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A new mathematical description of virus-host interaction in HCV infection that fits experimental data
Poster Sessions
152
30, 31, 32, 35, 38, 42, 49, 56 and month 3, 4, 5 and 6. HBV DNA was measured with the Digene Hybrid Capture II liquid hybridisation assay. Non-linear modelling executed in SAS 6.12 was used to fit individual patient data. Results: Analysis was based on 10 patients treated with entecavir. One patient was withdrawn from therapy after 1 week; this patient was evaluated for the first phase of viral decline only. Baseline HBV DNA was 1.7 x 109 geq/ml (range 5.5 x 107-1.5 x 1010). Median effectiveness of 4 doses of entecavir in blocking viral production was 96% (range 87%-98%). Median viral half-life is 16 hours (range 12-29). Median half-life of infected cells during the second phase is 257 hours (9 patients; range 112-762). All patients showed a biphasic return in viral replication after withdrawal of therapy. Conclusion: All patients on entecavir showed a biphasic decline during and a biphasic rebound after withdrawal of therapy.
~-']A
NEW MATHEMATICALDESCRIPTION OF VIRUS-HOST INTERACTION IN HCV INFECTION THAT FITS EXPERIMENTAL DATA
P. Colombatto, L. Civitano, F. Oliveri, B. Coco, P. Ciccorossi, A. Maina, G. Moscato, E Bonino, M.R. Brunetto. Hepatology and
monitored in a multicenter trial offering following regimes: STANDARD (= without daily dosing): month 1:5 MU IFN s.c. tiw + Ribavirin 1000-1200 mg p.o. daily INDUCTION (= with daily dosing): month 1: 5 MU IFN s.c. daily + Ribavirin 1000-1200 mg p.o. daily month 2-6 in both regimes: 5 MU IP-N s.c. tiw + Ribavirin 1000-1200 mg p.o. daily month 7-12:3 MU IFN s.c. tiw + Ribavirin 1000-1200 mg p.o. daily Results: 170 patients (m = 69%, f = 31%; age: 43.6 4- 9.8 y) were enrolled in the STANDARD-protocol and 63 patients (m = 63%, f = 37%; age: 41.9 4- 8.4 y) in the INDUCTION-protocol. The primary virological response was 62% for the standard-protocol and 84% for the induction-protocol. Due to a higher break-through rate in the induction-protocol end of treatment response was 54% (relapser = 81%, NR = 30%) in the standard-protocol and 61% (relapser = 87%, NR = 36%) in the induction-protocol. So far sustained response rates are 42% (35/83) and 43% (6/14), respectively. There were 20 break offs in the standard group and 6 break offs in the induction group mainly due to non-compliance. Side effects did not differ significantly between both groups. Conclusion: Initial daily dosing does enhance the primary virological response rate, but it does not enhance neither end of treatment nor sustained response both in interferon nonresponders and relapsers. Supported by ESSEX Pharma GmbH
Gastroenterology Unit, Azienda Ospedaliere University of Pisa, Italy Modeling kinetics of chronic HCV infection allowed Neumann et al to reach useful insights about the IFN effects on virus life cycle. It has been assessed that IFN can block over 96% of de novo viral RNA production, causing over 10 fold drop of viraemia within the first 48 hours. The further slower phase of HCV-RNA decrease was attributed to the clearance of infected hepatocytes by the immune system, whose function was represented in the equation as a constant. Thereof, changes affecting the number of infected cells always lead to an unlimited increase or decrease of viral load in this model. This interpretation, however, is in contrast with the experimental evidence in relapser patients. In order to overcome this limit, we developed a model in which the immune activity is not a constant but a function positively correlated to the number of infected hepatocytes. We also considered that IFN therapy can activate additional immune mechanisms independent from the number of infected cells. Two new parameters describing these effects have been introduced into the equations. Their determination needs the measurement of serum HCV-RNA variations when the clearance of infected cells has reduced the viral load of about 2-3 Logs. Both models were used for fitting HCV-RNA experimental data in 10 chronic hepatitis C patients undergoing IFN treatment. In our model the decrease of HCV-RNA serum levels modulated by the value of the newly introduced parameters fitted with the experimental data. In conclusion, we showed that more parameters are required to realistically represent the function of the immune-mediated clearance of the infected cells. We are evaluating whether their determination could be helpful to personalize treatment schedules for more cost-effective strategy.
~8-~
INTERFERON/RIBAVIRINCOMBINATION THERAPY WITH AND WITHOUT DAILY DOSING IN RETREATMENT OF CHRONIC HEPATITIS C
M.H. Frieser, T. Bernatik, H. Klinker, M. Scheurlen, H. Meyer, W. Norgauer, W. Rambach, K. Meier, E. Hahn, D. Schuppan, H.T. Schneider. Department of Medicine L University Erlangen,
Germany Background/Aims: To evaluate benefits of interferon/ribavirin combination-therapy with initial daily dosing in patients with chronic hepatitis C not successfully treated by interferon (IFN)-monotherapy compared to treatment without daily dosing. Material and Methods: Since April 1998 233 patients with chronic hepatitis C (non-responder n = 135; relapser n = 98) were prospectively
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DOPPLER MEASUREMENTS IN THE DECISION FOR THERAPY IN CHRONIC VIRAL HEPATITIS
T. Bernatik, D. Strobel, E.G. Hahn, D. Becker. Deparment of Medicine
L University Erlangen, Germany Background/Aims: Doppler parameters (DP) of portal vein have been reported to correlate with the stage of liver fibrosis in chonic viral hepatitis (CVH). However the value of Doppler measurement of all liver vessels in therapeutic decision in CVH has not yet been established. Materials/Methods: 35 consecutive patients with chronic hepatitis C who underwent liver biopsy for grading of inflammatory and fibrotic changes were enrolled. At the time of biopsy two independent investigators measured maximum blood flow velocity, mean velocity, resistance index (RI), diameter of the vessel and the blood flow volume in portal vein, hepatic artery and liver veins. All measurements were done by each investigator in triplicate. Mean values were correlated with the degree of liver fibrosis and inflammation using the Ludwig-score (LS) [Ludwig: The nomenclature of chronic active hepatitis. Gastroenterology 1993; 105: 274]. Results: No correlation could be found between DP and fibrosis stage or between DP and inflammation grade. Comparing patients with minimal histologic changes (LS-sum 1-2) to patients with futher progressed liver disease (LS-sum > 2) there was a significant difference in RI in the hepatic artery (p = 0.015). Although 92% (11/12) of patients with RI above 0.66 presented further progressed liver disease (LS-sum > 2), sensitivity of RI (cutoff 0.66) for severe histological changes (LS-sum > 2) is only 38% (specifity 92%). Conclusion: In patients with CVH Doppler measurements of none of the liver vessels are a valid surrogate marker of liver fibrosis or inflammation. Nevertheless increased RI does indicate further progressed histological changes and therefore might indicate need of therapy.
~ 6 " ~ OCCURENCE AND CLINICAL OUTCOME OF LAMIVUDINE RESISTANT HEPATITIS B REINFECTION AFTER LIVER TRANSPLANTATION D. Seehofer, N. Rayes, A.R. Mueller, T. Berg, U. Hopf, C. Radke, T. Steinmueller, P. Neuhaus. Charit' Campus Virchow, General-,
~sceral- and Transplant-Surgery, Berlin, Germany Purpose: Major problem of lamivudine treatment of HBV-infection after liver transplantation is a relatively fast resistance formation. Lamivudine
152
30, 31, 32, 35, 38, 42, 49, 56 and month 3, 4, 5 and 6. HBV DNA was measured with the Digene Hybrid Capture II liquid hybridisation assay. Non-linear modelling executed in SAS 6.12 was used to fit individual patient data. Results: Analysis was based on 10 patients treated with entecavir. One patient was withdrawn from therapy after 1 week; this patient was evaluated for the first phase of viral decline only. Baseline HBV DNA was 1.7 x 109 geq/ml (range 5.5 x 107-1.5 x 1010). Median effectiveness of 4 doses of entecavir in blocking viral production was 96% (range 87%-98%). Median viral half-life is 16 hours (range 12-29). Median half-life of infected cells during the second phase is 257 hours (9 patients; range 112-762). All patients showed a biphasic return in viral replication after withdrawal of therapy. Conclusion: All patients on entecavir showed a biphasic decline during and a biphasic rebound after withdrawal of therapy.
~-']A
NEW MATHEMATICALDESCRIPTION OF VIRUS-HOST INTERACTION IN HCV INFECTION THAT FITS EXPERIMENTAL DATA
P. Colombatto, L. Civitano, F. Oliveri, B. Coco, P. Ciccorossi, A. Maina, G. Moscato, E Bonino, M.R. Brunetto. Hepatology and
monitored in a multicenter trial offering following regimes: STANDARD (= without daily dosing): month 1:5 MU IFN s.c. tiw + Ribavirin 1000-1200 mg p.o. daily INDUCTION (= with daily dosing): month 1: 5 MU IFN s.c. daily + Ribavirin 1000-1200 mg p.o. daily month 2-6 in both regimes: 5 MU IP-N s.c. tiw + Ribavirin 1000-1200 mg p.o. daily month 7-12:3 MU IFN s.c. tiw + Ribavirin 1000-1200 mg p.o. daily Results: 170 patients (m = 69%, f = 31%; age: 43.6 4- 9.8 y) were enrolled in the STANDARD-protocol and 63 patients (m = 63%, f = 37%; age: 41.9 4- 8.4 y) in the INDUCTION-protocol. The primary virological response was 62% for the standard-protocol and 84% for the induction-protocol. Due to a higher break-through rate in the induction-protocol end of treatment response was 54% (relapser = 81%, NR = 30%) in the standard-protocol and 61% (relapser = 87%, NR = 36%) in the induction-protocol. So far sustained response rates are 42% (35/83) and 43% (6/14), respectively. There were 20 break offs in the standard group and 6 break offs in the induction group mainly due to non-compliance. Side effects did not differ significantly between both groups. Conclusion: Initial daily dosing does enhance the primary virological response rate, but it does not enhance neither end of treatment nor sustained response both in interferon nonresponders and relapsers. Supported by ESSEX Pharma GmbH
Gastroenterology Unit, Azienda Ospedaliere University of Pisa, Italy Modeling kinetics of chronic HCV infection allowed Neumann et al to reach useful insights about the IFN effects on virus life cycle. It has been assessed that IFN can block over 96% of de novo viral RNA production, causing over 10 fold drop of viraemia within the first 48 hours. The further slower phase of HCV-RNA decrease was attributed to the clearance of infected hepatocytes by the immune system, whose function was represented in the equation as a constant. Thereof, changes affecting the number of infected cells always lead to an unlimited increase or decrease of viral load in this model. This interpretation, however, is in contrast with the experimental evidence in relapser patients. In order to overcome this limit, we developed a model in which the immune activity is not a constant but a function positively correlated to the number of infected hepatocytes. We also considered that IFN therapy can activate additional immune mechanisms independent from the number of infected cells. Two new parameters describing these effects have been introduced into the equations. Their determination needs the measurement of serum HCV-RNA variations when the clearance of infected cells has reduced the viral load of about 2-3 Logs. Both models were used for fitting HCV-RNA experimental data in 10 chronic hepatitis C patients undergoing IFN treatment. In our model the decrease of HCV-RNA serum levels modulated by the value of the newly introduced parameters fitted with the experimental data. In conclusion, we showed that more parameters are required to realistically represent the function of the immune-mediated clearance of the infected cells. We are evaluating whether their determination could be helpful to personalize treatment schedules for more cost-effective strategy.
~8-~
INTERFERON/RIBAVIRINCOMBINATION THERAPY WITH AND WITHOUT DAILY DOSING IN RETREATMENT OF CHRONIC HEPATITIS C
M.H. Frieser, T. Bernatik, H. Klinker, M. Scheurlen, H. Meyer, W. Norgauer, W. Rambach, K. Meier, E. Hahn, D. Schuppan, H.T. Schneider. Department of Medicine L University Erlangen,
Germany Background/Aims: To evaluate benefits of interferon/ribavirin combination-therapy with initial daily dosing in patients with chronic hepatitis C not successfully treated by interferon (IFN)-monotherapy compared to treatment without daily dosing. Material and Methods: Since April 1998 233 patients with chronic hepatitis C (non-responder n = 135; relapser n = 98) were prospectively
~'~
DOPPLER MEASUREMENTS IN THE DECISION FOR THERAPY IN CHRONIC VIRAL HEPATITIS
T. Bernatik, D. Strobel, E.G. Hahn, D. Becker. Deparment of Medicine
L University Erlangen, Germany Background/Aims: Doppler parameters (DP) of portal vein have been reported to correlate with the stage of liver fibrosis in chonic viral hepatitis (CVH). However the value of Doppler measurement of all liver vessels in therapeutic decision in CVH has not yet been established. Materials/Methods: 35 consecutive patients with chronic hepatitis C who underwent liver biopsy for grading of inflammatory and fibrotic changes were enrolled. At the time of biopsy two independent investigators measured maximum blood flow velocity, mean velocity, resistance index (RI), diameter of the vessel and the blood flow volume in portal vein, hepatic artery and liver veins. All measurements were done by each investigator in triplicate. Mean values were correlated with the degree of liver fibrosis and inflammation using the Ludwig-score (LS) [Ludwig: The nomenclature of chronic active hepatitis. Gastroenterology 1993; 105: 274]. Results: No correlation could be found between DP and fibrosis stage or between DP and inflammation grade. Comparing patients with minimal histologic changes (LS-sum 1-2) to patients with futher progressed liver disease (LS-sum > 2) there was a significant difference in RI in the hepatic artery (p = 0.015). Although 92% (11/12) of patients with RI above 0.66 presented further progressed liver disease (LS-sum > 2), sensitivity of RI (cutoff 0.66) for severe histological changes (LS-sum > 2) is only 38% (specifity 92%). Conclusion: In patients with CVH Doppler measurements of none of the liver vessels are a valid surrogate marker of liver fibrosis or inflammation. Nevertheless increased RI does indicate further progressed histological changes and therefore might indicate need of therapy.
~ 6 " ~ OCCURENCE AND CLINICAL OUTCOME OF LAMIVUDINE RESISTANT HEPATITIS B REINFECTION AFTER LIVER TRANSPLANTATION D. Seehofer, N. Rayes, A.R. Mueller, T. Berg, U. Hopf, C. Radke, T. Steinmueller, P. Neuhaus. Charit' Campus Virchow, General-,
~sceral- and Transplant-Surgery, Berlin, Germany Purpose: Major problem of lamivudine treatment of HBV-infection after liver transplantation is a relatively fast resistance formation. Lamivudine