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645 VIROLOGICAL RESPONSE AT 12 WEEKS OF ENTECAVIR THERAPY PREDICTS HBeAg CLEARANCE IN HBeAg-POSITIVE CHRONIC HEPATITIS B PATIENTS
05g: VIRAL HEPATITIS − g) HEPATITIS C − CLINICAL (THERAPY) 643 PEG-IFN-l: ANTIVIRAL ACTIVITY AND SAFETY PROFILE IN A 4-WEEK PHASE 1B STUDY IN RELAPSED GENOTYPE 1 HEPATITIS C INFECTION M. Shiffman1 , E. Lawitz2 , A. Zaman3 , J. Vierling4 , B. Yoffe4 , J. Freeman5 , T. Gray5 , D. Hausman5 , A. Muir6 . 1 Virginia Commonwealth University Medical Center, Richmond, VA, 2 Alamo Medical Research, San Antonio, TX, 3 Oregon Health & Science University, Portland, OR, 4 Baylor College of Medicine, Houston, TX, 5 ZymoGenetics Inc, Seattle, WA, 6 Duke University, Durham, NC, USA E-mail: [email protected] Background: PEG-interferon-l1a (PEG-IFN-l/PEG-rIL-29) is a Type III interferon that binds to a unique receptor with more limited distribution than the Type I interferon receptor. In a Phase 1 healthy volunteer study, PEG-IFN-l was pharmacologically active without flu-like symptoms or hematologic side-effects. This ongoing Phase 1b study is evaluating the safety and efficacy of PEG-IFN-l in patients with relapsed genotype 1 hepatitis C virus (HCV) infection. Methods: Cohorts of 6 subjects each received 4-week treatment with subcutaneous PEG-IFN-l every other week (Q2W) or weekly (QW), alone or with daily ribavirin. Assessments included adverse events (AEs), laboratory abnormalities, and measurements of HCV RNA. Results: 18 subjects with a mean baseline log10 HCV RNA of 6.80 IU/L received PEG-IFN-l alone (1.5- and 3.0 mg/kg-Q2W, and 1.5-mg/kg QW). Antiviral activity (1-log10 decrease in HCV RNA) was observed in all cohorts. QW dosing was associated with the most robust response at Day 29: 6/6 subjects achieved >2-log10 decrease from baseline; 4/6 subjects had HCV RNA <1000 IU/L. Treatment was well tolerated without hematologic toxicities or treatmentrelated fever. All AEs were Grade 1/2; the most common were fatigue (n = 3) and myalgia (n = 2). Most laboratory abnormalities were Grade 1/2; two subjects (1 each at 3.0-mg/kg Q2W and 1.5-mg/kg QW) experienced reversible Grade 3 aminotransferase elevations. 1.5 mg/kg Q2W 3.0 mg/kg Q2W 1.5 mg/kg QW (N = 6) (N = 6) (N = 6) Mean maximum log10 decrease HCV RNA (95% CI) N with >2 log10 decrease in HCV RNA (any time on study) Mean neutrophils ×109 /L (range) baseline Day Mean platelets ×109 /L (range) baseline Day 29
2.2 (0.4−3.9)
1.9 (1.0−2.8)
3.6 (2.3−4.9)
2 (33%)
3 (50%)
6 (100%)
3.7 (2.6−5.0) 3.9 (2.7−6.9)
3.9 (2.1−5.6) 3.7 (2.2−6.1)
3.3 (1.9−5.2) 2.8 (1.8−3.9)
218 (173–270) 235 (165–316) 195 (140–259) 254 (174–323) 232 (182–300) 192 (149–250)
Conclusions: Repeated dosing with PEG-IFN-l was well tolerated with minimal constitutional symptoms. In contrast to effects of Type I interferons, there were no significant decreases from baseline values in neutrophil or platelet counts. Maximal antiviral activity was achieved with weekly dosing. Results with single-agent PEG-IFN-l support further study in combination with ribavirin or other antiviral agents. Updated results from the PEG-IFN-l + ribavirin cohorts will be presented at the meeting. 644 OPTIMAL LENGTH OF ANTIVIRAL THERAPY IN PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 2 AND 3: A META-ANALYSIS S. Slavenburg1 , I. Weggelaar2 , M.G.H. van Oijen2 , J.P.H. Drenth2 . 1 Department of Gastroenterology & Hepatology, 2 Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands E-mail: [email protected] Background: According to current guidelines the duration of combination treatment with peginterferon and ribavirin for patients infected
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with chronic hepatitis C virus (HCV) genotype 2 and 3, is 24 weeks. Recently, several clinical trials have investigated whether efficacy of shorter treatment duration is comparable to conventional treatment, but disconcordant results hamper interpretation. Aim: We conducted a meta-analysis of randomized controlled trials (RCTs) to determine the optimal length of treatment in patients with HCV genotype 2 and 3. Methods: A systematic literature search identified 8 studies that matched our a-priori criteria. Meta-analyses were carried out on SVR data on a total of 2001 included patients from 3 studies with randomization at baseline to either short (12−16 weeks) or standard (24 weeks) treatment, and on 785 patients in 5 studies with randomization at rapid viral response (RVR, i.e. at 4 weeks) to either short or standard treatment. Results were analyzed according to intention-to-treat analysis. Results: Sample size weighted pooled proportions of SVR rates in RCTs randomized at baseline were 74% in the standard (24 weeks) treatment compared to 63% in short treatment. After pooling the data SVR rates were statistically significantly higher in the 24 weeks of treatment with a relative risk (RR) of 0.88 (95% CI 0.76−1.01). In RCTs with randomization at RVR the sample size weighted pooled proportions of SVR rates were similar in short treatment group (82%) compared to standard treatment (83%). The pooled effect of short treatment compared with standard treatment is given by a RR of 1.00 (95% CI 0.92−1.09). Sensitivity analysis on duration of treatment (12 to 16 weeks) within the short duration group revealed no difference in outcome. Conclusion: A shorter course of therapy (12−16 weeks) with peginterferon and ribavirin is equally effective as a 24-week course, in case HCV genotype 2 and 3 patients achieve RVR at week 4. HCV patients genotype 2 and 3 without RVR should receive at least 24 weeks of treatment.
645 VIROLOGICAL RESPONSE AT 12 WEEKS OF ENTECAVIR THERAPY PREDICTS HBeAg CLEARANCE IN HBeAg-POSITIVE CHRONIC HEPATITIS B PATIENTS B.-C. Song1 , H.B. Chae2 , Y.N. Kim3 , B.S. Lee4 , Y.-K. Cho1 . 1 Internal Medicine, Jeju National University School of Medicine, Jeju, 2 Internal Medicine, Chungbuk National University, Cheongju, 3 Internal Medicine, Cheju Halla Hospital, Jeju, 4 Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea E-mail: [email protected] Background: It has been reported that virological response at 24 week of oral nucleos(t)ide analogues (NAs) predict HBeAg clearance and longterm antiviral response. Entecavir is one of the most potent antiviral agents, suggesting early virological response may predict HBeAg clearance during entecavir therapy. The aim of this study was to find out the predictive factors for HBeAg clearance using pretreatment variables and on-treatment virological response. Patients and Methods: Seventy-four consecutive HBeAg-positive chronic hepatitis B patients receiving entecarvir were retrospectively analyzed. HBV DNA levels were measured at 12-week intervals. Results: Sixteen (21.5%) of the 74 patients achieved HBeAg clearance within 48-week of entecavir therapy. Patients with low viremia (<2×106 IU/mL) had higher probability of HBeAg clearance compared to the patients with high viremia (>2×106 IU/mL) (40% vs. 14%; p = 0.04). Female patients showed higher tendency of HBeAg clearance compared with male patients (40% vs. 20%; p = 0.07). However, there was no difference of HBeAg clearance according to age and serum ALT levels. Probability of HBeAg clearance at 48-week was 61%, 18%, and 0% in patients with virological response (defined as HBV DNA <60 IU/mL) at 12-week, 24-week and in patients without virological response within 24-week, respectively (p < 0.0001). In multivariate analysis, pretreatment HBV DNA level and virologic response were independent predictive factors for HBeAg clearance at 48 week of entecavir therapy. Conclusions: This finding suggest that virological response at 12 week, and pretreatment HBV DNA level were major predictors for HBeAg clearance in patients receiving entecavir therapy.
2.2 (0.4−3.9)
1.9 (1.0−2.8)
3.6 (2.3−4.9)
2 (33%)
3 (50%)
6 (100%)
3.7 (2.6−5.0) 3.9 (2.7−6.9)
3.9 (2.1−5.6) 3.7 (2.2−6.1)
3.3 (1.9−5.2) 2.8 (1.8−3.9)
218 (173–270) 235 (165–316) 195 (140–259) 254 (174–323) 232 (182–300) 192 (149–250)
Conclusions: Repeated dosing with PEG-IFN-l was well tolerated with minimal constitutional symptoms. In contrast to effects of Type I interferons, there were no significant decreases from baseline values in neutrophil or platelet counts. Maximal antiviral activity was achieved with weekly dosing. Results with single-agent PEG-IFN-l support further study in combination with ribavirin or other antiviral agents. Updated results from the PEG-IFN-l + ribavirin cohorts will be presented at the meeting. 644 OPTIMAL LENGTH OF ANTIVIRAL THERAPY IN PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 2 AND 3: A META-ANALYSIS S. Slavenburg1 , I. Weggelaar2 , M.G.H. van Oijen2 , J.P.H. Drenth2 . 1 Department of Gastroenterology & Hepatology, 2 Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands E-mail: [email protected] Background: According to current guidelines the duration of combination treatment with peginterferon and ribavirin for patients infected
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with chronic hepatitis C virus (HCV) genotype 2 and 3, is 24 weeks. Recently, several clinical trials have investigated whether efficacy of shorter treatment duration is comparable to conventional treatment, but disconcordant results hamper interpretation. Aim: We conducted a meta-analysis of randomized controlled trials (RCTs) to determine the optimal length of treatment in patients with HCV genotype 2 and 3. Methods: A systematic literature search identified 8 studies that matched our a-priori criteria. Meta-analyses were carried out on SVR data on a total of 2001 included patients from 3 studies with randomization at baseline to either short (12−16 weeks) or standard (24 weeks) treatment, and on 785 patients in 5 studies with randomization at rapid viral response (RVR, i.e. at 4 weeks) to either short or standard treatment. Results were analyzed according to intention-to-treat analysis. Results: Sample size weighted pooled proportions of SVR rates in RCTs randomized at baseline were 74% in the standard (24 weeks) treatment compared to 63% in short treatment. After pooling the data SVR rates were statistically significantly higher in the 24 weeks of treatment with a relative risk (RR) of 0.88 (95% CI 0.76−1.01). In RCTs with randomization at RVR the sample size weighted pooled proportions of SVR rates were similar in short treatment group (82%) compared to standard treatment (83%). The pooled effect of short treatment compared with standard treatment is given by a RR of 1.00 (95% CI 0.92−1.09). Sensitivity analysis on duration of treatment (12 to 16 weeks) within the short duration group revealed no difference in outcome. Conclusion: A shorter course of therapy (12−16 weeks) with peginterferon and ribavirin is equally effective as a 24-week course, in case HCV genotype 2 and 3 patients achieve RVR at week 4. HCV patients genotype 2 and 3 without RVR should receive at least 24 weeks of treatment.
645 VIROLOGICAL RESPONSE AT 12 WEEKS OF ENTECAVIR THERAPY PREDICTS HBeAg CLEARANCE IN HBeAg-POSITIVE CHRONIC HEPATITIS B PATIENTS B.-C. Song1 , H.B. Chae2 , Y.N. Kim3 , B.S. Lee4 , Y.-K. Cho1 . 1 Internal Medicine, Jeju National University School of Medicine, Jeju, 2 Internal Medicine, Chungbuk National University, Cheongju, 3 Internal Medicine, Cheju Halla Hospital, Jeju, 4 Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea E-mail: [email protected] Background: It has been reported that virological response at 24 week of oral nucleos(t)ide analogues (NAs) predict HBeAg clearance and longterm antiviral response. Entecavir is one of the most potent antiviral agents, suggesting early virological response may predict HBeAg clearance during entecavir therapy. The aim of this study was to find out the predictive factors for HBeAg clearance using pretreatment variables and on-treatment virological response. Patients and Methods: Seventy-four consecutive HBeAg-positive chronic hepatitis B patients receiving entecarvir were retrospectively analyzed. HBV DNA levels were measured at 12-week intervals. Results: Sixteen (21.5%) of the 74 patients achieved HBeAg clearance within 48-week of entecavir therapy. Patients with low viremia (<2×106 IU/mL) had higher probability of HBeAg clearance compared to the patients with high viremia (>2×106 IU/mL) (40% vs. 14%; p = 0.04). Female patients showed higher tendency of HBeAg clearance compared with male patients (40% vs. 20%; p = 0.07). However, there was no difference of HBeAg clearance according to age and serum ALT levels. Probability of HBeAg clearance at 48-week was 61%, 18%, and 0% in patients with virological response (defined as HBV DNA <60 IU/mL) at 12-week, 24-week and in patients without virological response within 24-week, respectively (p < 0.0001). In multivariate analysis, pretreatment HBV DNA level and virologic response were independent predictive factors for HBeAg clearance at 48 week of entecavir therapy. Conclusions: This finding suggest that virological response at 12 week, and pretreatment HBV DNA level were major predictors for HBeAg clearance in patients receiving entecavir therapy.