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A phase II study of entecavir vs lamivudine in adults with chronic hepatitis B
24
I
1253
Suna’ay, April 22,200l
SAFETY AND EFFICACY OF ADEFOVIR DIPIVOXIL FOR LAMIVUDINE RESISTANT HBV IN HIV INFECTED PATIENTS
Y. Benhamou, M. Bochet, V. Thibault, C. Brosgart, P. Vig, C. Gibb, J. Fry, P Opolon, C. Katlama, T. Poynard. Hepatology Department, Groupe Hospitalier Pitie-Salpetriere, France
Background: Lamivudine resistance (LAM-R) to HBV occurs in 1532% of HBV and HIV/HBV co-infected patients after one year. Adefovir dipivoxil (ADV) has potent in vivo and in vitro activity against wild-type and LAM-R. Objective: To evaluate the safety and efficacy of ADV for the treatment of LAM-R HIV/HBV co-infected patients in an open label trial. Methods: Thirty five patients receiving LAM (150 mg bid) as a part of their anti-HIV therapy were enrolled in a 48 week study. Patients had controlled HIV RNA viral load (< 2.6 log10 copies/ml) and detectable serum HBV DNA (Roche PCR) at screening, despite LAM therapy (median time on LAM = 23 f 10 months). Mean (&SE) baseline HBV DNA was 8.64 f 0.08 log10 copies/mL. Genotypic analysis confirmed M552V or M5521 mutations of the HBV DNA polymerase gene in all patients. ADV 10 mg daily was added to the existing anti-HIV therapy. Results: Thirty-four males and 1 female, mean age of 41.2 f 1.6 years were enrolled. Two patients discontinued for reasons unrelated to ADV. Median time on ADV was 32 (24-36) weeks. Mean HBV DNA change from baseline (8.64 f 0.08 log10 copies/ml) = -2.90 f 0.12 log10 copies/ml at week 12, -3.40 f 0.12 log10 copies/ml at week 24, and -4.0 f 0.2 log10 copies/ml at week 36 (p
I
1309
GENOTYPIC ANALYSIS OF HBV ISOLATED FROM PATIENTS EXPOSED TO ADEFOVIR DIPIVOXIL (ADV) FOR 46 TO 60 WEEKS
I
1588
A PHASE II STUDY OF ENTECAVIR VS LAMIVUDINE IN ADULTS WITH CHRONIC HEPATITIS B
C. Lai, M. Rosmawati, J. Lao, H. Van Vlierberghe, F. Anderson, N. Thomas, D. De Hertogh. Department of Medicine, Queen Mary Hospital, University Hospital, Malaysia; Cebu Doctors Hospital, Philippines; University Hospital, Belgium; Vancouver Hospital, Canada; Bristol-Myers Squibb, USA
Background: Entecavir (ETV) is a guanosine nucleoside analogue which has demonstrated potent activity against hepatitis B virus (HBV) in vitro (EDsc=4nM), in animal models and in a previous 4-week dosing trial in adults with chronic hepatitis B. Methods: The safety and antiviral activity of 3 doses of ETV (0.01, 0.1 and 0.5 mg QD) given for 24 weeks compared to lamivudine (LVD) 100 mg QD were studied in a double-blind, randomized trial in 180 subjects (45/arm). HBeAg-positive and -negative subjects with HBV DNA levels 240 MEq/mL by the Quantiplex” bDNA assay who had not received r 12 weeks of prior anti-HBV therapy with nucleosides were eligible. The primary endpoint was mean log10 HBV DNA measured by the Roche Amplicoi” PCR assay at Week 22. Results: 177 subjects started study drug and 169 were evaluable for efficacy. The majority were male (74%). Asian (57%), HBeAg-positive (81%), with mean ALT of 109 ID/L and mean logta HBV DNA of 2.8 MEq/mL. 22% of subjects had received prior interferon therapy. All 3 doses of ETV were active, but the 0.01 mg dose was less effective than the 0.1 and 0.5 mg doses. ETV 0.1 and 0.5 mg doses were both superior to LVD with mean logto reductions in HBV DNA by PCR of 4.3, 4.7 and 3.4, respectively (p=O.OOOl)at Week 22. Only 6 subjects (4 ETV, 2 LVD) lost HBeAg. There was a suggestion of greater normalization of serum ALT for the 2 higher doses of ETV (83% and 66%) than for LVD (59%), but these differences were not statistically significant. ETV was generally well tolerated. Mild-to-moderate adverse events attributable to the nervous system were more frequent in the ETV 0.5 mg group than for LVD; however, only 1 ETV subject in the 0.1 mg group discontinued after 18 weeks of dosing due to lethargy andphotosensitivity. Conclusion: Entecavir at doses of 0.1 and 0.5 mg once daily has superior antiviral activity to lamivudine and is well tolerated.
X. Xiong, H. Yang, C. Westland, V. Ho, J. Fry, C. Brosgart, C. Gibbs, M. Miller. Gilead Sciences, USA
Background: Patients treated with 5-60 mg of ADV (n=29) or placebo (n=lO) daily for 12 weeks were enrolled in an open-label safety and efficacy study. At week 48 in the open-label study the patients had received a total ADV exposure of 48-60 weeks. Aim: To monitor the emergence of mutations potentially associated with resistance to ADV in this cohort of patients. Methods: Serum samples were available for 28 patients at baseline and at week 48 of the open-label study. Nested PCR was used to amplify a 1 kb fragment of the HBV polymerase (pol)/RT domain. 23 of these patients were PCR positive at baseline and week 48. We sequenced and compared the pol/RT domain (a.a. 354-693) at these time points for all 23 patients. Results: Genotypic analysis data revealed 56 mutations in the HBV pol/RT gene in 12 patients at week 48.39 mutations were silent mutations in HBV pol. Previously described polymorphisms accounted for 13 mutations and were not considered to be associated with ADV resistance. lwo mutations caused amino acid changes at polymorphic sites, T402 and Y474, but the specific substitutions observed have not been described previously. Two patients developed substitutions at conserved residues in HBV pol: E566 and Y593. However, all four patients with the T402, Y474, E566 or Y593 mutations had sustained viral load suppression at week 48 (< 400 copies/ml of HBV DNA), suggesting that these mutations were not associated with ADV resistance. Conclusion: No HBV polymerase mutations associated with ADV resistance have been identified in patients treated with ADV for 48 to 60 weeks.
S30
I658
General Session 5 - Viral hepatitis: basic aspects
IMPAIRED EFFECTOR FUNCTION OF HCV-SPECIFIC CD& T CELLS IN CHRONIC HEPATlTlS C VIRUS INFECTION
H. Wedemeyer r, X-S. He 3, M. Nascimbeni ‘, A.R. Davis I, H.B. Greenberg 3, H. Alter 2, B. Rehermann ‘. * Liver Diseases Section, NIDDK, National Institutes of Health; 2 Dep. of Transfusion Medicine, National Institutes of Health, Bethesda, MD, 3 Stanford University School of Medicine, Stanford, CA, USA
While the HCV specific T cell response has been reported to be less vigorous in chronically infected than in recovered patients, the immunological basis for this observation is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, and investigated the effector function of HCV-specific CD8+ T cells in 20 chronically infected and 12 long-term recovered patients. HCV-specific, tetramer-positive T cells were more frequently found in PBMC of chronically infected than recovered patients, but displayed an impaired proliferative capacity when stimulated in vitro with the specific HCV peptide. In contrast, tetramer-positive cells of recovered
I
1253
Suna’ay, April 22,200l
SAFETY AND EFFICACY OF ADEFOVIR DIPIVOXIL FOR LAMIVUDINE RESISTANT HBV IN HIV INFECTED PATIENTS
Y. Benhamou, M. Bochet, V. Thibault, C. Brosgart, P. Vig, C. Gibb, J. Fry, P Opolon, C. Katlama, T. Poynard. Hepatology Department, Groupe Hospitalier Pitie-Salpetriere, France
Background: Lamivudine resistance (LAM-R) to HBV occurs in 1532% of HBV and HIV/HBV co-infected patients after one year. Adefovir dipivoxil (ADV) has potent in vivo and in vitro activity against wild-type and LAM-R. Objective: To evaluate the safety and efficacy of ADV for the treatment of LAM-R HIV/HBV co-infected patients in an open label trial. Methods: Thirty five patients receiving LAM (150 mg bid) as a part of their anti-HIV therapy were enrolled in a 48 week study. Patients had controlled HIV RNA viral load (< 2.6 log10 copies/ml) and detectable serum HBV DNA (Roche PCR) at screening, despite LAM therapy (median time on LAM = 23 f 10 months). Mean (&SE) baseline HBV DNA was 8.64 f 0.08 log10 copies/mL. Genotypic analysis confirmed M552V or M5521 mutations of the HBV DNA polymerase gene in all patients. ADV 10 mg daily was added to the existing anti-HIV therapy. Results: Thirty-four males and 1 female, mean age of 41.2 f 1.6 years were enrolled. Two patients discontinued for reasons unrelated to ADV. Median time on ADV was 32 (24-36) weeks. Mean HBV DNA change from baseline (8.64 f 0.08 log10 copies/ml) = -2.90 f 0.12 log10 copies/ml at week 12, -3.40 f 0.12 log10 copies/ml at week 24, and -4.0 f 0.2 log10 copies/ml at week 36 (p
I
1309
GENOTYPIC ANALYSIS OF HBV ISOLATED FROM PATIENTS EXPOSED TO ADEFOVIR DIPIVOXIL (ADV) FOR 46 TO 60 WEEKS
I
1588
A PHASE II STUDY OF ENTECAVIR VS LAMIVUDINE IN ADULTS WITH CHRONIC HEPATITIS B
C. Lai, M. Rosmawati, J. Lao, H. Van Vlierberghe, F. Anderson, N. Thomas, D. De Hertogh. Department of Medicine, Queen Mary Hospital, University Hospital, Malaysia; Cebu Doctors Hospital, Philippines; University Hospital, Belgium; Vancouver Hospital, Canada; Bristol-Myers Squibb, USA
Background: Entecavir (ETV) is a guanosine nucleoside analogue which has demonstrated potent activity against hepatitis B virus (HBV) in vitro (EDsc=4nM), in animal models and in a previous 4-week dosing trial in adults with chronic hepatitis B. Methods: The safety and antiviral activity of 3 doses of ETV (0.01, 0.1 and 0.5 mg QD) given for 24 weeks compared to lamivudine (LVD) 100 mg QD were studied in a double-blind, randomized trial in 180 subjects (45/arm). HBeAg-positive and -negative subjects with HBV DNA levels 240 MEq/mL by the Quantiplex” bDNA assay who had not received r 12 weeks of prior anti-HBV therapy with nucleosides were eligible. The primary endpoint was mean log10 HBV DNA measured by the Roche Amplicoi” PCR assay at Week 22. Results: 177 subjects started study drug and 169 were evaluable for efficacy. The majority were male (74%). Asian (57%), HBeAg-positive (81%), with mean ALT of 109 ID/L and mean logta HBV DNA of 2.8 MEq/mL. 22% of subjects had received prior interferon therapy. All 3 doses of ETV were active, but the 0.01 mg dose was less effective than the 0.1 and 0.5 mg doses. ETV 0.1 and 0.5 mg doses were both superior to LVD with mean logto reductions in HBV DNA by PCR of 4.3, 4.7 and 3.4, respectively (p=O.OOOl)at Week 22. Only 6 subjects (4 ETV, 2 LVD) lost HBeAg. There was a suggestion of greater normalization of serum ALT for the 2 higher doses of ETV (83% and 66%) than for LVD (59%), but these differences were not statistically significant. ETV was generally well tolerated. Mild-to-moderate adverse events attributable to the nervous system were more frequent in the ETV 0.5 mg group than for LVD; however, only 1 ETV subject in the 0.1 mg group discontinued after 18 weeks of dosing due to lethargy andphotosensitivity. Conclusion: Entecavir at doses of 0.1 and 0.5 mg once daily has superior antiviral activity to lamivudine and is well tolerated.
X. Xiong, H. Yang, C. Westland, V. Ho, J. Fry, C. Brosgart, C. Gibbs, M. Miller. Gilead Sciences, USA
Background: Patients treated with 5-60 mg of ADV (n=29) or placebo (n=lO) daily for 12 weeks were enrolled in an open-label safety and efficacy study. At week 48 in the open-label study the patients had received a total ADV exposure of 48-60 weeks. Aim: To monitor the emergence of mutations potentially associated with resistance to ADV in this cohort of patients. Methods: Serum samples were available for 28 patients at baseline and at week 48 of the open-label study. Nested PCR was used to amplify a 1 kb fragment of the HBV polymerase (pol)/RT domain. 23 of these patients were PCR positive at baseline and week 48. We sequenced and compared the pol/RT domain (a.a. 354-693) at these time points for all 23 patients. Results: Genotypic analysis data revealed 56 mutations in the HBV pol/RT gene in 12 patients at week 48.39 mutations were silent mutations in HBV pol. Previously described polymorphisms accounted for 13 mutations and were not considered to be associated with ADV resistance. lwo mutations caused amino acid changes at polymorphic sites, T402 and Y474, but the specific substitutions observed have not been described previously. Two patients developed substitutions at conserved residues in HBV pol: E566 and Y593. However, all four patients with the T402, Y474, E566 or Y593 mutations had sustained viral load suppression at week 48 (< 400 copies/ml of HBV DNA), suggesting that these mutations were not associated with ADV resistance. Conclusion: No HBV polymerase mutations associated with ADV resistance have been identified in patients treated with ADV for 48 to 60 weeks.
S30
I658
General Session 5 - Viral hepatitis: basic aspects
IMPAIRED EFFECTOR FUNCTION OF HCV-SPECIFIC CD& T CELLS IN CHRONIC HEPATlTlS C VIRUS INFECTION
H. Wedemeyer r, X-S. He 3, M. Nascimbeni ‘, A.R. Davis I, H.B. Greenberg 3, H. Alter 2, B. Rehermann ‘. * Liver Diseases Section, NIDDK, National Institutes of Health; 2 Dep. of Transfusion Medicine, National Institutes of Health, Bethesda, MD, 3 Stanford University School of Medicine, Stanford, CA, USA
While the HCV specific T cell response has been reported to be less vigorous in chronically infected than in recovered patients, the immunological basis for this observation is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, and investigated the effector function of HCV-specific CD8+ T cells in 20 chronically infected and 12 long-term recovered patients. HCV-specific, tetramer-positive T cells were more frequently found in PBMC of chronically infected than recovered patients, but displayed an impaired proliferative capacity when stimulated in vitro with the specific HCV peptide. In contrast, tetramer-positive cells of recovered