followed case series) and exclusion criteria (foreign langnage, pediatric trials, trials not performed in humans, trials of other therapies, retrospective reports, trials with inadequate description of methods, lamivudine-resistant patients or patients with viral coinfection or significant comorbidities, etc.), independent reviewers extracted Week 48/52 histologic, virologic, biochemical, and serologic endpoints, which were subjected to statistical analysis by a fixed effects model. Results: Of 612 potential publications/data sources identified, 28 satisfied inclusion/exclusion criteria. LVD, ADV, and ETV were superior to placebo for all efficacy measures (HBeAg+/-). ETV was superior to ADV for all efficacy measures in HBeAg+ patients and virologic endpoints in HBeAg- patients (other endpoints comparable). LVD was superior to ADV in HBeAg+ patients for all efficacy measures except ~>2 point histologic activity index improvement and ranked assessment of necrosis/inflammation (NI), and in HBeAg- patients for virologic endpoints (other endpoints comparable). ETV was superior to LVD for all efficacy measures except ranked assessment of NI and fibrosis (HBeAg+/-), and HBeAg+ seroconversion (other endpoints comparable). Conclusions: For virologic endpoints, ETV is superior to LVD, which is superior to ADV. Based upon controlled trials of ETV and LVD and analyses of multiple studies in which LVD and ADV were analyzed individually, ETV consistendy ranks highest among tile three drugs across multiple endpoints for both HBeAg+ and HBeAg- patients with chronic hepatitis B.
I•
HEPATIC FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION CAN BE PARTIALLY REVERSED BY IFN-~
S. Dooleg I , B-E. Wang 3, J-D. Jia 3, W-E Wu 4, J-Z. Xiang 4, ER. Mertens 5, W-M. Cai 2, H-L. Weng2 . 1Medical Clinic II, University-Hospital
Mannheim, University of Heidelberg, Heidelberg, Germany; 2Institute of Infectious Diseases, First Affiliated Hospital, Medical School, Zhejiang University, Hangzt~ou, China; 3Liver Research Cente~ Beijing Friendship Hospital, Capital University of Medical Science, Beijing, China," 4Eighth Hospital of Guangzhou, Guangzhou, China," 5Department of Nephrology and Immunology, University Hospital, RWTH, Aachen, Germany Background: Hepatic fibrosis clue to chronic hepatitis B virus (HBV) infection has an enormous socio-economic impact. Besides strategies aiming at virus elimination, prevention or reversal of liver fibrosis is amenible. Given the antifibrotic activity of IFN-¥, a randomized openlabeled multicenter trial was initiated to test IFN-¥ in HBV infection. Methods: HBs-antigen positive patients with biopsy proven hepatic fibrosis (n= 99, stages 2 4 according to Scheuer criterion) were treated with diammone glycyrrhizinate and potassium magnesium aspartate. Treatment with 50 mg IFN-y i.m. on a daily basis for three months and on alternate days the subsequent six months was performed in 66 randomly assigned patients. Efficacy was evaluated by liver biopsy and serologic markers. Results: 54 patients in the IFN-¥ group and 29 patients in tile control group completed the study protocol. The hepatic fibrosis score was significantly reduced in 63 percent of IFN-¥ treated patients compared to 24.1 percent in the control group as assessed by a serniquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for total fibrosis score decreased from 13.8±5.8 to 10.1±5.1 in the IFN-¥ group, whereas they were unchanged in controls (13.2±6.8 versus 12.6±4.8 after 9 months). Tile Scheuer fibrosis scoring system revealed 12 out of 54 patients improved ~>1 stage(s) in the IFN-¥ compared to 1/29 in the control group. Antffibrotic activity may be attributed to decreased TGF-[3 signaling via phospho-Smad2 and reduced number of activated, a smooth muscle actin positive hepatic stellate cells.