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Sequential treatment with lamivudine and interferon in patients with chronic hepatitis B non responder to interferon alone
Viral hepatitis: clinical aspects
[
P/C06/25
]
SEQUENTIAL TREATMENT WITH LAMIVUDINE AND INTERFERON IN PATIENTS WITH CHRONIC HEPATITIS B NON RESPONDER TO INTERFERON ALONE D. Thabut, L. Seffaty, T. Andrtani, H. Fontaine, O. Chazouilltres, S. Pol, R. Poupon Liver Units, St-Antoine and Necker hospital, Paris, France. High viral load is associated with poor response to interferon (IFN) in patients with chronic hepatitis B virus (HBV) infection. Lamivudine induces early negativation of HBV-DNA in almost all patients. However, relapse is frequent after the discontinuation of treatment. Aim of this study was to assess wether pretreatment with lamivudine was able to improve response to IFN in previously non responders with high viral load. Methods : 14 male patients, median age 40 yrs, non responder to IFN (absence of prolonged HBV DNA negativation) with HBV DNA > 100pg/ml (bDNA Chiron), were treated with lamivudine 100mg/d for 6 months then with IFN 5MUx3/wk for 6 months. Characteristics of patients are shown below. Median Knodell score was 9.5 and cirrhosis was present in 5/14. HCV, HDV and HIV serologies were negative in all. Patients were already given 786 MU of IFN. 10 control patients were treated with lamivudine 100mg/d during 12 months. Results : All patients have completed sequential treatment and 11/14 have a 6 months follow-up post-treatment. At 1 month of treatment, 12114 patients had negative HBV DNA and none had breakthrough during lamivudine. During IFN therapy, 3 patients had ALT increase>5N (1 stopped treatment because ALT>35N), associated with reappearance of I-IBVDNAin 2 of them. Before treatment End of treatment 6 mo after treatment ALT N 0/14 (134 IU/1) 6114 5111 HBV DNA- 0112 (3350 pg/ml) 8/14 6111 HBeAg2/14 5/14 5/11 I-IBsA~0/14 2/14 2/11 215 patients had histological improvement on control liver biopsy. In control group, 8/10 patients relapsed after discontinuation of lamivudine. (~onelusion : These preliminary results suggest that sequential treatment with lamivudine and ~ is able to induce prolonged response in patients with chronic hepatitis B not responding to IFN alone.
I P/coer26 I HISTOLOGICAL AND VIROLOGICAL EVOLUTION OF LONG TERM RESPONSE AFFER RIBAVIRIN AND INTERFERON-a COMBINATION H. Fontaine, B. Nalpas, J.-L. Lag~eau, H. Zylberberg, C. Brtchot, S. Pol, a French multicentric study group Unit6 d'Htpatologie and INSERM U-370, Htpital Necker, Paris, France. Aim: Despite the recognized efficacy of Ribavirin-Interferon-tx (IFN) in HCV infection treatment, there is no long scale-based report on its long term efficacy.We have therefore analysed a serie of 44 patients with a long-term follow-up (mean=20.7 months after treatment) for persistent HCV negativation. Methods: Forty-four patients (34 naive, 7 relapsers and 3 non responders after a first treatment with IFN monotherapy ) who were sustained complete responders (normal ALAT and HCV RNA negative 6 months after discontinuation of the combination therapy) were followed by PCR serially each 6 months. They were all treated with a 12-month course of IFN; rihavirin was given during 4 months in 6 (14%), 6 months in 10 (23%) and 12 months in 28 (63%) of patients. They were 18 men and 26 women with a mean age of 48 years, a mean duration of infection, evaluable in 27, of 15 years. HCV genotypes were lb (n=32), 3a (n=6), 2 (n=3), 4/5 (n=l), 5 (n=l) and undetermined (n=l). Mean pre-treatment Knodell score was 8.8 :i: 3.0. Results : Respectively 44, 24, 14 and 9 patients were followed 12, 18, 24 and at least 30 months after discontinuation of therapy. Only one (2.3%) patient out of the 44 relapsed between 6 and 12 months alter discontinuation. Mean post-treatment Knodell score was 4.7 + 1 (p<0.001) and significant improvement (A pre- vs. post-Tt score >- 2) was identified in 86.7 % of patients after the end of therapy and 27.6% had a normal liver (Knodell score _<2). Condnsion: Our study demonstates 1. the long term efficacy of ribavirin/IFN, 2. the very low risk of relapse when HCV multiplication is stopped 6 months after the end of therapy and 3. the significant improvement in liver biopsy in such long term response.
I P/C0~Z7 [ RET ATMENT OF IrN NONRESPO OE OR REL SERS (REL) WITH CHRONIC HEPATITIS C WITH HIGH DOSE INTERFERON (IFN) IN COMBINATION WITH RIBAVlRIN P.J. Steindl-Munda, D.C. Kopty, P. Ferenci, W. Vogel, Ch. Datz, H. Brunner, R. Stauber, for the Austrian Hepatitis Study Group Vienna, Innsbruck, Saltzburg, Graz, Austria.
To investigate the impact of induction therapy (Tx) in combination with ribavirin in REL and N-R, the virologic response to various initial IFN-doses in combination with ribavirin was studied. Study protocol: 155 pts. with chronic hepatitis C (74 REL and 81 NR; 70% subtype 1; mean age: 45 a; male: 110, female 45) were randomized to receive ribavirin (1 to 1.2 g/d) in combination with IFN-o2b (IntronA®, SPI; first 14 weeks: group A: 10 MU/d for 2 weeks, then 10 MU/2d; B: 5 MU/d; C: 5 MU/2d; thereafter all received 5 MU/2d for 24 wks). Response to "Ix was defined by neg. serum HCV-RNA (<1000 copies/ml) at end of Tx (ETR) and 6 months thereatter (SR). Results: in % HCV neg Group N REL ETR REL SR NR ETR NR SR A 50 79% 67% 38% 25% B 52 56% 45% 40% 40% C 53 76% 53% 52% 20% At the time of writing this abstract 127 pts, completed Tx and 6 months follow up was available in 94. Conclusion: Both, NR and REL benefit from retreatment with IFN/ribavirin combination therapy. A high initial IFN dose does not increase response to Tx.
P/CO6/28
]
THYROID PEROXIDASE IS A MOLECULAR MIMICRY TARGET OF ANTI-HEPATITIS C VIRUS HUMORAL RESPONSE DP. Bogdanos l, M. Lenzi 2, M. Okamoto l, Y. Ma l, P. Aluigi 2, E Lari 2, L. Muratori 2, R. Williams l, EB. Bianchi 2, D. Vergani 1 1Institute of Hepatology, Royal Free & University College London Medical School, UK. 2Department of Internal Medicine, University of Bologna, Italy.
BACKGROUND: Thyroid Peroxidase (TPO) autoantibodies have been frequenUy reported in chronic HCV infection, especially during IFN..o treatment. Using biotinylated paptldes (Chiron Technologies, Australia) we have recently demonstrated humoral double reactivity against HCV and TPO epitopes sharing 80-100% aminoacid similarity, in anti-TPO positive-HCV infected patients (Hepatology 1999;(30)4:Suppl 2, p.363A). AI__.M.MTo : investigate if the observed double reactivity is cross-reective. METHODS: Compatltion ELISAs were performed using both viral and TPO peptides prepared at concentrations of 1000, 500, 250, 125 and 62.5 p.glml and recombinant TPO protein (Phan'nacia & Upjohn, UK). Two 'scrambled' paptldes and the Pyruvate Kinase protein (Sigma, Dorset, UK) were used as controls. RESULTS: Antibody binding to individual HCV sequences was inhibited not only by preinoubation with the HCV paptides (48-92%) but also by the TPO homologues (47-84%) and by the recombinant TPO protein (51-89%), but not by the control peptides or the control protein...C..ONCLUSION Anti-HCV response, probably through a molecular mimicry mechanism, targets Thyroid Peroxidase, the major antigen of thyroid autoimmunity, providing an explanation for the frequent association between the viral infection and the autoimmune endocrine pathology.
103
[
P/C06/25
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SEQUENTIAL TREATMENT WITH LAMIVUDINE AND INTERFERON IN PATIENTS WITH CHRONIC HEPATITIS B NON RESPONDER TO INTERFERON ALONE D. Thabut, L. Seffaty, T. Andrtani, H. Fontaine, O. Chazouilltres, S. Pol, R. Poupon Liver Units, St-Antoine and Necker hospital, Paris, France. High viral load is associated with poor response to interferon (IFN) in patients with chronic hepatitis B virus (HBV) infection. Lamivudine induces early negativation of HBV-DNA in almost all patients. However, relapse is frequent after the discontinuation of treatment. Aim of this study was to assess wether pretreatment with lamivudine was able to improve response to IFN in previously non responders with high viral load. Methods : 14 male patients, median age 40 yrs, non responder to IFN (absence of prolonged HBV DNA negativation) with HBV DNA > 100pg/ml (bDNA Chiron), were treated with lamivudine 100mg/d for 6 months then with IFN 5MUx3/wk for 6 months. Characteristics of patients are shown below. Median Knodell score was 9.5 and cirrhosis was present in 5/14. HCV, HDV and HIV serologies were negative in all. Patients were already given 786 MU of IFN. 10 control patients were treated with lamivudine 100mg/d during 12 months. Results : All patients have completed sequential treatment and 11/14 have a 6 months follow-up post-treatment. At 1 month of treatment, 12114 patients had negative HBV DNA and none had breakthrough during lamivudine. During IFN therapy, 3 patients had ALT increase>5N (1 stopped treatment because ALT>35N), associated with reappearance of I-IBVDNAin 2 of them. Before treatment End of treatment 6 mo after treatment ALT N 0/14 (134 IU/1) 6114 5111 HBV DNA- 0112 (3350 pg/ml) 8/14 6111 HBeAg2/14 5/14 5/11 I-IBsA~0/14 2/14 2/11 215 patients had histological improvement on control liver biopsy. In control group, 8/10 patients relapsed after discontinuation of lamivudine. (~onelusion : These preliminary results suggest that sequential treatment with lamivudine and ~ is able to induce prolonged response in patients with chronic hepatitis B not responding to IFN alone.
I P/coer26 I HISTOLOGICAL AND VIROLOGICAL EVOLUTION OF LONG TERM RESPONSE AFFER RIBAVIRIN AND INTERFERON-a COMBINATION H. Fontaine, B. Nalpas, J.-L. Lag~eau, H. Zylberberg, C. Brtchot, S. Pol, a French multicentric study group Unit6 d'Htpatologie and INSERM U-370, Htpital Necker, Paris, France. Aim: Despite the recognized efficacy of Ribavirin-Interferon-tx (IFN) in HCV infection treatment, there is no long scale-based report on its long term efficacy.We have therefore analysed a serie of 44 patients with a long-term follow-up (mean=20.7 months after treatment) for persistent HCV negativation. Methods: Forty-four patients (34 naive, 7 relapsers and 3 non responders after a first treatment with IFN monotherapy ) who were sustained complete responders (normal ALAT and HCV RNA negative 6 months after discontinuation of the combination therapy) were followed by PCR serially each 6 months. They were all treated with a 12-month course of IFN; rihavirin was given during 4 months in 6 (14%), 6 months in 10 (23%) and 12 months in 28 (63%) of patients. They were 18 men and 26 women with a mean age of 48 years, a mean duration of infection, evaluable in 27, of 15 years. HCV genotypes were lb (n=32), 3a (n=6), 2 (n=3), 4/5 (n=l), 5 (n=l) and undetermined (n=l). Mean pre-treatment Knodell score was 8.8 :i: 3.0. Results : Respectively 44, 24, 14 and 9 patients were followed 12, 18, 24 and at least 30 months after discontinuation of therapy. Only one (2.3%) patient out of the 44 relapsed between 6 and 12 months alter discontinuation. Mean post-treatment Knodell score was 4.7 + 1 (p<0.001) and significant improvement (A pre- vs. post-Tt score >- 2) was identified in 86.7 % of patients after the end of therapy and 27.6% had a normal liver (Knodell score _<2). Condnsion: Our study demonstates 1. the long term efficacy of ribavirin/IFN, 2. the very low risk of relapse when HCV multiplication is stopped 6 months after the end of therapy and 3. the significant improvement in liver biopsy in such long term response.
I P/C0~Z7 [ RET ATMENT OF IrN NONRESPO OE OR REL SERS (REL) WITH CHRONIC HEPATITIS C WITH HIGH DOSE INTERFERON (IFN) IN COMBINATION WITH RIBAVlRIN P.J. Steindl-Munda, D.C. Kopty, P. Ferenci, W. Vogel, Ch. Datz, H. Brunner, R. Stauber, for the Austrian Hepatitis Study Group Vienna, Innsbruck, Saltzburg, Graz, Austria.
To investigate the impact of induction therapy (Tx) in combination with ribavirin in REL and N-R, the virologic response to various initial IFN-doses in combination with ribavirin was studied. Study protocol: 155 pts. with chronic hepatitis C (74 REL and 81 NR; 70% subtype 1; mean age: 45 a; male: 110, female 45) were randomized to receive ribavirin (1 to 1.2 g/d) in combination with IFN-o2b (IntronA®, SPI; first 14 weeks: group A: 10 MU/d for 2 weeks, then 10 MU/2d; B: 5 MU/d; C: 5 MU/2d; thereafter all received 5 MU/2d for 24 wks). Response to "Ix was defined by neg. serum HCV-RNA (<1000 copies/ml) at end of Tx (ETR) and 6 months thereatter (SR). Results: in % HCV neg Group N REL ETR REL SR NR ETR NR SR A 50 79% 67% 38% 25% B 52 56% 45% 40% 40% C 53 76% 53% 52% 20% At the time of writing this abstract 127 pts, completed Tx and 6 months follow up was available in 94. Conclusion: Both, NR and REL benefit from retreatment with IFN/ribavirin combination therapy. A high initial IFN dose does not increase response to Tx.
P/CO6/28
]
THYROID PEROXIDASE IS A MOLECULAR MIMICRY TARGET OF ANTI-HEPATITIS C VIRUS HUMORAL RESPONSE DP. Bogdanos l, M. Lenzi 2, M. Okamoto l, Y. Ma l, P. Aluigi 2, E Lari 2, L. Muratori 2, R. Williams l, EB. Bianchi 2, D. Vergani 1 1Institute of Hepatology, Royal Free & University College London Medical School, UK. 2Department of Internal Medicine, University of Bologna, Italy.
BACKGROUND: Thyroid Peroxidase (TPO) autoantibodies have been frequenUy reported in chronic HCV infection, especially during IFN..o treatment. Using biotinylated paptldes (Chiron Technologies, Australia) we have recently demonstrated humoral double reactivity against HCV and TPO epitopes sharing 80-100% aminoacid similarity, in anti-TPO positive-HCV infected patients (Hepatology 1999;(30)4:Suppl 2, p.363A). AI__.M.MTo : investigate if the observed double reactivity is cross-reective. METHODS: Compatltion ELISAs were performed using both viral and TPO peptides prepared at concentrations of 1000, 500, 250, 125 and 62.5 p.glml and recombinant TPO protein (Phan'nacia & Upjohn, UK). Two 'scrambled' paptldes and the Pyruvate Kinase protein (Sigma, Dorset, UK) were used as controls. RESULTS: Antibody binding to individual HCV sequences was inhibited not only by preinoubation with the HCV paptides (48-92%) but also by the TPO homologues (47-84%) and by the recombinant TPO protein (51-89%), but not by the control peptides or the control protein...C..ONCLUSION Anti-HCV response, probably through a molecular mimicry mechanism, targets Thyroid Peroxidase, the major antigen of thyroid autoimmunity, providing an explanation for the frequent association between the viral infection and the autoimmune endocrine pathology.
103