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Hepatitis B virus-specific T-cell reactivity during adefovir dipivoxil (ADV) treatment: a multicentre, controlled study
Parallel Session 1: Hepatitis B Methods: Patients with compensated, HBeAg-positive CHB, HBV DNA > 6 log 10 copies/mL (Roche Amplicor PCR), confirmed YMDD-mutation, ALT > 1.2 x ULN were enrolled in this double-blind, 48-week study. The primary endpoint was time-weighted average change from baseline in serum HBV DNA through week-16 (DAVG16). Results: Fifty-nine patients were randomised to LAM 100 mg qd (n = 19), ADV 10 mg qd + LAM (n = 20) or ADV (n = 20); one patient withdrew (ADV group) pre-treatment. Baseline characteristics were similar between the treatment groups: 79% male; 60% Caucasian, 36% Asian; median age 45 years (40-53), ALT 2.0 x ULN (1-14.8) and Child-Pugh score 5 (56). Median HBV DNA (logl0 copies/mL) was 8.20, 7.94 and 8.42 in the LAM, LAM + ADV and ADV arms, respectively. At week-16, the median HBV DNA change (DAVG16 logl0 copies/mL) was -0.07 in the LAM arm, compared to -2.45 in the LAM + ADV and -2.46 in ADV arms (p < 0.0001, respectively). ALT normalised in 8 (42%) (p = 0.008) and 6 (32%) (p = 0.039) LAM + ADV and ADV recipients respectively, compared to 1 (6%) LAM recipient. No clinically significant changes in laboratory parameters were observed. One SAE (renal colic, ADV group) was considered unrelated to treatment. Conclusion: ADV I0 mg, alone or in combination with LAM, significantly reduced HBV DNA and ALT compared to LAM in patients with LAMresistant HBV.
adefovir dipivoxil (ADV) 10 mg once daily. Patients were randomized to receive LAM (n = 19), ADV (n = 20) or ADV + LAM (n = 20) in a 1:1:1 ratio. All patients were required to have YMDD mutations (rtM21MV or I) by sequencing at baseline. Objective: To evaluate the status of YMDD mutations in different treatment arms at week 16. Method: YMDD mutations were determined by sequencing at baseline and week 16. Results: At week 16, the median viral load reduction was 2.9 logl0 copies/mL in both the ADV and the ADV + LAM arms compared to a 0.1 logl0 reduction in the LAM arm. Of the 18 patients with sequencing data in the ADV ann, four patients (22%) completely lost their YMDD mutations and reverted to wild-type sequence by week 16. Of the 20 patients treated with ADV + LAM, HBV in one patient completely reverted to wild-type sequence and partially reverted in the other patient. HBV from all 19 patients who received LAM monotherapy maintained their YMDD mutations at week 16. Conclusion: Initiation of adefovir dipivoxil therapy in lamivudine-resistant HBV patients resulted in significant decrease in HBV DNA and reversion of YMDD mutants to wild-type HBV in up to 22% of patients after 16 weeks of therapy.
~'I -] THIRTY YEARS FOLLOW-UP OF CHRONIC ASYMPTOMATIC HBsAg CARRIERS: IMPORTANCE OF OCCULT INFECTIONS
7
HEPATITIS B VIRUS-SPECIFIC T-CELL REACTIVITY DURING ADEFOVlR DIPIVOXIL (ADV) TREATMENT: A MULTICENTRE, CONTROLLED STUDY
Mauro Manno 1, Antonella Grottola l, Ilva Ferretti l, Alessandra Colantoni l, Nicola De Maria 1, Francesco Giannini I, Chiara Vecchi2, Marisa De Palma 2, Federico Manenti l , Erica Villa 1. l University of Modena and
Helen Cooksley 1, S. Chokshi 1, H. Wedemeyer 2, P. Andreone 3, R. Gilson 4, T. Warnes 5, S. Paganin 6, E Zoulim 7, Anant Jain s , Craig James 8, Craig Gibbs s , John Fry 8, Carol Brosgart 8, N. Naoumov 1.
Reggo Emilia; 2Azienda Policlinico di Modena, Italy
1Institute of Hepatology, University College London, London; 4The Mortimer Market Centre, London; 5Manchester Royal Infirmary, Manchester, UK; 2Medical School Hannover, Hannover, Germany; 3University of Bologna, Bologna; 6University of Turin, Turin, Italy; 71NSERM, Lyon, France; SGilead Sciences, Foster City, California, USA
296 HBsAg+ former blood donors and their 157 HBsAg- controls (Lancet 1982; 2: 1243--4) were recalled to assess the impact of HBV infection on survival, morbidity and infectivity after 30 years. Methods: search through AVIS, General Registry Office, Hospital records. Biochemical and HBV/HCV markers were performed. Results: complete data are available on 441 (284 HBV; 157 controls): death occurred in 30 (10.1%) HBV (only 4 liver-related) and in 14 (8.9%) controls (1 liver-related) (X2:NS). 182/254 HBV+ and 81/143 controls were tested. Among HBV+, 59 (32.4%) became HBsAg- during follow-up: 31 developed antiHBs; 9/123 still HBsAg+ subjects developed anti-HBs. HBV DNA by PCR was positive in 77/182 (42.3%): it was also positive in 4/59 (11.1%) now HBsAg- and in 4/9 (44.4%) HBsAg+/anti-HBs+. ALTs were altered in 28/182 (15.3%) HBsAg+ and in 2/31 (6.4%) HBsAg- (p = 0.038, Fisher's exact test). ALTs related with GGT elevation (p = 0.002) and history of alcohol abuse (p < 0.0001). Clear-cut liver disease was present only in 4/130 (3.0%). AntiHCV was positive in 7/182 (3.8%) HBV+ and in 3/81 (3.7%) controls. Conclusions: 1. survival in HBsAg+ patients was not significantly different from control population; 2. Liver-related deaths were a minority; 3. ALTs alteration was mostly related with alcohol abuse; 4. Apparent clearance of HBV infection was a common event; however, only half of the subjects who had become HBsAg- developed antiHBs and 4/28 HBsAg- subjects were still viremic. This has important implications, e.g. for safety of blood transfusion; however, natural history of HBV infection in this population of former blood donors seems quite benign.
~ - ~ LOSS OF LAMIVUDINE RESISTANCE MUTATIONS AFTER PATIENTS SWITCHED TO ADEFOVlR DIPIVOXlL THERAPY Christopher Westland, Craig Gibbs, Michael Miller, Mark Sullivan, John Fry, Carol Brosgart, Michael Wulfsohn, Shelly Xiong. Gilead
Sciences, Foster City, CA, USA Introduction: 59 chronic hepatitis B patients who developed lamivudine (LAM)-resistant HBV were enrolled in a Phase III trial (GS-00-461) of
Objective: Prospective evaluation of HBV-specific T-cell responses during ADV therapy and correlation of these with treatment outcome. Methods: 22 HBeAg(+) patients from 6 European centres, randomized to placebo or ADV for 48 weeks. PBMC were obtained serially. HBV-specific T-cell reactivity was analyzed by: i) T-cell proliferation assay; ii) Elispot assays for CD4 T-cells producing IFN-gamma or IL-10, and CD8 T-cells producing IFN-gamma, iii) in vitro cytokine production. HBV DNA was quantitated by Roche PCR. Results: In ADV treated patients (n = 16), HBV DNA levels decreased by mean 3.9 logl0 copies/ml; 7/16 (44%) lost HBeAg at week 48. No changes in HBV DNA or HBeAg occurred in the placebo group (n = 6). During study, significant T-cell proliferation to HBcAg was more frequently detected in ADV treated patients (27%) compared with placebo (10%, p < 0.05). Based on virological response at week 48, 3 groups were identified: Good Responders, GR (n = 7): HBeAg ( - ) patients; mean HBV DNA decrease -5.1 logl0 copies/mL; Moderate Responders, MR (n = 7): HBeAg(+) patients; mean HBV DNA decrease - 3 . 4 logl0 copies/mL; Non-Responders, NR (n = 8): HBeAg(+) patients; minimal HBV DNA change ( - 0 . 9 logl0 copies/mL). All placebo patients were amongst NR. During study, T-cell proliferation was greater in GR vs. NR (p < 0.01), but no different between MR vs. NR (p > 0.05). The ratio of IFN-gamma/IL10 producing CD4+ T-cells increased 7.5-fold as compared to baseline in GR, while both MR and NR showed only 2-fold increase. Conclusions: ADV enhances T-cell reactivity to HBV, favouring Thl pattern, in a proportion of treated patients. These changes are dependent on the magnitude of HBV DNA suppression.
adefovir dipivoxil (ADV) 10 mg once daily. Patients were randomized to receive LAM (n = 19), ADV (n = 20) or ADV + LAM (n = 20) in a 1:1:1 ratio. All patients were required to have YMDD mutations (rtM21MV or I) by sequencing at baseline. Objective: To evaluate the status of YMDD mutations in different treatment arms at week 16. Method: YMDD mutations were determined by sequencing at baseline and week 16. Results: At week 16, the median viral load reduction was 2.9 logl0 copies/mL in both the ADV and the ADV + LAM arms compared to a 0.1 logl0 reduction in the LAM arm. Of the 18 patients with sequencing data in the ADV ann, four patients (22%) completely lost their YMDD mutations and reverted to wild-type sequence by week 16. Of the 20 patients treated with ADV + LAM, HBV in one patient completely reverted to wild-type sequence and partially reverted in the other patient. HBV from all 19 patients who received LAM monotherapy maintained their YMDD mutations at week 16. Conclusion: Initiation of adefovir dipivoxil therapy in lamivudine-resistant HBV patients resulted in significant decrease in HBV DNA and reversion of YMDD mutants to wild-type HBV in up to 22% of patients after 16 weeks of therapy.
~'I -] THIRTY YEARS FOLLOW-UP OF CHRONIC ASYMPTOMATIC HBsAg CARRIERS: IMPORTANCE OF OCCULT INFECTIONS
7
HEPATITIS B VIRUS-SPECIFIC T-CELL REACTIVITY DURING ADEFOVlR DIPIVOXIL (ADV) TREATMENT: A MULTICENTRE, CONTROLLED STUDY
Mauro Manno 1, Antonella Grottola l, Ilva Ferretti l, Alessandra Colantoni l, Nicola De Maria 1, Francesco Giannini I, Chiara Vecchi2, Marisa De Palma 2, Federico Manenti l , Erica Villa 1. l University of Modena and
Helen Cooksley 1, S. Chokshi 1, H. Wedemeyer 2, P. Andreone 3, R. Gilson 4, T. Warnes 5, S. Paganin 6, E Zoulim 7, Anant Jain s , Craig James 8, Craig Gibbs s , John Fry 8, Carol Brosgart 8, N. Naoumov 1.
Reggo Emilia; 2Azienda Policlinico di Modena, Italy
1Institute of Hepatology, University College London, London; 4The Mortimer Market Centre, London; 5Manchester Royal Infirmary, Manchester, UK; 2Medical School Hannover, Hannover, Germany; 3University of Bologna, Bologna; 6University of Turin, Turin, Italy; 71NSERM, Lyon, France; SGilead Sciences, Foster City, California, USA
296 HBsAg+ former blood donors and their 157 HBsAg- controls (Lancet 1982; 2: 1243--4) were recalled to assess the impact of HBV infection on survival, morbidity and infectivity after 30 years. Methods: search through AVIS, General Registry Office, Hospital records. Biochemical and HBV/HCV markers were performed. Results: complete data are available on 441 (284 HBV; 157 controls): death occurred in 30 (10.1%) HBV (only 4 liver-related) and in 14 (8.9%) controls (1 liver-related) (X2:NS). 182/254 HBV+ and 81/143 controls were tested. Among HBV+, 59 (32.4%) became HBsAg- during follow-up: 31 developed antiHBs; 9/123 still HBsAg+ subjects developed anti-HBs. HBV DNA by PCR was positive in 77/182 (42.3%): it was also positive in 4/59 (11.1%) now HBsAg- and in 4/9 (44.4%) HBsAg+/anti-HBs+. ALTs were altered in 28/182 (15.3%) HBsAg+ and in 2/31 (6.4%) HBsAg- (p = 0.038, Fisher's exact test). ALTs related with GGT elevation (p = 0.002) and history of alcohol abuse (p < 0.0001). Clear-cut liver disease was present only in 4/130 (3.0%). AntiHCV was positive in 7/182 (3.8%) HBV+ and in 3/81 (3.7%) controls. Conclusions: 1. survival in HBsAg+ patients was not significantly different from control population; 2. Liver-related deaths were a minority; 3. ALTs alteration was mostly related with alcohol abuse; 4. Apparent clearance of HBV infection was a common event; however, only half of the subjects who had become HBsAg- developed antiHBs and 4/28 HBsAg- subjects were still viremic. This has important implications, e.g. for safety of blood transfusion; however, natural history of HBV infection in this population of former blood donors seems quite benign.
~ - ~ LOSS OF LAMIVUDINE RESISTANCE MUTATIONS AFTER PATIENTS SWITCHED TO ADEFOVlR DIPIVOXlL THERAPY Christopher Westland, Craig Gibbs, Michael Miller, Mark Sullivan, John Fry, Carol Brosgart, Michael Wulfsohn, Shelly Xiong. Gilead
Sciences, Foster City, CA, USA Introduction: 59 chronic hepatitis B patients who developed lamivudine (LAM)-resistant HBV were enrolled in a Phase III trial (GS-00-461) of
Objective: Prospective evaluation of HBV-specific T-cell responses during ADV therapy and correlation of these with treatment outcome. Methods: 22 HBeAg(+) patients from 6 European centres, randomized to placebo or ADV for 48 weeks. PBMC were obtained serially. HBV-specific T-cell reactivity was analyzed by: i) T-cell proliferation assay; ii) Elispot assays for CD4 T-cells producing IFN-gamma or IL-10, and CD8 T-cells producing IFN-gamma, iii) in vitro cytokine production. HBV DNA was quantitated by Roche PCR. Results: In ADV treated patients (n = 16), HBV DNA levels decreased by mean 3.9 logl0 copies/ml; 7/16 (44%) lost HBeAg at week 48. No changes in HBV DNA or HBeAg occurred in the placebo group (n = 6). During study, significant T-cell proliferation to HBcAg was more frequently detected in ADV treated patients (27%) compared with placebo (10%, p < 0.05). Based on virological response at week 48, 3 groups were identified: Good Responders, GR (n = 7): HBeAg ( - ) patients; mean HBV DNA decrease -5.1 logl0 copies/mL; Moderate Responders, MR (n = 7): HBeAg(+) patients; mean HBV DNA decrease - 3 . 4 logl0 copies/mL; Non-Responders, NR (n = 8): HBeAg(+) patients; minimal HBV DNA change ( - 0 . 9 logl0 copies/mL). All placebo patients were amongst NR. During study, T-cell proliferation was greater in GR vs. NR (p < 0.01), but no different between MR vs. NR (p > 0.05). The ratio of IFN-gamma/IL10 producing CD4+ T-cells increased 7.5-fold as compared to baseline in GR, while both MR and NR showed only 2-fold increase. Conclusions: ADV enhances T-cell reactivity to HBV, favouring Thl pattern, in a proportion of treated patients. These changes are dependent on the magnitude of HBV DNA suppression.