38th Annual Meeting of the European Association for the Study of the Liver
 
Istanbul, Turkey. March 28-April 1, 2003

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Page Four

	EFFICACY OF PEGINTERFERON ALFA-2A (40KD) (PEGASYS) PLUS RIBAVIRIN FOR 24 WEEKS IN GENOTYPE 1 PATIENTS WITH CHRONIC HEPATITIS C FOLLOWED BY MONO OR COMBINATION THERAPY FOR 22 WEEKS: PRELIMINARY ANALYSIS OF AN OPEN, MULTICENTER, RANDOMIZED TRIAL         J.P. Bronowicki*,1 D. Ouzan,2 T. Asselah,3 H. Desmorat,4 J.P. Zarski,5 J. Foucher,6 M. Bourliere,7 C. Renou,8 A. Tran,8 P. Melin,9 C. Hezode,10 M. Chevallier,11 M. Bouvier,10 J.M. Pawlotsky,10 I. Lonjon-Domanec,12 *Presenting Author 1Hosp Brabois, Nancy, 2Arnaud Tzanck Institute, St Laurent Du Var, 3Hosp Beaujon, Clichy, 4Clin Du Parc, Toulouse, 5Univ Hosp, Grenoble, 6Hosp Haut Leveque, Pessac, 7Hosp Saint Joseph, Marseille, 8Hosp Acad 2, Nice, 9Hosp Saint, Dizier, 10Hosp Henri Mondor, Creteil, 11Lab Meyrieux 12Roche, Neuilly France   Recent clinical studies have shown that patients infected with HCV genotype 1 derive significant benefit from combination therapy with Peginterferon plus ribavirin (RBV) given for 48 weeks. However, ribavirin may have severe side effects, that may lead to discontinuation.   Objective: The objective of this study was to determine if shorter RBV administration could improve tolerance without altering efficacy in patients infected with HCV genotype 1 who respond to combined therapy.   Methods: 524 naive patients with HCV genotype 1 chronic infection were included. They received Peginterferon alfa 2-a (40KD) 180µg/week plus RBV (800mg/day) for 24 weeks. The virologic responders at week 24 were randomized at week 26 into: Group A Peginterferon alfa 2-a (40KD) plus ribavirin, or group B, Peginterferon alfa 2-a (40KD) alone for 22 additional weeks. Qualitative HCV-RNA detection was performed at weeks 30, 36, 42, 48, 52, 60 and 72 in each group.   Results of preliminary analysis: At week 24, 366 patients were negative by PCR which corresponds to a virologic response rate of 70%. Only age (<44vs>44 years), fibrosis (F1-2 vs F3-4) and male gender were independently predictive of response at week 24. At week 26, 360 patients were randomized. Currently, 234 patients have reached to week 48 and were tested for HCV RNA: 2.7% patients (3/ 111) relapsed during therapy in group A vs 11.4% (14/123) in group B.   Conclusions: the results of this preliminary analysis reveal a trend toward a higher rate of virological breakthrough in the peginterferon alfa 2-a monotherapy arm after week 24.
	Entecavir for HBV in Lamivudine Failures         SUSTAINED VIRAL LOAD AND ALT REDUCTION FOLLOWING 48 WEEKS OF ENTECAVIR TREATMENT IN HBEAG-NEGATIVE AND -POSITIVE PATIENTS WITH CHRONIC HEPATITIS B WHO HAVE FAILED PRIOR LAMIVUDINE THERAPY   R. Gish*, 1 T.T. Chang, 2 S. Hadziyannis, 3 J. Cianciara, 4 M. Rizzetto, 5 E. Schiff, 6 G. Pastore, 7 K. Klesczewski, 8 G. Densiky, 8 J. Zhu, 8 D. DeHertogh, 8 R. Hindes, 8 *Presenting Author 1California Pacific Medical Center, San Francisco, CA, USA 2National Cheng Kung Univ Hosp, Tainan, Taiwan 3Henry Dunant Hosp, Athens, Greece 4Instytutu Chorob Zakaznych Akademii Medycznej, Warsaw, Poland 5Ospedale Molinette, Torino, Italy 6Univ Of Miami, Miami, FL, USA 7Univ Di Bari, Bari, Italy 8Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA   Background: Entecavir (ETV) is a potent and selective antiviral in phase III clinical trials for chronic hepatitis B (CHB). CHB patients with HBeAg-negative disease generally experience good response to antivirals, but often relapse with treatment discontinuation. Aim: analyze impact of HBeAg status on response, as measured by HBVDNA reduction and ALT normalization.   Methods: 181 patients with serum HBVDNA > 10MEq/mL (Quantiplex assay) after at least 24 weeks of LVD therapy or YMDD mutation and serum ALT <10x ULN were randomized to ETV 0.1, 0.5, or 1.0 mg, or LVD 100 mg daily for up to 52 weeks.   Results: Treatment groups were comparable for baseline demographics, HBeAg status (67% positive), mean HBVDNA (8.1 log10 copies/ml PCR), and median ALT (71 u/L). Mean decrease from baseline in HBVDNA for all ETV doses was superior to LVD at 48 weeks. For HBeAg-negative patients in the ETV 0.1, 0.5, and 1.0 mg groups, mean log10 HBVDNA reductions were 2.9, 4.0 and 5.6, respectively, versus 0.7 for LVD; whereas ALT normalization occurred in 5/10, 10/12, and 9/10 ETV patients, respectively, versus 0/13 LVD. For HBeAg-positive patients, mean log10 HBVDNA reductions were 2.8, 4.6 and 4.7 respectively, versus 1.8 for LVD; whereas ALT normalization occurred in 6/11, 7/12, and 9/15 ETV patients, respectively, versus 2/10 LVD. Preliminary analysis demonstrates durable virologic suppression and ALT normalization through 6 months off treatment follow-up in a substantial proportion of ETV patients.   Conclusion: In patients previously failing LVD therapy, HBVDNA reduction and ALT normalization after 48 weeks of ETV therapy were comparable in HBeAg-positive and negative patients. HBeAg-negative patients who responded to ETV treatment frequently demonstrated a durable post-treatment response.
	EFFICIENCY OF DNA VACCINE IN ASSOCIATION WITH LAMIVUDINE FOR CHRONIC HEPATITIS B THERAPY         A. Thermet*, 1 J. Rhodes, 2 C. Trepo, 1 F. Zoulim, 1 L. Cova, 1 *Presenting Author 1INSERM Unit271, Lyon, France 2GlaxoSmithKline, Stevenage, UK   Combination of antiviral drugs with immunotherapeutic approaches may be a promising new strategy for treatment of chronic hepatitis B. We have used the duck HBV (DHBV) infection model and explored whether combination therapy associating a lamivudine treatment with DNA-immunization to viral structural proteins may lead to the complete viral clearance.   Pekin ducklings chronic DHBV-carriers received intraperitoneal lamivudine treatment alone or followed by DNA-immunization. The DNA-immunization consisted in intramuscular injections of either a plasmid encoding viral large envelope and/or a plasmid encoding core protein. The viremia and anti-preS humoral response evolution were followed during 9 months.   During the lamivudine administration period, a decrease by 70% in mean viremia titers was observed in the drug-treated as compared with the untreated duck groups, which was followed by persistence of viral replication. DHBV DNA analysis of autopsy liver samples showed no viral DNA clearance within the lamivudine only treated duck group. Importantly, 7/30 (23%) of animals that received specific DNA-based therapy, in association or not with lamivudine, have completely cleared intrahepatic DHBV DNA including the cccDNA form. Combination therapy associating lamivudine and DNA vaccine to envelope protein appeared as more effective since 38% of ducks have undetectable viral DNA in their livers as assessed by real time PCR. Our results demonstrate that DNA-immunization to hepadnaviral structural proteins is able to induce a complete virus clearance in chronic virus carriers. Combination therapy associating lamivudine and DNA-based vaccine to envelope protein appears as a promising new approach for chronic hepatitis B therapy.
	THE EFFECT OF PEGINTERFERON ALFA-2A (40 KD) ON LIVER HISTOLOGY IN CHRONIC HEPATITIS C: A META-ANALYSIS OF INDIVIDUAL PATIENTS DATA         C. Camma*, 1, 2 D. Di Bona, 1 F. Schepis, 3 E.J. Heathcote, 4 S. Zeuzem, 5 P.J. Pockros, 6 P. Marcellin, 7 A. Alberti, 8 A. Craxi, 1 *Presenting Author 1Cattedra Di Gastroenterologia, Istituto Di Clinica Medica, University Of Palermo, Palermo, 2IBIM, Consiglio Nazionale Delle Ricerche, Palermo, 3Dipartimento Di Medicina Sperimentale E Clinica, University Of Magna Graecia, Catanzaro, Italy 4Department Of Medicine, University Health Network, Toronto Western Hospital, Toronto, Canada 5Klinikum Der Johann Wolfgang Goethe University, Frankfurt, Germany 6Scripps Clinic, La Jolla, CA, USA 7INSERM U481, Service D'Hepatologie Hospital Beaujon, Clichy, France 8Dipartimento Di Medicina Clinica E Sperimentale, University Of Padova, Padova, Italy   The benefit of peginterferon alfa-2a (40KD) on liver histology has been extensively studied however, the results are still equivocal. Methods: We performed a MIPD on 1013 naive patients with pre- and post-treatment biopsies from 3 RCTs in order to assess the differences between peginterferon alfa-2a (40KD) and interferon alfa-2a in liver histology, to determine if the histological benefit of peginterferon alfa-2a is related to virological response and to identify predictors of histological improvement. We used a random-effects model to quantify the average effects of peginterferon alfa-2a (40KD) on liver histology and identify predictors of fibrosis improvement by logistic regression.   Results: Peginterferon alfa-2a (40KD) compared to interferon alfa-2a significantly reduced fibrosis (net change -0.14; 95% confidence interval [CI] from -0.27 to -0.01, p: 0.04). An impressive reduction in fibrosis after treatment was observed in sustained virological responders (SVR) (-0.59; 95% CI from -0.89 to -0.30;P<0.0001) and in relapsers (-0.34; 95% CI from -0.54 to -0.14;P: 00007), whereas no significant reduction was observed in nonresponders (-0.13; 95% CI from -0.32 to +0.05;P: 0.15). By logistic regression, fibrosis improvement was predicted independently by SVR (odds ratio 1.52, 95% CI from 1.26 to 1.83) and by baseline body mass index (odds ratio 1.34, 95% CI from 1.26 to 1.83). Regression of fibrosis was never observed.   Conclusions: In patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa-2a (40KD) significantly improved fibrosis compared with interferon alfa-2a. The benefit of peginterferon on liver histology is closely related to virological response.
	Clevudine, New Drug for HBV         A PHASE I/II DOSE ESCALATING TRIAL EVALUATING SAFETY, TOLERABILITY, PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF CLEVUDINE IN PATIENTS CHRONICALLY INFECTED WITH HBV   P. Marcellin, 1 G.K.K. Lau*, 2 H. Mommeja-Marin, 3 S. Sacks, 4 D. Sereni, 5 J.P. Bronowicki, 6 B. Conway, 7 C. Trepo, 8 E. Mondou, 3 A. Snow, 3 B.C. Yoo, 9 H.S. Lee, 10 F. Rousseau, 3 *Presenting Author 1Hosp Beaujon, Clichy, France 2Queen Mary Hosp, Univ of Hong Kong, SAR, China 3Triangle Pharmaceuticals, Inc, Durham, USA 4Viridae, Vancouver, BC, Canada 5Hosp Saint Louis, Paris, France 6Hosp Brabois, Nancy, France 7Univ of British Columbia, Vancouver, BC, Canada 8Hotel Dieu, Lyon, France 9Sam Sung Medical Center, Sang Kyun Kwan Univ, Sang Kyun Kwan, Korea 10Seoul National Univ Hosp, Seoul, Korea   Background: Clevudine (CLV, L-FMAU) is a potent inhibitor of HBV replication in vitro. In woodchucks, CLV caused a sustained viral suppression after completion of a 12 week dosing period.   Methods: Multicenter, open-label, dose escalation study evaluating 10, 50, 100 and 200 mg CLV QD for 28 days (n=5, 10, 10 and 7/group, respectively). Patients were followed post-treatment for 6 months. Eligible patients had baseline (BL) HBV DNA levels (VL) ≥ 3mEg/mL, were nucleoside treatment naïve and without HIV or HCV co-infection. VL was assayed using Digene Hybrid Capture II and genotype by di-deoxy sequencing.   Results: 32 patients were enrolled. At BL, median VLs were 7.3, 8.0, 8.8 and 8.4 log c/mL and median ALTs were 55, 119, 106 and 64 U/L in the 10, 50, 100 and 200mg QD cohorts, respectively. After 28 days of dosing, the median log VL change from BL was -2.5, -2.7, -3.0 and -2.6, in the 10, 50, 100 and 200mg groups, respectively. At 6 months post-dose sustained biochemical responses were observed and median log VL changes from BL were -1.2, -1.4, -2.7 and -1.6 in the 10, 50, 100 and 200mg arms, respectively. Seven patients (28%) lost HBeAg, 5 (19%) seroconverted to HBeAb. CLV was well tolerated, without limiting adverse events. No treatment emergent mutations in the HBV DNA polymerase domain were observed 5 months after treatment.   Conclusion: These results confirm in humans the antiviral activity and a unique post-treatment antiviral effect as predicted by the pre-clinical profile of clevudine.
	PHARMACOKINETICS OF PEGINTERFERON ALFA-2A (40KD, PEGASYS) COMPARED TO PEGINTERFERON ALFA-2B (12KD, PEGINTRON) IN NAIVE PATIENTS WITH CHRONIC HEPATITIS C (CHC)         R. Bruno*, P. Sacchi, V. Ciappina, E. Maffezzini, S.F.A. Patruno, C. Zocchetti, G. Filice, *Presenting Author Infectious And Tropical Diseases, IRCCS San Matteo Hospital - University Of Pavia, Pavia, Italy   Background: The currently available pegylated interferon (PEG-IFN) formulations, PEG-IFN ALFA-2A (40KD, PEGASYS) and PEG-IFN ALFA-2B (12KD, PEG-Intron), 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 (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 125 pg/ml).   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-Intron administration should be intensified to twice weekly to avoid "blips" in viral replication. Differences in pharmacokinetics could explain the differences observed in HCV decay.
	Study Suggests More Than 48 Weeks Therapy for Patients with high baseline viral loads, HCV genotype 1, and cirrhosis may be necessary         "PREDICTORS OF VIROLOGIC RELAPSE IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) TREATED WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS) ALONE OR IN COMBINATION WITH RIBAVIRIN (COPEGUS)"   Comments from Jules Levin: A previous study called I think the Benelux Study found that 18 months treatment may improve response rates for some patients. It's my understanding that a study examining 18 months therapy is ongoing. Some doctors are using 18 months therapy for hard to treat patients including patients with multiple characteristics for hard to treat patients including previous non-responders to interferon+ribavirin, cirrhotics, high HCV viral load, HCV/HIV coinfected. The study below suggests 18 months may be more effective than 12 months therapy but well designed safety and efficacy studies need to be conducted. The safety concerns of 18 months therapy need more characterization.   V. Balan*, 1 S. Zeuzem, 2 H. Sette, 3 M. Fried, 4 D. Jensen, 5 G. Pastore, 6 P. Marcellin, 7 F. Sedarati, 8 *Presenting Author 1Mayo Clinic, Phoenix, Scottsdale, USA 2Saarland University Hospital, Homburg, Germany 3Instituto De Infectologia, Sao Paolo, Brazil 4University Of North Carolina, Chapel Hill, North Carolina, USA 5Rush-Presbyterian St. Luke's Hospital, Chicago, Illinois, USA 6Clinic Of Infectious Diseases, University Of Bari, Bari, Italy 7Hopital Beaujon, Clichy, France 8Hoffman-La Roche Inc, Nutley, New Jersey, USA   Background: Some patients treated for CHC still relapse after an end-of-treatment (EOT) virologic response (VR), particularly patients infected with HCV genotype 1.   Objectives: To determine the frequency of relapse in patients treated with peginterferon alfa-2a (40KD) (Pegasys) ± ribavirin (Copegus) and to identify baseline parameters associated with viral relapse.   Methods: Chronic hepatitis C (CHC) patients (N=1375) received peginterferon alfa-2a (40KD) 180 mg/week ± ribavirin 800-1200 mg/day for 24 or 48 weeks. Sustained viral response was defined as undetectable HCV RNA at the end of follow-up; and relapse, as detectable HCV RNA following a documented end of treatment response.   Results: High baseline viral load, and, to a lesser degree, cirrhosis, were found to be associated with relapse, particularly in HCV genotype 1 patients.   Conclusion: Treatment with peginterferon alfa-2a (40KD) (Pegasys) /ribavirin (Copegus) results in lower relapse rates than monotherapy in all patients. CHC genotypes 2/3 patients experience lower relapse, regardless of ribavirin dose given, compared with HCV genotype 1 patients whose relapse is dependent on ribavirin dose and duration of treatment. More than 48 weeks treatment for CHC patients with high baseline viral loads, HCV genotype 1, and cirrhosis may be necessary and should be investigated.
	72 weeks HCV Therapy (PegIFN/RBV): is it effective?         "Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders: A report of 9 cases"   In a letter to the editor in the May issue of the journal Hepatology (May 203, Volume 37, Number 5), researchers from Spain and Israel treated 9 selected patients for 72 weeks and 7/8 achieved a sustained viral response (SVR). These patients achieved undetectable HCV RNA between 12 and 24 weeks on therapy. The authors concluded that further research should be conducted to see if longer duration therapy can improve response rates. The study is small but important. Findings from a previously conducted study (The Benelux Study) which was presented at the European hepatitis conference (EASL) suggested similarly that longer duration therapy of 18 months may improve response rates, particularly in hard to treat patient populations; such as previous non-responders and partial responders, people with HIV, and genotype 1. I believe a study is ongoing now to explore this question but further research is needed. This is an important concept that may improve response rates in difficult to treat cases. Personally, I was a previous non-responder to IFN/RBV, have HIV and had cirrhosis. I completed 18 months PegIFN/RBV in August 2002. Six months after stopping therapy my viral load was undetectable. Of course there is no way to determine if I would have achieved this success with 12 months therapy as well. But extending therapy may be crucial for some individuals. So further research needs to be conducted so medical care providers can have data upon which to base this decision.   To the editor:   The large number of chronic hepatitis C patients infected by genotype 1 constitutes an important therapeutic challenge because they are the most resistant to combination therapy with interferon alfa and ribavirin. In these patients, the sustained virologic response to peginterferon and ribavirin for 48 weeks is around 42%. It has been shown that one important factor of sustained virologic response (SVR) is rapid hepatitis C virus (HCV)-RNA clearance, ranging from 75% for those patients who cleared the virus at week 12 to only 32% for those who lost HCV RNA at week 24. It has been suggested that extending therapy in patients who cleared HCV RNA between weeks 12 and 24 (i.e., late responders) could increase SVR.   We selected 9 patients with chronic hepatitis C who were infected with genotype 1 in treatment with pegylated interferon alfa-2b plus ribavirin who cleared HCV RNA between weeks 12 and 24 for therapy prolonged to 72 weeks. Three were men and 6 were women, with a median age of 41 ± 14.57 years. All patients had elevated alanine aminotransferase levels, positive HCV RNA, and a liver examination showing chronic hepatitis. Patients were treated with a mean dose of 1.0 µg/kg of peginterferon alfa-2b once weekly (PEG-INTRON, Schering-Plough, Kenilworth, NJ), plus 800 mg/d of ribavirin (Rebetol, Schering-Plough). HCV RNA was analyzed by using a quantitative, real-time, reverse-transcriptase polymerase chain reaction technique with a lower limit of detection of 100 IU/L.4   Eight patients completed therapy and 6 months of follow-up. One patient stopped therapy at week 48 because of thyroid alterations. Table 1 shows patient characteristics and changes in HCV-RNA levels from baseline to week 12.   Table 1. Baseline characteristics of the 9 patients treated and HCV-RNA changes in logs from baseline to week 12 and HCV-RNA decline from baseline to week 12. All 9 patients had chronic hepatitis C, and 8 of the 9 had moderate stage histology. Patient 3 had mild chronic HCV stage disease. HCV-RNA logs are in IU/ml unit of measure. To give you some understanding of the log values: 5.97 HCV-RNA logs is about 1 million IU/ml; 6.61 HCV-RNA logs is about 4 million; 5.4 logs is about 250,000 IU/ml; 6.18 is 1.5 million. Under 2 million is consider a low viral load. In large studies patients with low viral load tend to respond better to therapy, but in this small study patients with high viral load responded as well as patients with lower viral load. Perhaps the extended duration of therapy helped.         RESULTS: In all patients, HCV RNA was positive at week 12 of therapy but undetectable at week 24 and throughout the 72 weeks of therapy. At week 24 of follow-up, 7 patients maintained an SVR and one relapsed (case 3).   This study, with a small number of patients, showed that prolonged combination therapy with peginterferon and ribavirin is very useful in late virologic responders because it increases SVR. HCV-RNA determination has an important role not only in the decision to stop therapy but also in better adjusting therapy. Currently, nonresponders can be detected by a quantitative HCV-RNA test at week 12, showing a decline of less than 2 logs in HCV-RNA concentrations. In these patients, combination therapy should be stopped because the probabilities of a sustained response are almost nil. In patients who achieve an early virologic response, the probabilities of achieving an SVR were 80% for those who cleared HCV RNA at week 12 and sooner, and 40% for those who achieved a 2-log reduction in HCV-RNA concentrations but still remained HCV-RNA positive as a recent review of multicenter studies has shown.5 All of our patients had a 2-log decline but remained HCV-RNA positive at week 12 and, taking into account the previous results, their probabilities of achieving an SVR are lower than those patients who were HCV-RNA negative at week 12. In this subgroup of patients, with a slower decline in HCV-RNA levels, usually genotype 1 patients with high baseline viral levels, continuing therapy to 72 weeks could be the best way to ensure an SVR with acceptable tolerability and safety.   In summary, extending therapy with peginterferon alfa plus ribavirin to 72 weeks for late virologic responders may induce a higher SVR. These results merit further prospective, randomized, controlled studies, using the optimal doses of peginterferon and ribavirin for longer duration versus the current standard 48-week therapy in this subset of patients.   Maria Buti, M.D. Auristela Valdes Francisco Sanchez-Avila Rafael Esteban, M.D. Liver Unit, Hospital General Universitari Vall d'Hebron, Barcelona, Spain   Yoav Lurie, M.D. Liver Clinic, Gastroenterology Institute, Kaplan, Israel   http://www.natap.org/