- Email: [email protected]
Pharmacokinetics of peginterferon ALFA-2A (40KD, PEGASYS) compared to peginterferon ALFA-2B (12KD, PEGINTRON) in naive patients with chronic hepatitis C (CHC)
Category 6: Viral hepatitis: clinical aspects HEPATITIS C IS AN INDEPENDENT NON-ACCIDENTAL
MORTALITY
BASED COHORT
PREDICTOR
OF
AMONG A POPULATION-
OF HIV-INFECTED
HIGHLY ACTIVE ANTIRETROVIRAL
INDIVIDUALS THERAPY
INITIATING
(HAART)
l? Braitstein’,2, V. Montessori’, B. Yip’, J.S.G. Montaner’,3, M.T. Schechter’,2, M.V. O’Shaughnessy 1,4 , PR. Harrigan 1,3, R.S. Hogg 1,2. ‘BC Center For Excellence In HIV/AIDS, Vancouves Canada; 2Dept. Of Health Care And Epidemiology, University Of British Columbia, Vancouves Canada; ‘Dept. Of Medicine, University Of British Columbia, Vancouves Canada; 4Dept. Of Pathology And Laboratory Medicine, University Of British Columbia, Vancouves Canada Objective: To determine whether hepatitis C (HCV) is predictive of non-accidental mortality among HIV+ individuals initiating HAART in a population-based program. Methods: The HIV/AIDS Drug Treatment Program distributes, at no cost to eligible individuals, all ART in this Canadian province. Individuals were eligible for this analysis if they initiated HAART between 08/96 and 07/00, and had documented HCV antibody (Ab) test results. Mortality data were obtained through Vital Statistics of BC, and censored in 02/02. Cumulative mortality rates were obtained by Kaplan-Meier methods, and Cox proportional hazards regression was used to calculate adjusted hazard ratios (AHR). Results: 1416 individuals initiated HAART. 5.52 have recorded HCV-Ab test results (39%), of whom 235 (43%) were HCV-Ab+. At time of censoring, 68 (12.3%) individuals died of non-accidental causes, including 40 (17%) of HCV+ individuals, and 28 (9%) HCV-. The product limit estimate (SE) of the cumulative mortality rate at 48 months for HCV+ individuals was 21.7% (0.03) and for HCV- 10.3% (0.02) (p=O.O02). Associated with mortality were baseline CD4 count 1.50 cells/mm3 (UOR 3.5;95%CI: 1.9?6.4), between 50 and 199 cells/mm3 (UOR 2.1;95%CI: 1.2?3.6), AIDS diagnosis (UOR 3.0;95%CI: 1.6?5.4), >75% adherent to HAART (UOR 0.49;95%CI: 0.29?0.85), being HCV-Ab+ (UOR2.1;95%CI: 1.3?3.6), having a higher log HIV RNA (5.3vs.5.1, p=O.OOS), and median age (40 vs.37 yrs, p
RE-TREATMENT
OF INTERFERON
(RBV) NONRESPONDERS ALFA-2A
(IFN) PLUS RIBAVIRIN
WITH PEGINTERFERON
(40KD) (PEGASYS)
(AMA) OR IFN ALFA-2A (ROFERON-A) INTERIM RESULTS
(PEG-IFN)
PLUS RBV AND AMANTADINE
OF A MULTICENTER
PLUS RBV AND AMA. RANDOMIZED
STUDY
S. Brillanti’, A. Mangia2, L. Cimino3, A. Civolani4, F. Fatuzzo’, L. Fenoglio6, M. Levrero7, G. Minoli’, M. Persico9, M.G. Rumi”. ‘Internal Medicine And Gastroenterology Department, University Of Bologna, Bologna, Italy; 2Gastroenterology Division, IRCCS Casa Sollievo Della Sofferenza, San Giovanni, Rotondo, Italy; ‘Epatogastroenterology Division, University ‘Fedetico II’, Napoli, Italy; 4Gastroenterology Department, University Of Cagliati, Cagliati, Italy; 51nfectious Diseases Division, Hospital ‘V.E. Ferrarotto S. Bambino’, Catania, Italy; 6General Medicine, Hospital ‘Le Molinette’, Torino, Italy; 71nternal Medicine Department, University ‘La Sapienza’, Roma, Italy; ‘Medicine/Endoscopy Department, Hospital Of Valduce, Coma, Italy; 9V Division Of General Medicine, II Policlinico, Napoli, Italy; “V Division Of General Medicine, Centro Migliavacca Policlinico, Milano, Italy A small randomized trial indicated AMA, plus IFN and RBV, was superior to IFN+RBV in re-treating IFN monotherapy nonresponders with chronic hepatitis C (CHC) (Brillanti et al. Hepatology 2000;) suggesting a synergistic effect in enhancing viral clearance. Aim: To determine the SVR rates of AMA plus PEG-IFN or IFN, in combination with RBV, in previous nonresponders to combination (IFN+RBV) therapy.
129
Methods: 240 CHC patients without any virological response to a previous cam-se of at least 12.week of IFN+RBV, and with persistently elevated ALT, have been randomized to receive 180 mcg once-weekly of PEG-IFN alfa-2a (40KD) (Pegasys) plus RBV (1000-1200 mg/daily) plus AMA (200 mgldaily) (group A) or 6 MIU every other day of IFN alfa-2a (Roferon-A) plus RBV (1000-1200 mgldaily) plus AMA (200 mgldaily) (group B) for 48 weeks, with a 24.week follow-up. Therapy was stopped in patients who were HCV-RNA positive at 24 weeks of treatment. Results: Patients baseline characteristics were similar in both groups (mean age 54 vs. 52 years; genotype 1: 80% vs. 78%). Virological response rates, in patients who were treated for at least 12 weeks, are reported in the table. To date, no severe or unexpected serious adverse events have been reported in either group with the addition of AMA. Conclusions: Interim results indicate a clinically significant response rate in this difficult to re-treat population. We expect to show the complete results, after 24 weeks of therapy, at the EASL annual meeting.
I 442
INTERFERON
ALPHA PLUS RIBAVIRIN
INTERFERON
ALPHA FOR CHRONIC
UPDATED, SYSTEMATIC
COCHRANE
VERSUS
HEPATITIS C-AN REVIEW
J. Brok, L.L. Kjaergard,
C. Gluud. Copenhagen Trial Unit, Copenhagen University Hospital, H: S Rigshospitalet, Copenhagen, Denmark
Aims: To asses the beneficial and harmful effects of ribavirin plus interferon alpha versus interferon alpha for interferon na ve, relapser, and non-responder patients with chronic hepatitis C. Methods: A systematic review of randomised trials comparing ribavirin plus interferon alpha versus interferon alpha. Electronic and manual searches were combined until September 2002. Results: A total of 66 trials randomised 8521 patients to interferon with or without ribavirin. Only five trials had high methodological quality. Compared with interferon, combination therapy significantly increased the risk of having a sustained virological response by 28% in naive patients (relative risk (RR) 0.72; 95% confidence interval (CI) 0.68.0.76), 32% in relapsers (RR 0.68; 95% CI 0.60.0.76), and 10% in non-responders (RR 0.90; 95% CI 0.85-0.95). Irrespective of previous therapy, combination therapy significantly increased the risk of having improved histology (RR 0.67; 95% CI 0.56-0.81). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.56; 95% CI 0.25-1.28). Combination therapy significantly increased the risk of treatment discontinuation (RR 1.25; 95% CI 1.08-1.46) and several types of adverse events. Conclusions: Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological and histological response, but also the occurrence of several adverse events. Combination therapy had no significant effect on morbidity plus mortality. However, no trials followed the patients long enough to assess the effect on long-term liver-related morbidity and mortality.
I 443
PHARMACOKINETICS PEGASYS)
OF PEGINTERFERON
COMPARED
(12KD, PEGINTRON)
TO PEGINTERFERON
ALFA-2A
(40KD,
ALFA-2B
IN NAIVE PATIENTS WITH CHRONIC
HEPATITIS C (CHC)
R. Bnmo, l? Sacchi, V. Ciappina, E. Maffezzini, S.F.A. Patruno, C. Zocchetti, G. Filice. Infectious And Tropical Diseases, IRCCS San Matte0 Hospital University Of Pavia, Pavia, Italy Background: The currently available pegylated interferon (PEG-IFN) formulations, PEG-IFN ALFA-2A (4OKD, PEGASYS) and PEG-IFN ALFA2B (12KD, PEG-In&-on), have different pharmacokinetic profiles. Aim: Objective of this randomized trial is to compare the pharmacokinetics of the two PEG-IFNs in patients with CHC. Patients & Methods: 30 treatment naive patients with CHC and persistently elevated ALT levels have been randomized to receive 180 mcg PEGASYS once-weekly (n=16) or 1.0 mcg/kg once-weekly of PEG-Intron
130
Poster Sessions
(n=14). Serum concentrations of both PEG-IFNs were measured at baseline and 24,48, 120 and 168 hours after administration using a quantitative sandwich ELISA (lower limit of detection 12.5 pglml). Results: Serum concentration of PEG-Intron achieved maximum levels at 24 hours after injection and decreased rapidly until 120 hours. Drug was undetectable 120 and 168 hours after injection in 7 (50%) and 11 (78%) subjects, respectively. In contrast, PEGASYS concentrations increased continuously overtime, reaching maximum levels from 48 to 168 hours. Conclusions: Our data demonstrate substantial differences in plasma concentration profiles between PEGASYS and PEG-Intron. Five days after injection concentrations of PEG-Intron are marginal or undetectable, while those of PEGASYS remain stable overtime. These findings suggest that PEG-In&-on administration should be intensified to twice weekly to avoid “blips” in viral replication. Differences in pharmacokinetics could explain the differences observed in HCV decay.
I 444
FACTORS RELATED TO POST-TREATMENT CHRONIC
RELAPSE
IN
HEPATITIS B PATIENTS WHO LOST HBEAG AFTER
LAMIVUDINE
THERAPY
K.S. Bvun’, J.E. Yeon’, C.H. Lee’, O.S. Kwon2, J.H. Kim2. ‘Korea University College Of Medicine, Internal Medicine, Seoul, South Korea; 2Gachon University College Of Medicine, Inchon, South Korea Background: It is uncertain that HBeAg loss after lamivudine therapy is durable. In Korean patients, the relapse rate is high after discontinuation of lamivudine therapy. Prolonged additional lamivudine therapy after HBeAg loss may be a proposal to reduce relapse rate. Aims: We evaluated the factors and the patterns of relapse after lamivudine therapy. Patients and Methods: 541 Korean chronic hepatitis B (CHB) patients with HBeAg positive were treated with lamivudine. Post-treatment monitoring continued. Results: HBeAg loss occurred in 212 patients and lamivudine therapy was discontinued in 1.53 patients. Total 132 patients eligible to study were followed up after cessation of lamivudine therapy. 75 patients were relapsed (HBV DNA+ve and/or raised ALTs, cumulative relapse rate: 56% at 6 months). Relapse were occurred within 6 months in 68 of 75 patients. Sustained response, which had not relapsed over 6 months after discontinuing lamivudine therapy, was seen in only 32 patients. In multivariate analysis, the older age, higher total bilirubin, and shorter duration of additional lamivudine therapy were significant factors for relapse. Almost all patients with relapse had elevated ALT and reemergence of HBV DNA. HBeAg reappeared in 55 patients and twenty were HBeAg-ve relapse. There were 5 cases of breakthrough after HBeAg loss. Conclusions: To reduce relapse after lamivudine therapy in CHB, age and serum bilirubin level of patients as well as duration of additional lamivudine therapy should be considered.
I 445
PRESENCE
OF MULTIPLE
RESPONSE
TO INTERFERON
HCV GENOTYPES
AND
THERAPY
N. Bzowei , Y. Phung, L. Brooks, M. Bonacini,
A. Wakil, R. Gish. Department Of Liver Transplantation, California Pacijc Medical Centec San Francisco, CA, USA
Hypothesis: Presence of multiple genotypes is associated with nonresponse to interferon. Methods: 4 sustained responders (SR), 4 relapsers (R) and 4 nonresponders (NR) were selected. Baseline, end of treatment and follow up serum samples were analyzed. Primers specific for 6 genotypes & 9 subtypes were used to amplify the core region. Extended PCR (45 cycles) was used. Genotypes were identified by comparison of visible bands on gels with known standards. Negative controls were performed. Results: At baseline, patients with 1 or 2 genotypes by commercial assay were found to have between 2 and 4 genotypes. Results for SR and R are
shown below. NR demonstrated therapy and at follow up.
persistence
of multiple genotypes
during
Patient
Commercial
BaSeline
BaSeline
End of Treatment
Group
Genotype
Genotype
Genotype
Genotype
Follow
Genotype
Up
(30 cycles
(45 cycles
(45 cycles
(45 cycles
PCR)
PCR)
PCR)
PCR)
la,2a
la
la
SR 1
2
la,2a
SR2
la
la
la,lb,2a,3a
la
NA
SR3
la
PCR negative
lq2a,2b,3a
la
la
SR4
NA
3a
la,2a,3a
la
la
Rl
la
la,2a
la,2a,3b
la
la,2a
R2
la
la,3b
la
la,2a,2b,3b
R3
la
la,lb,2a
la,2a,2b
la
la,2b
R4
la, lb
la,lb,2a
la,lb,2a
la
lq2a,2b
la
* NA= Not available.
Summary: 1) Multiple genotypes is common; 2) Patients with multiple genotypes at baseline had detectable viremia at follow up; 3) Genotype la appeared to be more resistant to therapy; 4) In some, IFN therapy resulted in detection of additional genotypes not observed at baseline. Conclusions: 1) SR determined by commercial assays may represent sustained suppression of virus rather than clearance. This may explain the development of late relapse; 2) Host responses to virus and presence of multiple HCV genotypes may represent important factors associated with nonresponse. Further study is required to determine if lower viral clearance is attributable to genotype la.
I
446
HEPATITIS B VIRUS GENOTYPES OF CHRONIC
AND THE PROGRESSION
LIVER DISEASE
F! Cacoub’,
M. Bourliere2, D. Saadoun’, H. Khiri3, A. Martineau3, V. Thibault’, M. Rotilly4, l? Halfon3. ‘Internal Medicine Department La Pitie Salpettiere Hospital, Paris, France; 2Hepatogastroenterology Department Saint Joseph Hospital, Marseille, France; ‘Virological Department, Alphabio Laboratory, Marseille, France; 4Clinsearch Laboratory, Paris, France Hepatitis B virus (HBV) can be classified into seven genotypes and a different geographical distribution can be demonstrated for these different genotypes. The aims of this study were to determine the HBV genotype distribution in France, and to correlate HBV genotypes and clinical outcomes. Patients and Methods: Using a polymerase chain reaction and reverse hybridization assay (LiPA, Innogenetics, Ghent), HBV genotypes were determined for 119 patients with an histologically proven HBV chronic hepatitis, including cirrhosis in 40. Results: Main characteristics were: 88 (74%) males, high alcohol intake in 5, age 46 & 16 yrs (m & SD), AST 2.6 & 3.3 N, ALT 11.5 & 18.3 N, GGT 1.6 & 1.4 N, Knodell total score 8.3 & 4.1. The HBV genotype distribution was as follows: A, 48 (40.3%); B, 9 (7.6%); C, 15 (12.6%); D, 50 (42%); E, 15 (12.6%); F, 6 (5%); G, 9 (7.6%), mixed 26 (15%) and unclassified, 4 (4%). A precore mutation was present in 81 (75.7%) patients. The prevalence of HBeAg positive was greater for genotype C carriers (60% vs 26%, p=O.O08), but lower for genotype D carriers (6.3% vs 48.5%, p=O.OOOl), and precore mutant (23% vs 56%, p=O.O07). The prevalence of HbeAb positive was lower for genotype C carriers (43% vs 74%, p=O.O2), but greater for genotype D (93% vs 53%, p=O.OOOl), and precore mutant (77% vs 42%, p=O.OOS). Patients with severe chronic hepatitis, i.e. F3-F4 Knodell fibrosis score, had more frequently a genotype D (p=O.O2), and a precore mutant (p=O.O3). Precore mutant was associated with severe portal necrosis (15% vs 0%, p=O.O5), severe portal inflammation (69% vs 40%, p=O.O5), and F3-F4 Knodell fibrosis score (50% vs 30%, p=O.O3). Conclusion: These results suggest that, in patients with chronic HBV infection, genotype D and precore mutant are strongly associated with the more severe cases of liver disease.
MORTALITY
BASED COHORT
PREDICTOR
OF
AMONG A POPULATION-
OF HIV-INFECTED
HIGHLY ACTIVE ANTIRETROVIRAL
INDIVIDUALS THERAPY
INITIATING
(HAART)
l? Braitstein’,2, V. Montessori’, B. Yip’, J.S.G. Montaner’,3, M.T. Schechter’,2, M.V. O’Shaughnessy 1,4 , PR. Harrigan 1,3, R.S. Hogg 1,2. ‘BC Center For Excellence In HIV/AIDS, Vancouves Canada; 2Dept. Of Health Care And Epidemiology, University Of British Columbia, Vancouves Canada; ‘Dept. Of Medicine, University Of British Columbia, Vancouves Canada; 4Dept. Of Pathology And Laboratory Medicine, University Of British Columbia, Vancouves Canada Objective: To determine whether hepatitis C (HCV) is predictive of non-accidental mortality among HIV+ individuals initiating HAART in a population-based program. Methods: The HIV/AIDS Drug Treatment Program distributes, at no cost to eligible individuals, all ART in this Canadian province. Individuals were eligible for this analysis if they initiated HAART between 08/96 and 07/00, and had documented HCV antibody (Ab) test results. Mortality data were obtained through Vital Statistics of BC, and censored in 02/02. Cumulative mortality rates were obtained by Kaplan-Meier methods, and Cox proportional hazards regression was used to calculate adjusted hazard ratios (AHR). Results: 1416 individuals initiated HAART. 5.52 have recorded HCV-Ab test results (39%), of whom 235 (43%) were HCV-Ab+. At time of censoring, 68 (12.3%) individuals died of non-accidental causes, including 40 (17%) of HCV+ individuals, and 28 (9%) HCV-. The product limit estimate (SE) of the cumulative mortality rate at 48 months for HCV+ individuals was 21.7% (0.03) and for HCV- 10.3% (0.02) (p=O.O02). Associated with mortality were baseline CD4 count 1.50 cells/mm3 (UOR 3.5;95%CI: 1.9?6.4), between 50 and 199 cells/mm3 (UOR 2.1;95%CI: 1.2?3.6), AIDS diagnosis (UOR 3.0;95%CI: 1.6?5.4), >75% adherent to HAART (UOR 0.49;95%CI: 0.29?0.85), being HCV-Ab+ (UOR2.1;95%CI: 1.3?3.6), having a higher log HIV RNA (5.3vs.5.1, p=O.OOS), and median age (40 vs.37 yrs, p
RE-TREATMENT
OF INTERFERON
(RBV) NONRESPONDERS ALFA-2A
(IFN) PLUS RIBAVIRIN
WITH PEGINTERFERON
(40KD) (PEGASYS)
(AMA) OR IFN ALFA-2A (ROFERON-A) INTERIM RESULTS
(PEG-IFN)
PLUS RBV AND AMANTADINE
OF A MULTICENTER
PLUS RBV AND AMA. RANDOMIZED
STUDY
S. Brillanti’, A. Mangia2, L. Cimino3, A. Civolani4, F. Fatuzzo’, L. Fenoglio6, M. Levrero7, G. Minoli’, M. Persico9, M.G. Rumi”. ‘Internal Medicine And Gastroenterology Department, University Of Bologna, Bologna, Italy; 2Gastroenterology Division, IRCCS Casa Sollievo Della Sofferenza, San Giovanni, Rotondo, Italy; ‘Epatogastroenterology Division, University ‘Fedetico II’, Napoli, Italy; 4Gastroenterology Department, University Of Cagliati, Cagliati, Italy; 51nfectious Diseases Division, Hospital ‘V.E. Ferrarotto S. Bambino’, Catania, Italy; 6General Medicine, Hospital ‘Le Molinette’, Torino, Italy; 71nternal Medicine Department, University ‘La Sapienza’, Roma, Italy; ‘Medicine/Endoscopy Department, Hospital Of Valduce, Coma, Italy; 9V Division Of General Medicine, II Policlinico, Napoli, Italy; “V Division Of General Medicine, Centro Migliavacca Policlinico, Milano, Italy A small randomized trial indicated AMA, plus IFN and RBV, was superior to IFN+RBV in re-treating IFN monotherapy nonresponders with chronic hepatitis C (CHC) (Brillanti et al. Hepatology 2000;) suggesting a synergistic effect in enhancing viral clearance. Aim: To determine the SVR rates of AMA plus PEG-IFN or IFN, in combination with RBV, in previous nonresponders to combination (IFN+RBV) therapy.
129
Methods: 240 CHC patients without any virological response to a previous cam-se of at least 12.week of IFN+RBV, and with persistently elevated ALT, have been randomized to receive 180 mcg once-weekly of PEG-IFN alfa-2a (40KD) (Pegasys) plus RBV (1000-1200 mg/daily) plus AMA (200 mgldaily) (group A) or 6 MIU every other day of IFN alfa-2a (Roferon-A) plus RBV (1000-1200 mgldaily) plus AMA (200 mgldaily) (group B) for 48 weeks, with a 24.week follow-up. Therapy was stopped in patients who were HCV-RNA positive at 24 weeks of treatment. Results: Patients baseline characteristics were similar in both groups (mean age 54 vs. 52 years; genotype 1: 80% vs. 78%). Virological response rates, in patients who were treated for at least 12 weeks, are reported in the table. To date, no severe or unexpected serious adverse events have been reported in either group with the addition of AMA. Conclusions: Interim results indicate a clinically significant response rate in this difficult to re-treat population. We expect to show the complete results, after 24 weeks of therapy, at the EASL annual meeting.
I 442
INTERFERON
ALPHA PLUS RIBAVIRIN
INTERFERON
ALPHA FOR CHRONIC
UPDATED, SYSTEMATIC
COCHRANE
VERSUS
HEPATITIS C-AN REVIEW
J. Brok, L.L. Kjaergard,
C. Gluud. Copenhagen Trial Unit, Copenhagen University Hospital, H: S Rigshospitalet, Copenhagen, Denmark
Aims: To asses the beneficial and harmful effects of ribavirin plus interferon alpha versus interferon alpha for interferon na ve, relapser, and non-responder patients with chronic hepatitis C. Methods: A systematic review of randomised trials comparing ribavirin plus interferon alpha versus interferon alpha. Electronic and manual searches were combined until September 2002. Results: A total of 66 trials randomised 8521 patients to interferon with or without ribavirin. Only five trials had high methodological quality. Compared with interferon, combination therapy significantly increased the risk of having a sustained virological response by 28% in naive patients (relative risk (RR) 0.72; 95% confidence interval (CI) 0.68.0.76), 32% in relapsers (RR 0.68; 95% CI 0.60.0.76), and 10% in non-responders (RR 0.90; 95% CI 0.85-0.95). Irrespective of previous therapy, combination therapy significantly increased the risk of having improved histology (RR 0.67; 95% CI 0.56-0.81). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.56; 95% CI 0.25-1.28). Combination therapy significantly increased the risk of treatment discontinuation (RR 1.25; 95% CI 1.08-1.46) and several types of adverse events. Conclusions: Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological and histological response, but also the occurrence of several adverse events. Combination therapy had no significant effect on morbidity plus mortality. However, no trials followed the patients long enough to assess the effect on long-term liver-related morbidity and mortality.
I 443
PHARMACOKINETICS PEGASYS)
OF PEGINTERFERON
COMPARED
(12KD, PEGINTRON)
TO PEGINTERFERON
ALFA-2A
(40KD,
ALFA-2B
IN NAIVE PATIENTS WITH CHRONIC
HEPATITIS C (CHC)
R. Bnmo, l? Sacchi, V. Ciappina, E. Maffezzini, S.F.A. Patruno, C. Zocchetti, G. Filice. Infectious And Tropical Diseases, IRCCS San Matte0 Hospital University Of Pavia, Pavia, Italy Background: The currently available pegylated interferon (PEG-IFN) formulations, PEG-IFN ALFA-2A (4OKD, PEGASYS) and PEG-IFN ALFA2B (12KD, PEG-In&-on), have different pharmacokinetic profiles. Aim: Objective of this randomized trial is to compare the pharmacokinetics of the two PEG-IFNs in patients with CHC. Patients & Methods: 30 treatment naive patients with CHC and persistently elevated ALT levels have been randomized to receive 180 mcg PEGASYS once-weekly (n=16) or 1.0 mcg/kg once-weekly of PEG-Intron
130
Poster Sessions
(n=14). Serum concentrations of both PEG-IFNs were measured at baseline and 24,48, 120 and 168 hours after administration using a quantitative sandwich ELISA (lower limit of detection 12.5 pglml). Results: Serum concentration of PEG-Intron achieved maximum levels at 24 hours after injection and decreased rapidly until 120 hours. Drug was undetectable 120 and 168 hours after injection in 7 (50%) and 11 (78%) subjects, respectively. In contrast, PEGASYS concentrations increased continuously overtime, reaching maximum levels from 48 to 168 hours. Conclusions: Our data demonstrate substantial differences in plasma concentration profiles between PEGASYS and PEG-Intron. Five days after injection concentrations of PEG-Intron are marginal or undetectable, while those of PEGASYS remain stable overtime. These findings suggest that PEG-In&-on administration should be intensified to twice weekly to avoid “blips” in viral replication. Differences in pharmacokinetics could explain the differences observed in HCV decay.
I 444
FACTORS RELATED TO POST-TREATMENT CHRONIC
RELAPSE
IN
HEPATITIS B PATIENTS WHO LOST HBEAG AFTER
LAMIVUDINE
THERAPY
K.S. Bvun’, J.E. Yeon’, C.H. Lee’, O.S. Kwon2, J.H. Kim2. ‘Korea University College Of Medicine, Internal Medicine, Seoul, South Korea; 2Gachon University College Of Medicine, Inchon, South Korea Background: It is uncertain that HBeAg loss after lamivudine therapy is durable. In Korean patients, the relapse rate is high after discontinuation of lamivudine therapy. Prolonged additional lamivudine therapy after HBeAg loss may be a proposal to reduce relapse rate. Aims: We evaluated the factors and the patterns of relapse after lamivudine therapy. Patients and Methods: 541 Korean chronic hepatitis B (CHB) patients with HBeAg positive were treated with lamivudine. Post-treatment monitoring continued. Results: HBeAg loss occurred in 212 patients and lamivudine therapy was discontinued in 1.53 patients. Total 132 patients eligible to study were followed up after cessation of lamivudine therapy. 75 patients were relapsed (HBV DNA+ve and/or raised ALTs, cumulative relapse rate: 56% at 6 months). Relapse were occurred within 6 months in 68 of 75 patients. Sustained response, which had not relapsed over 6 months after discontinuing lamivudine therapy, was seen in only 32 patients. In multivariate analysis, the older age, higher total bilirubin, and shorter duration of additional lamivudine therapy were significant factors for relapse. Almost all patients with relapse had elevated ALT and reemergence of HBV DNA. HBeAg reappeared in 55 patients and twenty were HBeAg-ve relapse. There were 5 cases of breakthrough after HBeAg loss. Conclusions: To reduce relapse after lamivudine therapy in CHB, age and serum bilirubin level of patients as well as duration of additional lamivudine therapy should be considered.
I 445
PRESENCE
OF MULTIPLE
RESPONSE
TO INTERFERON
HCV GENOTYPES
AND
THERAPY
N. Bzowei , Y. Phung, L. Brooks, M. Bonacini,
A. Wakil, R. Gish. Department Of Liver Transplantation, California Pacijc Medical Centec San Francisco, CA, USA
Hypothesis: Presence of multiple genotypes is associated with nonresponse to interferon. Methods: 4 sustained responders (SR), 4 relapsers (R) and 4 nonresponders (NR) were selected. Baseline, end of treatment and follow up serum samples were analyzed. Primers specific for 6 genotypes & 9 subtypes were used to amplify the core region. Extended PCR (45 cycles) was used. Genotypes were identified by comparison of visible bands on gels with known standards. Negative controls were performed. Results: At baseline, patients with 1 or 2 genotypes by commercial assay were found to have between 2 and 4 genotypes. Results for SR and R are
shown below. NR demonstrated therapy and at follow up.
persistence
of multiple genotypes
during
Patient
Commercial
BaSeline
BaSeline
End of Treatment
Group
Genotype
Genotype
Genotype
Genotype
Follow
Genotype
Up
(30 cycles
(45 cycles
(45 cycles
(45 cycles
PCR)
PCR)
PCR)
PCR)
la,2a
la
la
SR 1
2
la,2a
SR2
la
la
la,lb,2a,3a
la
NA
SR3
la
PCR negative
lq2a,2b,3a
la
la
SR4
NA
3a
la,2a,3a
la
la
Rl
la
la,2a
la,2a,3b
la
la,2a
R2
la
la,3b
la
la,2a,2b,3b
R3
la
la,lb,2a
la,2a,2b
la
la,2b
R4
la, lb
la,lb,2a
la,lb,2a
la
lq2a,2b
la
* NA= Not available.
Summary: 1) Multiple genotypes is common; 2) Patients with multiple genotypes at baseline had detectable viremia at follow up; 3) Genotype la appeared to be more resistant to therapy; 4) In some, IFN therapy resulted in detection of additional genotypes not observed at baseline. Conclusions: 1) SR determined by commercial assays may represent sustained suppression of virus rather than clearance. This may explain the development of late relapse; 2) Host responses to virus and presence of multiple HCV genotypes may represent important factors associated with nonresponse. Further study is required to determine if lower viral clearance is attributable to genotype la.
I
446
HEPATITIS B VIRUS GENOTYPES OF CHRONIC
AND THE PROGRESSION
LIVER DISEASE
F! Cacoub’,
M. Bourliere2, D. Saadoun’, H. Khiri3, A. Martineau3, V. Thibault’, M. Rotilly4, l? Halfon3. ‘Internal Medicine Department La Pitie Salpettiere Hospital, Paris, France; 2Hepatogastroenterology Department Saint Joseph Hospital, Marseille, France; ‘Virological Department, Alphabio Laboratory, Marseille, France; 4Clinsearch Laboratory, Paris, France Hepatitis B virus (HBV) can be classified into seven genotypes and a different geographical distribution can be demonstrated for these different genotypes. The aims of this study were to determine the HBV genotype distribution in France, and to correlate HBV genotypes and clinical outcomes. Patients and Methods: Using a polymerase chain reaction and reverse hybridization assay (LiPA, Innogenetics, Ghent), HBV genotypes were determined for 119 patients with an histologically proven HBV chronic hepatitis, including cirrhosis in 40. Results: Main characteristics were: 88 (74%) males, high alcohol intake in 5, age 46 & 16 yrs (m & SD), AST 2.6 & 3.3 N, ALT 11.5 & 18.3 N, GGT 1.6 & 1.4 N, Knodell total score 8.3 & 4.1. The HBV genotype distribution was as follows: A, 48 (40.3%); B, 9 (7.6%); C, 15 (12.6%); D, 50 (42%); E, 15 (12.6%); F, 6 (5%); G, 9 (7.6%), mixed 26 (15%) and unclassified, 4 (4%). A precore mutation was present in 81 (75.7%) patients. The prevalence of HBeAg positive was greater for genotype C carriers (60% vs 26%, p=O.O08), but lower for genotype D carriers (6.3% vs 48.5%, p=O.OOOl), and precore mutant (23% vs 56%, p=O.O07). The prevalence of HbeAb positive was lower for genotype C carriers (43% vs 74%, p=O.O2), but greater for genotype D (93% vs 53%, p=O.OOOl), and precore mutant (77% vs 42%, p=O.OOS). Patients with severe chronic hepatitis, i.e. F3-F4 Knodell fibrosis score, had more frequently a genotype D (p=O.O2), and a precore mutant (p=O.O3). Precore mutant was associated with severe portal necrosis (15% vs 0%, p=O.O5), severe portal inflammation (69% vs 40%, p=O.O5), and F3-F4 Knodell fibrosis score (50% vs 30%, p=O.O3). Conclusion: These results suggest that, in patients with chronic HBV infection, genotype D and precore mutant are strongly associated with the more severe cases of liver disease.