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Digestive Diseases Week, May 19-21, 2002
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Date Posted: Mon, May 20 2002, 8:38:43 PDT
Sunday, May 19, 2:45-3:00 PM
Prediction of Early Virologic Response to Treatment with 40KD Pegylated (PEG)-Interferon (IFN) Alfa2a/Ribavirin in Patients with Chronic Hepatitis C (Genotype 1)
Peter Ferenci, Wolfgang Jessner, Franz Hackl, Michael Gschwantler, Harald Brunner, Brigitte Hellmich, Hermann Laferl, Rudolf Stauber, Rainer Hubmann, Christian Datz, Wien, Austria; Linz, Austria; Graz, Austria; Salzburg, Austria
Objective: Response to antiviral therapy in chronic hepatitis C can be measured at various time points. The 24h response to a single IFN dose (24hVR) identifies IFN resistance to standard IFN/ribavirin therapy (a decrease in viral load of <0.8 log predicted nonresponse with 100 percent specificity; Jessner et al, Lancet 2001). Early virologic response (EVR) after 12 weeks has a high predictive value to achieve a sustained response to 48 weeks of 40kD-PEG-IFNalfa2a/ribavirin therapy (Ferenci et al, AASLD 2001). Methods: In an ongoing prospective trial which compares amantadine and placebo in addition to treatment with 180 μg 40KDPEG-IFNalfa2a (Roche, Basel, CH)/week + 1-1.2g ribavirin/d in chronic hepatitis C (genotype 1) patients are stratified according to the 24hVR at randomization. All patients had a liver biopsy and none had received an antiviral therapy before signing an informed consent. Currently 77 of the planned 220 patients were recruited, and 33 completed 12 weeks of treatment. In these patients the 24hVR was compared with the 12 week EVR (defined as HCV-RNA neg). Analysis was done without knowing to which treatment group a patient was assigned. The 24hVR was performed 2 weeks prior randomization and was calculated from the decrease in viral load 24 hours following a single dose of 9 MU IFNalfa2a (Roferon®, Roche, Basel, CH). Viral load was determined by the Cobas Amplicor Monitor HCV Test®, v2.0 (Roche Diagnostic Systems, USA). Results: Of the 33 patients 21 (63.4%) became HCV-RNA negative by week 12. The 24hVR in EVR was 1.19 (log decline) +0.43 (SD) and 0.55+0.36 in nonresponders (p=0.00014). The magnitude of the 24hVR correlated with the 12 week EVR: 7/7(100%), 10/13 (77%), and 4/13 (30.7%) pts. with an 24hVR of >1.5, 0.8-1.49, or <0.8 log decline, respectively, were responders (p=0.004).
Conclusion: The 24hVR is a good predictor of the 12 week EVR in patients on 40KDPEG-IFNalfa2a/ribavirin therapy. Patients with predicted poor response to standard-IFN/ribavirin therapy may still achieve a virologic response on PEG-IFNalfa2a/ribavirin therapy. Thus, PEG-IFNalfa2a may overcome IFN-resistance in HCV-genotype 1 patients. Prediction of response to antiviral therapy may help to optimize treatment.
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Sunday, May 19, 3:30-3:45 PM
Pegylated (40 kDa, Branched) Interferon Alfa-2a (PEG-IFN) and Ribavirin (RIBA) in IFN-naive Patients with Hepatitis C and Advanced Fibrosis/Cirrhosis: Interim Results of a Randomized, Controlled Trial
Beat Helbling, Ivan Stamenic, Andreas Cerny, Jan Borovicka, Jean-Jacques Gonvers, Beat Muellhaupt, Eberhard L. Renner, Swiss Association For The Study Of The Liver, Zürich, Switzerland; Lugano, Switzerland; St Gallen, Switzerland; Lausanne, Switzerland
PEG-IFN alone (180ug sc weekly for 48 wks) lead to sustained HCV-clearance in 26/87 (30%) patients (pts) with chronic hepatitis C and advanced fibrosis/cirrhosis (Heathcote et al. NEJM 343: 1673, 2000). Only few pts with advanced fibrosis/cirrhosis were included in recent trials on pegylated interferons plus RIBA (Manns et al. Lancet 358: 958, 2001; Fried et al. Gastro 120 (suppl 1): A55, 2001). Thus, despite the high medical need for therapy, little is known on efficacy and tolerability of PEG-IFN and RIBA in pts with advanced HCV-associated fibrosis/cirrhosis. AIM: To compare efficacy and tolerability of PEG-IFN (180ug sc weekly) and RIBA (1000/1200 mg vs. 600/800 mg po QD) in treatment-naive pts with HCV-associated advanced fibrosis/cirrhosis. DESIGN/PATIENTS: Open-label, randomized, controlled, trial in 11 Swiss centers. Inclusion criteria: naive pts (both genders, 18-70 yrs old) with HCV-associated biopsy-proven (£12 months) advanced fibrosis/cirrhosis (Metavir F3-F4) and <8 Child-Pugh points, elevated ALT and pos. HCV-RNA in serum (Amplicor® HCV MonitorTM). Randomization (1:1) stratified according to genotype (2/3 vs. other; Inno-Lipa®) to PEG-IFN (180ug sc once weekly) and either RIBA (£75kg: 1000mg, >75kg: 1200mg po QD) or (£75kg: 600mg, >75kg: 800mg po QD) for 48 wks with 24 wks of follow-up. Primary endpoint: sustained virologic response, secondary endpoints: initial (24 wks of treatment) and end-of-treatment virologic responses, tolerability. RESULTS: So far, 88 pts enrolled (40 (45%) females; 30 (45%) genotype 2/3, 40 (45%) genotype 1). 43 pts randomized to higher, 45 pts to lower RIBA dose. Interim analysis at 24 wks of treatment: HCV-RNA in serum negative (<1000 cps/ml) after 2, 4, 8, 12 and 24 wks of treatment in 24/71 (34%), 36/65 (55%), 43/63 (68%), 37/53 (70%) and 25/28 (89%) pts, respectively, with no difference between treatment arms. Treatment prematurely terminated in 5 (6%) pts for AEs, of which two were severe (attempted suicide, incidental PEG-IFN over-dose); dose reduction was necessary in 38 (43%) pts with no difference between treatment arms.
CONCLUSION: 24 wks of PEG-IFN+RIBA negativates HCV-RNA in serum in almost 90% of pts with advanced HCV-associated fibrosis/cirrhosis and is acceptably tolerated. In which proportion this high initial response rate translates into sustained HCV clearance remains to be seen. Supported by Roche Pharma (Schweiz) AG, Switzerland
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Monday, May 20, 8:00 AM-5:00 PM
Clinical and Virological Features of Chronic Hepatitis C Patients with Normal ALT Levels
Stefan Zeuzem, Robert Reindollar, Rajender K. Reddy, Moises Diago-Madrid, Paul Pockros, Mitchell Schiffman, Francois Lamour, Karen Rittweger, Pilar Lardelli, Frankfurt am Main, Germany; Charlotte, NC; Philadelphia, PA; Valencia, Spain; La Jolla, CA; Richmond, VA; Basel, Switzerland; Nutley, NJ
A large proportion of patients with chronic hepatitis C (CHC) have persistently normal alanine aminotransferase (ALT) but the clinical and virological features and natural history of these patients are not well defined. Objectives: To characterize the natural history of normal ALT CHC patients and the evolution of the disease regarding viremia and ALT. Methods: A multicenter study evaluating efficacy and safety of treatment with 40 kDa pegylated interferon alfa-2a and ribavirin in normal ALT CHC patients is ongoing. Patients in the control group will be observed untreated for 72 weeks. CHC infection must be documented by both positive anti-HCV antibody and HCV RNA PCR tests at least 6 months prior to the study. Persistently normal ALT was defined by at least 3 determinations equal or below the ULN, minimum 4 weeks apart, with one value within screening period and another between 6 and 18 months before onset. Liver disease consistent with CHC was confirmed by biopsy within 36 months before trial. Results: At the time of this interim analysis 73 patients were randomized to the control group; 4 withdrew at baseline and 36 have been followed for 24 weeks or more. Demographic features: mean age 41.8 years, male to female ratio 28:45, mean weight 71 Kg. Mode of infection i.v. drug use 34%, transfusion 20%, other 14%, unknown 32%. 65.8% of patients had genotype 1. Histological activity (Ishak score): 2 or less for necroinflammatory changes in 86% of the patients, fibrosis score 3 or less in 90%. Baseline mean and median viral load were 1286512 and 789500 IU/mL, respectively, and remained stable. Of 36 patients followed for 24 weeks, ALT stayed within normal limits in 53%. Of 69 subjects, sporadic ALT elevations of <2x ULN occurred in 33%. One patient had an isolated 12x ULN ALT flare accompanied by a moderate AST increase. No significant hematological or biochemical changes were observed. 8 patients presented CHC-related symptoms at onset. Mild adverse events were reported in 14 subjects.
Conclusions: Normal ALT population has distinct biological and virological features. According to previous data from studies on abnormal ALT CHC patients, there are no differences in age, weight and infection source; however, the male to female ratio is inverted in the normal ALT population. Genotype distribution is similar, while baseline viremia appears to be lower in normal ALT patients. Liver disease is also milder. During follow-up, viremia was stable and ALT values stayed within normal or near normal range. The majority of the patients remained asymptomatic.
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Monday, May 20, 8:00 AM-5:00 PM
Pegylated (Pegasys) or Recombinant Interferon Alfa 2a 3 MU TIW in Combination with Ribavirin and Amantadine versus Standard Therapy in Naive Patients with Chronic HCV: A Randomised Controlled Trial
Alessandra Mangia, Giovanni L. Ricci, Nicola Minerva, Marcello Persico, Vito Carretta, Donato Bacca, Franco Vinelli, Vincenzo Guadagnino, A. Andriulli, San Giovanni Rotondo, Italy; Rome, Italy; Canosa, Italy; Napoli, Italy; Venosa, Italy; Casarano, Italy; Foggia, Italy; Catanzaro, Italy
Background: We have previously shown that the addition of amantadine(AMA) to recombinant IFN a2a was able to increases the efficacy of IFN monotx in pts with Chronic Hepatitis C (CHC). No data are available on naïve pts to document whether triple therapy of AMA +Ribavirin (RBV) and pegylated IFN (group A) or recombinant IFN a2a (Group B) improves the success rate over dual therapy with recombinant IFN + RBV. Methods: 354 naïve pts with serologically and biopsy-proven CHC, persistently elevated ALT and positive HCV RNA randomized to a 3- arm. Multicentre trial, as follows: Group A: PEG IFN a2a 180 mg sc qw sc + RBV 1-1,2 g/qd + Ama 200 mg/qd Group B: IFN a2a 3MU TIW sc +RBV1-1,2 g/qd + Ama 200 mg/qd Group C: IFN a2a 3MU TIW sc +RBV1-1,2 g/qd Results: Of 267 (75%) so far enrolled pts 55.5% were male; mean age was 51 yrs (range 20-65); genotype 1 was found in 57.6% of cases. Severe fibrosis or cirrhosis were found in 23.2%. The treatments were well tolerated; no major safety concerns were noted at the moment. One hundred and thirty pts have completed 3 month of Tx: at this time the percentage of pts with normal ALT were 51% in group A, 54% in group B and 51% in group C, HCV RNA was negative in 54%, 42% and 42% , respectively. This study is ongoing at the moment and more data are needed to prove or disprove the value of triple therapy over the current standard.
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Tuesday, May 21, 2:45-3:00 PM
Peginterferon Alpha-2a Alone or in Combination with Ribavirin Enhances Restoration of the HCV Specific T Cell Responses in Patients with Chronic Hepatitis C
Sanaa M. Kamal, Jutta E. Fehr, Bernd Roesler, Thomas Peters, Jens Rasenack, Freiburg, Germany
BACKGROUND/AIMS: Pegylated interferons without or with ribavirin were shown in phase III studies to improve sustained virological response compared to standard interferon alpha-2a therapy. This study investigated if the greater efficacy of pegylated interferons might be related to modulation of immunological responses. PATIENTS & METHODS: HCV-specific CD4+ T-cell responses, cytotoxic CD8+ T cell response and cytokine production to various HCV proteins (ELISPOT assay) in peripheral blood mononuclear cells were prospectively assessed in 42 patients receiving IFN alpha-2a monotherapy, peginterferon alpha-2a monotherapy or peginterferon alpha-2a plus ribavirin and correlated to the outcome of therapy. RESULTS: The sustained virological response rate was significantly higher in the peginterferon groups (42% in peginterferon alpha-2a monotherapy, 57% in peginterferon alpha-2a/ribavirin combination) than in the standard IFN alpha-2a group (14%). Patients with HCV genotype 1 infection benefited most from peginterferon alpha-2a/ribavirin combination therapy (SVR 48%). Pre-treatment HCV specific CD4+ responses and CD8+ cytotoxic responses were either absent or weak in all patients. Peginterferon alone or combined with ribavirin induced significant increase in the frequency, strength and breadth of HCV-specific CD4+ T-helper 1 responses; while interferon alpha-2a monotherapy was associated with lower, fluctuating, short lived responses. Sustained responders developed strong multi-specific maintained HCV specific CD4+ T cell responses with enhanced IFN-gamma production and IL-10 suppression. Relapsers and partial responders initially displayed significant HCV specific CD4+ T cell responses, which waned or were lost. CTL responses were more common in sustained responders compared to non-responders.
CONCLUSION: the results indicate that the efficacy of peginterferon alpha-2a alone or in combination with ribavirin in inducing high rates of sustained virological response may be to restoration and maintenance of significant multi-specific HCV-specific CD4+T helper 1 and CTL responses.
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