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Low frequency of cirrhosis in HCV(1b)-infection after more than 20 years
136
Poster Sessions
PEG) 1 x/wk+Ribavarin (RebetolTM; RIB) 1-1.2 g/d; B: 100 meg PEG 1 x/wk+RIB 1-1.2 g/d; C: 200 meg PEG 1 x/wk; D: 100 meg PEG 1 x/wk. After induction, all patients receive PEG 100 meg 1 x/wk+RIB 1-1.2 g/d for 12 months as maintenance-treatment. Viral titers are measured from serum on day 0 (= baseline-D, day 1, days 7 (baseline-2), 8, 11, 14 and 21 by the Clinical-Molecular-Biology Lab of the Schering-Plough-ResearchInstitute (lower limit of detection: 100 c/mi). 92 patients have been analysed to date (n -- A: 22, B: 26, C: 22, D: 22). Demographics were homogeneously distributed among the treatment groups. The median baseline viral titers (bvt's) are shown in table 1. Due to the uneven distribution of bvt's the bvt was used as covariable for evaluation of viral kinetics. Results: The mean decline in viral titer after injection of IFN and PEG is shown in table 2. 76 patients were evaluable for qualitative PCR after 3 months of maintenance treatment: Responserates (per protocol) were: A: 65%, B: 63%, C: 80% and D: 58%. Bvt and reduction of viral titer in responders (R) and nonresponders (NR) is shown in table 3. Conclusions: 1) IFN and PEG have a profound and comparable initial effect on viral titer 2) Viral suppression is sustained with PEG over a week whereas, with Ib2q, viral titers return to baseline levels 3) Bvt's are significantly lower in responders than in nonresponders 4) Initial reduction in viral load is significantly greater in responders than in nonresponders 5) This difference increases at the following timepoints, suggesting that the predictive value of viral kinetics for response may be improved by surveillance over a period of 2-3 weeks.
~8"-~ DOSING GUIDELINES FOR ADEFOVIR DIPIVOXlL IN THE TREATMENT OF HBV INFECTED PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT Wanda Knight 1, Sandra Hayashi l , Yves Benhamou 2, Graeme Cuttle l , Ramin Ebrahimi t, Stan Gill 1, John Fry 1, Brian Kearney 1, Carol Brosgart 1. t Clinical Research, Gilead Sciences, Foster City,
California, USA; 2Service of Hepatology, Pitie Salpetriere, Paris, France Background: Minimal to severe liver dysfunction are sequelae of Chronic hepatitis B virus (HBV) infection. Severe liver disease may be associated with renal impairment. Adefovir Dipivoxil (ADV), a chronic HBV therapy, is eliminated unchanged in the urine by glomerular filtration and tubular secretion. Objectives: To evaluate pharmacokinetics (PK) and provide dosing guidelines for subjects with renal or hepatic impairment. Methods: Two studies were conducted, one in renally impaired patients stratified by creatinine clearance (CLcr) (mild 50-80 mL/min, moderate 30--49 mL/min, severe <30 ml_Jmin, and hemodialysis) and one in hepatically impaired patients stratified by Child-Pugh score (moderate 7-9, severe >9). Healthy subjects were recruited as controls. All patients received a single oral dose of ADV 10 mg, except dialysis patients, who received 2 doses (intradialysis and interdialysis) by monitoring. Safety was also assessed. Results: 16 healthy, 16 hepatically impaired, and 33 renally impaired subjects completed the studies. ADV was well tolerated in all subjects. The PK of ADV was similar to healthy subjects in patients with all stages of hepatic impairment, and in patients with mild renal impairment (CLcr >50 mL/min). Compared to healthy patients (AUC 197 ng*hr/mL, Cmax 16.7 ng/mL), ADV exposure was increased in patients with moderate (AUC 420 ng*hr/mL, Cmax 27.3 ng/mL) and severe (AUC 1115 ng*hr/mL, Cmax 50.7 ng/mL) renal impairment, and in hemodialysis patients, therefore modified dosing regimens are necessary. C o n t u s i o n : No change in ADV dosing is required in patients with hepatic impairment or mild renal impairment. ADV dosing recommendations in patients with CLcr <50 mL/min will be presented.
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STEATOSIS ACCELERATES FIBROSIS DEVELOPMENT OVER TIME IN HEPATITIS C VIRUS GENOTYPE 3 INFECTED PATIENTS
Johan Westin I , Hans Nordlinder 2, Martin Lagging 3, Gunnar Norkrans I , Rune Wejstal I . 1Department of lnfectious Diseases, Goteborg University,
Goteborg; 2Department of Pathology, Goteborg University, Goteborg; 3Department of Clinical Virology, Goteborg University, Goteborg, Sweden Background: Steatosis is a frequent histological finding in liver biopsies from patients with chronic hepatitis C virus (HCV) infection. Its cause and influence on disease progression is only partially understood. The aim of this study was m evaluate the impact of steatosis on fibrosis progression over time in relation to HCV genotype. Methods: We retrospectively analysed 98 patients who underwent dual liver biopsies prior to antiviral treatment. Median time between the biopsies was 6.3 years. Biopsy specimens were assessed for necroinflammatory activity and fibrosis according to the Ishak protocol, as well as for steatosis (grade 0-3). Univariate analysis as well as multiple logistic regression analysis was used. Results: Both prevalence and high grade (3 2) of steatosis were strongly associated with HCV genotype 3, independent of gender, age, body mass index and alcohol use. Progressive fibrosis was more prevalent in patients whose initial biopsy showed steatosis. This effect was mainly seen in genotype 3 infected patients. Low-grade steatosis was observed in overweight patients with genotype non-3, but high-grade steatosis was associated with genotype 3, independent of body weight. Conclusions: Our data confirm that steatosis is associated with HCV genotype 3 infection. Furthermore, steatosis was associated with progressive fibrosis over time, especially in genotype 3 patients. These data imply that hepatitis C patients should avoid overweight. Genotype 3 infected patients with steatosis ought to be selected for early antiviral therapy to avoid progressive fibrosis and to benefit from the relatively good treatment results in this group of patients.
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LOW FREQUENCY OF CIRRHOSIS IN HCV(lb)-INFECTION AFTER MORE THAN 20 YEARS
Mantled Wiese 1, Frieder Bert 2, Heiner Porst 3. I Clinic St. Georg, Dpt. Hepatology, Leipzig; 2Clinic Int. Med. II, Univ. Leipzig; 3Clinic Int. Med. IIl, Dresden-Friedrichstadt, Germany From August 1978 until March 1979, 14 batches of anti-D immune globulin contaminated with hepatitis C virus genotype lb from a single erythrocyte donor had been administered for prophylaxis of rhesus isoimmuniszation. Methods: All 2867 women involved had been recalled after January 12, 1979 for repeated screening of aminotranferases. They were prospectively followed in 9 regional centers. Now a cohort of 1018 women was reexamined by members of the EAST GERMAN HCV STUDY GROUE Results: Within 6 months after anti-D vaccination, 10% of these women had no evidence of disease, 90% acute hepatitis C (n = 917) including 49% with symptomatic and 22% with icteric course. After 23 years, 85% of the 917 affected women still tested positive for anti-HCV and 55% for HCV RNA, among them 52% with chronic hepatitis C and 3% apparent HCV carriers. Only 0.4% had overt liver cirrhosis. Histology obtained in 44% of the viremic women showed hepatitis of minimal to moderate grade in 96%, portal fibrosis in 47% and septal fibrosis in 3% of the cases. Conclusion: Formerly healthy young women, without hepatic comorbidity, may clear HCV(lb) infection in half of the cases or develop mild chronic hepatitis C with low risk of progression to cirrhosis within 23 years.
Poster Sessions
PEG) 1 x/wk+Ribavarin (RebetolTM; RIB) 1-1.2 g/d; B: 100 meg PEG 1 x/wk+RIB 1-1.2 g/d; C: 200 meg PEG 1 x/wk; D: 100 meg PEG 1 x/wk. After induction, all patients receive PEG 100 meg 1 x/wk+RIB 1-1.2 g/d for 12 months as maintenance-treatment. Viral titers are measured from serum on day 0 (= baseline-D, day 1, days 7 (baseline-2), 8, 11, 14 and 21 by the Clinical-Molecular-Biology Lab of the Schering-Plough-ResearchInstitute (lower limit of detection: 100 c/mi). 92 patients have been analysed to date (n -- A: 22, B: 26, C: 22, D: 22). Demographics were homogeneously distributed among the treatment groups. The median baseline viral titers (bvt's) are shown in table 1. Due to the uneven distribution of bvt's the bvt was used as covariable for evaluation of viral kinetics. Results: The mean decline in viral titer after injection of IFN and PEG is shown in table 2. 76 patients were evaluable for qualitative PCR after 3 months of maintenance treatment: Responserates (per protocol) were: A: 65%, B: 63%, C: 80% and D: 58%. Bvt and reduction of viral titer in responders (R) and nonresponders (NR) is shown in table 3. Conclusions: 1) IFN and PEG have a profound and comparable initial effect on viral titer 2) Viral suppression is sustained with PEG over a week whereas, with Ib2q, viral titers return to baseline levels 3) Bvt's are significantly lower in responders than in nonresponders 4) Initial reduction in viral load is significantly greater in responders than in nonresponders 5) This difference increases at the following timepoints, suggesting that the predictive value of viral kinetics for response may be improved by surveillance over a period of 2-3 weeks.
~8"-~ DOSING GUIDELINES FOR ADEFOVIR DIPIVOXlL IN THE TREATMENT OF HBV INFECTED PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT Wanda Knight 1, Sandra Hayashi l , Yves Benhamou 2, Graeme Cuttle l , Ramin Ebrahimi t, Stan Gill 1, John Fry 1, Brian Kearney 1, Carol Brosgart 1. t Clinical Research, Gilead Sciences, Foster City,
California, USA; 2Service of Hepatology, Pitie Salpetriere, Paris, France Background: Minimal to severe liver dysfunction are sequelae of Chronic hepatitis B virus (HBV) infection. Severe liver disease may be associated with renal impairment. Adefovir Dipivoxil (ADV), a chronic HBV therapy, is eliminated unchanged in the urine by glomerular filtration and tubular secretion. Objectives: To evaluate pharmacokinetics (PK) and provide dosing guidelines for subjects with renal or hepatic impairment. Methods: Two studies were conducted, one in renally impaired patients stratified by creatinine clearance (CLcr) (mild 50-80 mL/min, moderate 30--49 mL/min, severe <30 ml_Jmin, and hemodialysis) and one in hepatically impaired patients stratified by Child-Pugh score (moderate 7-9, severe >9). Healthy subjects were recruited as controls. All patients received a single oral dose of ADV 10 mg, except dialysis patients, who received 2 doses (intradialysis and interdialysis) by monitoring. Safety was also assessed. Results: 16 healthy, 16 hepatically impaired, and 33 renally impaired subjects completed the studies. ADV was well tolerated in all subjects. The PK of ADV was similar to healthy subjects in patients with all stages of hepatic impairment, and in patients with mild renal impairment (CLcr >50 mL/min). Compared to healthy patients (AUC 197 ng*hr/mL, Cmax 16.7 ng/mL), ADV exposure was increased in patients with moderate (AUC 420 ng*hr/mL, Cmax 27.3 ng/mL) and severe (AUC 1115 ng*hr/mL, Cmax 50.7 ng/mL) renal impairment, and in hemodialysis patients, therefore modified dosing regimens are necessary. C o n t u s i o n : No change in ADV dosing is required in patients with hepatic impairment or mild renal impairment. ADV dosing recommendations in patients with CLcr <50 mL/min will be presented.
•]
STEATOSIS ACCELERATES FIBROSIS DEVELOPMENT OVER TIME IN HEPATITIS C VIRUS GENOTYPE 3 INFECTED PATIENTS
Johan Westin I , Hans Nordlinder 2, Martin Lagging 3, Gunnar Norkrans I , Rune Wejstal I . 1Department of lnfectious Diseases, Goteborg University,
Goteborg; 2Department of Pathology, Goteborg University, Goteborg; 3Department of Clinical Virology, Goteborg University, Goteborg, Sweden Background: Steatosis is a frequent histological finding in liver biopsies from patients with chronic hepatitis C virus (HCV) infection. Its cause and influence on disease progression is only partially understood. The aim of this study was m evaluate the impact of steatosis on fibrosis progression over time in relation to HCV genotype. Methods: We retrospectively analysed 98 patients who underwent dual liver biopsies prior to antiviral treatment. Median time between the biopsies was 6.3 years. Biopsy specimens were assessed for necroinflammatory activity and fibrosis according to the Ishak protocol, as well as for steatosis (grade 0-3). Univariate analysis as well as multiple logistic regression analysis was used. Results: Both prevalence and high grade (3 2) of steatosis were strongly associated with HCV genotype 3, independent of gender, age, body mass index and alcohol use. Progressive fibrosis was more prevalent in patients whose initial biopsy showed steatosis. This effect was mainly seen in genotype 3 infected patients. Low-grade steatosis was observed in overweight patients with genotype non-3, but high-grade steatosis was associated with genotype 3, independent of body weight. Conclusions: Our data confirm that steatosis is associated with HCV genotype 3 infection. Furthermore, steatosis was associated with progressive fibrosis over time, especially in genotype 3 patients. These data imply that hepatitis C patients should avoid overweight. Genotype 3 infected patients with steatosis ought to be selected for early antiviral therapy to avoid progressive fibrosis and to benefit from the relatively good treatment results in this group of patients.
(-~
LOW FREQUENCY OF CIRRHOSIS IN HCV(lb)-INFECTION AFTER MORE THAN 20 YEARS
Mantled Wiese 1, Frieder Bert 2, Heiner Porst 3. I Clinic St. Georg, Dpt. Hepatology, Leipzig; 2Clinic Int. Med. II, Univ. Leipzig; 3Clinic Int. Med. IIl, Dresden-Friedrichstadt, Germany From August 1978 until March 1979, 14 batches of anti-D immune globulin contaminated with hepatitis C virus genotype lb from a single erythrocyte donor had been administered for prophylaxis of rhesus isoimmuniszation. Methods: All 2867 women involved had been recalled after January 12, 1979 for repeated screening of aminotranferases. They were prospectively followed in 9 regional centers. Now a cohort of 1018 women was reexamined by members of the EAST GERMAN HCV STUDY GROUE Results: Within 6 months after anti-D vaccination, 10% of these women had no evidence of disease, 90% acute hepatitis C (n = 917) including 49% with symptomatic and 22% with icteric course. After 23 years, 85% of the 917 affected women still tested positive for anti-HCV and 55% for HCV RNA, among them 52% with chronic hepatitis C and 3% apparent HCV carriers. Only 0.4% had overt liver cirrhosis. Histology obtained in 44% of the viremic women showed hepatitis of minimal to moderate grade in 96%, portal fibrosis in 47% and septal fibrosis in 3% of the cases. Conclusion: Formerly healthy young women, without hepatic comorbidity, may clear HCV(lb) infection in half of the cases or develop mild chronic hepatitis C with low risk of progression to cirrhosis within 23 years.