- Email: [email protected]
Beneficial effects of antiviral therapy in advanced chronic liver disease due to HCV infection: A pilot study
T1208
required in 22% of pts most commonly due to leukopenia and anemia Penn,anent discontinuation of therapy was required in 8% most often due to: depression or anxiety Serious adverse events: (1.8% of 439 pts) Included one patient each with neutropenia/MRSA sepsis, optic neuritis with monocular blindness, perirectal abg:'ess, cellulitis and multi-organ failure, cutaneous and puhrmnary sarcoidosis, pneumonia, homicidal ideation, and suicide. Conclusions: 1) Overall ETR was 46% and SVR was 33%. 2) SVR was significantly higher in genotype non-1 patients and (nose Who failed previous monotherapy 3) 15% ot G1 I~on responders to Rebetrmr achieved an SVR (16% Caucasian, 12% Black) 4) It is hoped that a weight based dose of Ribavirin "~qll be associated with lower relapse rates and improved sustained response rates particularly in G1 pts.
Non-lnvasive Assessment of Fibrosis Resolution/Progression in Chronic Hepatitis C Patients Who Received Anti-Viral Therapy Yasushi Shiraton, Haruki Yamada, Yusei lkeda, Masayuki Matsumura, Naoaki Hashimoto, Ryo Nakata, Masao Oraata Liver fihros~s is a dynamic process, '4th phases of either net matrk,: deposition or net degradation leading, respectively, to progression or regression of fibrosis. Recently, there are several ~*'ports indicating that fibrosis of the liver regressed in patients with sustained virological response Fibrosis progression was also retarded in patients who received IFN therapy (Shiratori Y, Ann Intern Med 2000) Fihrnsis regression stage could be assessed by repeated liver biopsy, but liver biopsy sometimes induces serinns event of bleeding or death. Thus it utay be benefit tbr the patients to assess fibrosis regression state using blood truly. (Methods) To evaluate the dynamics of fibrusis progressinn/regression in chronic hepatitis C patients thmy-seven patients who received a daily administration of 6 to 10 million unit (MU) of interteron-alla 2b thrice weekly for 24-26 weeks were enrolled. PIIIP levels, cytokines contnhuting to matrix production (PDGF, TGF-beta), and the enzymes regulating matrix degradation (MMP-1 TIMP-1) in ~:rum were measured &ring therapy, at the completion ot therapy, and 2 4 48, and 72 weeks after the end of therapy. (Resuhs)Ve2qen the patients were categorized according to sustained response state to interterou, PIIIP levels was markedly decreased in sustained msponders during treatment and after the end of treatment, while it was not decreased in the non-sustained responders. Both TGE-beta and PDGF levels ",*,'ere markedly decreased in sustained responders dunng IFN therapy and shordy thereafter, but these values in non-sustained responders were not changed afier dre end of tberapy. Although MMP-1 level was not changed in sustained responders as well as non-sustained responders dunng treatment and after the end of treatment, TIMP-1 level in sustained responder was sigmficandy reduced after the end of treatment and thereafter, while that in non-sustained responders was not changed. (Concluslon)Tbese results suggest that there is an increase in matrix degeneration prOCeSswbich may be associated with a decrease in the level of TIMPs. Once the source of liver injury could be removed, it is possible to restore effective extracellular mamx degradation even after the end of t*vatment. The present data may indicate that extracdlnlar mamx degradation persists m sustained responders. By measuring these cy~okines and enzymes, the process of degradation of mamx could be evaluated w~thout lwer biopsy
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GI (83)
44
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44 60 27
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T1211 Prospective Evaluation of The 24 Hour Interferon-Induced Dedine in Hepatitis C Virus Genotype 1 Load to Predict Response to Peginterteron-Alfa2a/Ribavirin Courbination Therapy Peter Ferenci, Gschwantler Michael, Hermann Laferl, Harald Brunner, Wollgang Jessner, Franz Hackl, Elisabeth Formann, Rudolf Stauber, Rainer Hubmann 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 unresponsiveness to standard IFN/ribavirin therapy (a decrease in viral load of <0.8 log predicted nonresponse with 100 pe~'ent 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 40kDPEG-1FNalf:a2a/rihavirin therapy. Aim of this study was to nivestigate the value of 24hVR prospectively. Methods: In an ongoing prospective trial which compares amaraadine and placebo in addition to treatment with 180 microg 40KDPEGqFNalla2a (PEGASYS, Roche, Basel, CH)/week + 1-1.2g ribavimr/d in chronic hepatitis C (genotype 1) patients are stratified according to the 24hVR at randomization (stratum A: >1.5 log decrease in '%aI load within 24 hrs; stratum B: 0.8-1.49; stratum C: < 0.8). All patients had a hver biopsy and none had received an antiviral therapy, before signing an intbrmed consent Currently all planned 220 patients were recruited, and 131, 101, and 35 completed 12,24, and 48 weeks of treatment, respectively In these patients the 24h\~ was compared with the 12 week EVR, the 24 week and end of treatment response (each ddlned as HCV-RNA neg). Analysis was done without knownrg to which treatment group a patient was assigned The 24hVR was pertormed 2 weeks prior randomization and was calculated from the decrease in viral load 24 hours following a single dose of 9 MU IFNalfa2a (Roche, Basel, CH). Viral load was determined by the Cohas Amplicor Mointor HCV Test, v20 (Roche Diagnostic Systems, USA). Results: The table below summarizes the data. Conclusion: The 24hVR is a good predictor of the response to PEGASYSlribavirin therapy. Patients with predicted poor response to standard-lFN/ribavirin therapy may still achieve a virologic response on PEGASYS/ribavirin therapy.
T1209 SafeLy and Efficacy"of Pegylated Interferon (peg lNF)-Alfa-2b Plus Ribavirin (RBV) tot The Treatment of Chronic Hepatitis C in HlV-Cointected Patients: 48 Week Results Esther Voigt Christian Cx'hulz, Gerd Klausen, Joachim Goelz, Stefan Manss, Antonius Mutz, Franz A. Mosthaf, Elke Lauenroth-Mai, Juergen K Rockstrnh Background: The uatural course of chromc hepatitis C is accelerated in HIV coinfected patients Therefore specifm treatment strategies are urgently needed We evaluated long term efhcacy and satety ot peg INF-alta-2b plus RBV tbr treannent of HCV in HIV-coint)cted patients Methods: Within this open label, uncontrolled, muhicenter trial patients received peg INF 1,5 mug/kg plus 800 mg RBV per day over 48 weeks with HCV genotypes 1 or 4, and 24 weeks with genotypes 2 or 3. Quantitative HCV RNA, HIV RNA and CD4 cell count as well as blood count and liver enzymes were assessed at baseline and at weeks 4, 12, 24, 48 105 panents have been enrolled so far Follow up is still ongoing. Hem we presem data on 52 patients who have completed 48 weeks Results: At baseline 52 patients (median age 3 8 5 years,range 23-58 71% male, 62% t.v drug users) showed a median ttCV RNA of 5 9 3 log cps/ml (range 3.8-79) 52% were int;ected with HCV genot)qpe 1, 133% with genotypes 2 or 3 Median HIV RNA was 326 cpsJml (range <50 to 76852 cps/ ml), median CD4 cell count was 417/nml (range 150 to 1288/mul) at baseline, respectively 48% of patients were receiving concomitant antimtro'viral treatment. 23/52 patients (44%) showed an end of treatment l~slxmse with HCV RNA below detection limit of 500 cps/ml, 26% ot patients with genotype 1, compared with 87% with genoty-pe 3 8 patients (15%) di~-ontinued study treatment prematurely due to adverse events, 4 due to psychiatric disorders, 2 due to blood count abnormalities. 21 (41%) patients discontinued due to ,;qrological uon response CD4 cell count declined significantly at week 12 and 24. However, relative C[N count remained stable as well as HIV RNA. Conclusions: Antiviral efficacy of peg INF plus RBV appears to be lower in HIV/HCV coinfected compared with HCV nronointi:cted patients. Overall, discontinuation rate is low However, psTchiatric disorders are a major problem in this cohort with a high proportion of tbrmer drug users
Virologic on treatment responseIN HCV RNA neg/N total) Stratum
week 12
week 24
A B C p (A/B; A/C; B / C }
27129(9&t%) 23/24 (95.8%) 35/49(71.4%) 37/44 {84.1%) 'U/52 {32.7%) 24143{55.8%) 0.04;0.00001;0.0002 024;0.0016;0,008 treatedper protocolanalysis,* only HCV-RNAneg pats.at week24.
end of Tx*
8..'9 17/17 7.~,
T1212 Beneficial Effects of Antiviral Therapy in Advanced Chronic Liver Disease Due to HCV Infection: A Pilot Study' Rakesh Kumar, Sudhir Kumar, Jagdeep Singh, Brijesh C Sharma, Shlv K. Sarm Background: Antiviral therapy is an effective treammm lor chronic hepatitis and cirrhosis due to HCV infection. However, limited data on antiviml tberapy is a'ailable in advanced chronic liver disease due to HCV infection (ACI.D-C) Aim: To study- the totembility and efficacy of antiviral therapy in patients with ACI_D-C Patients & Methods: HCV RNA positive patients of ACLD-C with ascites or Childs score greater than or equal to 7 were treated ,,'ith escalating dose of interferon (1FN) and ribavirin (R) starting from l MIU/d and 200 nrg/d respectively, up to 3 MIU/d and 600 mg/d respectively. The therapy was continued for a maximum of 4 years or till 3 m o alter HCV RNA loss. ,4n interim analysis of patients completing at least 6 mo follow-up was done. Results: Twenty patients (18 male) wvre analyzed. All patients had ascites and 6 (30%) had bled. Their median age, Childs score and serum albumin were 51 y (19-75), 8 [Childs B (n= 17), Childs C (n=3)] and 2 9 g/ dl (2.1-3.8) respectively. "11lepatients t~ceived IFN 1.5 MIU/d (range 1-3 MIU/d) and R 400 mg/dl (range 200-600 mg/d) for 10.3 mo. ( range 1- 36 too.) and 6.5 m o (range 0.5-14 tno.) respectively. 1>mng Mlow-up, serum albumin and Childs score improved significantly from baseline levels (3 0 plusminus 0.5 g/dl vs. 3.6 plusminus 0.4 g/dl; p = 0.01 ) and (8.2 plusminus 1.3 vs. 7.4 plusminus 1.8; p=0.03) respectively. HCV RNA loss ,was seen in 8 (40%) patients at 12 mo. (range 6-20 mo.) with sustained viral response in 4 (20%) patients. Drug discontinuation requiring permanent withdrawal was needed in 3 (15%) patients. TemporaB,- withdrawal and dose modification were required in 9 (45%) and 7 (35%) patients respectively. One or the other adverse event occurred in 19 (95%) patients, namely leucopenia in 12 (60%); thrombocytopenia in 6 (30%); anemia and SBP in 2 (10%) patients each; and pulmonary" TB, diarrhea and orbital cellulins in 1 (5%) patient each. Death on therapy occurred in 1 (5%) patient due to orbital cellulins The median duration of tbllow-up was 12 mo. (range 6- 62 mo). Conclusion: Antivirai therapy in
TI210 Treatment With Pegylated Interferon Alpha 2B and Ribavirin Produces Significant Sustained Virologic Response Rates in HCV Infected Patients who Failed Prior Therapy Paul J Gaglin, Melissa Brown, David Zimmemlan, James Choi, Larry Heller, Robert Brown Jr. Imroduction: Eradicating HCV in the majority of infected patients remains an elusive goal, particularly in previoudy treated patients who iailed or relapsed tollowing prior therapy. We hypothesize lhat response rates in these patients who are re-treated with Pegylated Interferon and I~abavirin will Ix- improved compared to standard interferon preparations with or vmhout Rihavirirc The pre~nt prospective study is designed to determine the efficacy and satety of treatment with PEG-Intmn (pegylated interterun alla-2b) and Ribavirin in a group of patients who laiied prior therapy with Interferon with or without Ribavirin. Methods: 439 patmnts are presendy enrolled in this muhi-cemer study. The first 250 enrolled patients were treated with 15 mg/kg of PEG-lntron sc q week, and Ribavirin 800 mg po qd. The remaniing patients received 15 mg/kg of PEG-Intron and weight based Ribavirin (8001400rag) The intended duration of treatment is 48 weeks regardless ot 24 week HCV RNA. 192 patients have been treated t0r at least 48 weeks and SVR data at week 72 is available in 98 patients, all treated with 800mg Ribavirin/d Adverse events: Dose reduction was
A-767
AASLD
Abstracts
advanced chronic liver disease due to HCV intection achieves significant improvement in hepatic synthetic flanction and Cfiilds score v,ath sustained virological response in l/5th of the patients Adverse events are common necessitating dose monitoring.
with IFN/RBV. At baseline, the median CD4 count was 425/microL, 64% of patients had undetectable HIV viral loads, and 68% were on highly active antiretroviml therapy. The median duration of treatment was 39 weeks. Twelve of 31 patients (42%) had an end-oftreatment response (defined as the absence of detectable HCV RNA at cessation of therapy). Of those twelve responders, HCV RNA was <400 copies/ml in nine patients (77%) by week 12. Of the remaining three responders, two patients had a 2 log decrease in viral load within 12 weeks, and one had a 2 hog decrease in HCV viral load by 24 weeks. Conclusions: In patients with predominately genotype 1 HCV and HIV infection, the response to therapy almost always occurs within 12 weeks. If patients do not have at least a 2 log decrease in HCV viral load by 12 weeks, discontinuation of therapy should be considered
T1213 Study of Vitamin E Response on Chronic Hepatitis C Patients Under Inter Feron Plus Ribavirin Therapy Ashraf R Abulfutuh, Mohammed Morsy, Al~d El Ghany Solyman, Said El Hendawy, Mohammed El Desouky, Salwa El I-ladad, Moemena Kamel Background:Interferon-alpha plus Ribavirin is the treatment of choice in patients with chronic hepalitis C(CHC); un{brtunately , t~uly- a minority of patients have a sustained response .Aim and Methods:We conducted a randomised-placebo control study to evaluate the effect of \fltamin E after IFN-alpha plus Ribavirin therapy on the durability, of the biochemical and virological response Serum HCV-RNA , ALT and Vitamin E were determined every two months lor 48 weeks The 126 CHC patients enrolled were treated with 6MU recombinant 1FN-alpha2a thrice/week plus Ribav~irin (1,200 my/day) for 6 months. Results :after six momhs of antiviral therapy , 66 patients were non responders and 16 patients presented intolerance to therapy ; the remainders 44 responder patients randomly received either Vitamin E (900 mgJday) or placebo tot 6 months .in the Vitamin E group, 20 out of 22 patients (91%) showed the persiste~me of complete response m therapy, one patient had serum HCV-RNA but normal AI_T at the tiourffi month and one patient relapsed at the second month .In the Placebo group subjects presenting a complete sustained response were oNy 13 (59%), 7 patients relapsed after 2 month from antiviral therapy and 2 patients showed HCV-RNA but normal ALT, Conclusion : a long-term Vitamm E administration significantly (p<0,05, Fisher test) improves the durability of antiviral therapy .These data support the hypothesis that Vitamin E may play a role in modulating the immunological response in chronic viral hepatitis.
T1216
Retreatment with Pegylated Interferon-Alpha2b Plus Ribavirin in Patients with Chronic Hepatitis C Not Responding to a Previous Antiviral Treatment with Standard Interferons Combined with Ribavirin Gerlinde Teuber, Birgit KaUinowski, Claus Niederau, Hans Klinker, Peter R. Galle, Myrga Zankel, Stefan Zeuzem In interferon (IFN) non-responders with chronic hepatitis C retreatment with standard interferons combined w/th ribavirin showed sustained virologic response rates of 2040%, Concerning the efficacy of antiviral retreatment in patients not responding to a previous treatment with standard interferons combined with ribavirin only limited data with conflicting results are available. Therefore, the aims of the presem trial were to evaluate efficacy and safety of a retreatment with pegylated IFN-alpa2b plus ribavirin in 240 patients (162 males, 78 females, mean age 45.5 years) not responding to previous antiviral treatment with standard mterferons combined with ribavirin. Patients received pegylated IFN-alpha2b 100 pg/week s.c. for 8 weeks followed by 50 pg/week s.c. for 40 weeks in combination with ribavirin 800 mg/d for 48 weeks, Treatment was discontinued in patients with detectable semm HCV-RNA after treatment week 24. A virologic end-of-treatment response was achieved in 25/240 (10.4%) patients while after a followmp period of 24 weeks a sustained virologic response was observed in 15/240 (6.3%) patients. Patiems infected with HCV genot)~ non-1 were more Likely to respond to antiviral retreatment than patients infected with HCV genotype 1 (6.8% vs. 17%). In conclusion, antiviral retreatment with pegylated interferonalpha2b plus ribavirin in this flat and low dose showed only a limited therapeutic efficacy in patients with chronic hepatitis C not responding to previous treatment with standard interferons and ribavlrin. In these patients, virologic response rates may be improved by administering pegylated interferon-alpha2b and ribavirin bodyweight adapted or by the addition of other antiviral agents.
T1214 interleukin-ll In Patients With Chronic Hepatitis C And Advanced Liver Disease 'Who Have Been Nonresponsive To Antiviral Therapy Eric J Lawilz, Thomas Casey, Norma S. Cantu Backgruund: Those with advanced liver disease as a result of Hepatitis C are at risk for decompensation requiring liver trausplamation or the development of hepatocellular carcinnma hnmune mediated injury is the primary mechanism of injury resulting m hepatic inflammation and fibrogenesis It has been shown that there is a positive correlation between both gaomla interleron and lntefleukin (IL)-2 mRNA expression and the severity of both hepatic inflamnlation and fibrosis IL-11 decreases the TH-] cytokines such as gamma interteron and IL-2 (Keith, Cytokme Reference 2000, 565) In the setting of psoriasis, ILl i has been shown to suppress the THd response at doses as Iow as 2.5 mcg/kg/day, which is greater than ten told lower than the currently approved dose for thrombocylopenia (Trepicchio, ,J Cfin Invest 1999; i04(11),1527). A1M: To evaluate the effect of IL-11 on the histologlc actmty index (HAl) in patients who have been nonrespousive to antiviral therapy yet have advanced liver disease. Methods: A baseline liver biopsy was pertbrmed in those with advanced liver disease defined as a Metovir score of F3-F4 All participants "were treated with rhlL-115.0mcg/k~/day subcutaneously daily Jbr 3 momhs. At the completion of therapy a post therapy hver biopsy" was perfocmed. HCV-RNA was obtained at the initiation and completion of therapy. Results: IM'enty adult participants with Metovtr F3-F4 fibrosis with compensated liver disease were enrolled The mean age is 50.5 years with a mean weight is 7 9 6 kg. Sixty percent were male. Mean baseLine HCV-RNA 5,595,6CK) copies/ml. Mean baseline HAl is 7 0 with Metovir fibrosis scores of F3 in 50% and F4 m 50%. Fourteen participants have completed 8 weeks and 9 have completed therapy. Mean baseline AkT was 144 which was reduced to 56 after 12 weeks of therapy Mean baseline platelet count was 140 which rose to 210 after 12 weeks of therapy The effects of 12 weeks of therapy on HAl are seen in the chart below The therapy has been well tolerated to date with scant pretibial edema in 19/20 responsive to bydrochlorothiazide One participant (1/20) discontinued medication early due to significant fluid retention Conclusion: rfilL-11 is well tolarated at a dose of 5.0mcWkg/day in participants with advanced liver disease. Fifty six percent of treated participants have a 2 point or greater reduction in HAl to date. Further study is warranted to extend the duration of therapy to evaluate the elfect on fibrosis. HAl Point Reduction 0 d -2 -3 4
T1217
Study in CHC Patients Comparing Three Different Combination Therapies with Interferon a-2b (fiN) and Rihavirin (Rebetol): Weekly PEG-IFN (Peg- lntron) Versus Daily IFN (lntron A Pen) Versus Standard Regimen of 1FN (Intron A Pen) , Yves Horsmans, I. Coil< H. Van Vlierberghe, Ph Langlet, M Adler, R. Brenard, P. Michielsen, N. Bourgeois, V. Lef~bvre, J. Henrion, X De Koninck, L Bruckers, on behalf of the Belgian Association for the Study of the Liver The combination of PEG-interferon a-2b and nhavirin is considered to be the standard treatment for naive chronic HCV patients. A study was initiated to compare the sustained virological response and safety of daily lntronA ~versus Peglntron ~, both in combination with Rebetol ~. Naive chronic HCV patients were randomized in three groups with a ratio of 2:2:1. Group A: daily interferon el-2b (4 MIU s.c. for patients > 65 kg or 0.06 MIU/kg for patients < 65 kg) and ribavirin, group B: PEG-interferon a-2b (100~g s.c. weekly for patients > 65 kg or 15~g/kg weekly' for patients < 65 kg) and ribavirin arid group C (reierence arm): interferon ix-2b (3 MIU s.c. TWI) and ribawrin. ]'he duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period. 317 patients were enrolled: 130 in group A, 119 in group B and 68 in group C. We are presenting the results of an interim analysis performed on the available patient data. Demographic data, PCR results and reasons for early withdrawal have been statistically analysed. At baseline, the 3 groups didfft show any statistical difference regarding age, gender, race, genotype and METAVlR score. At week 24 on treatment, HC~' RNA (Amplicor) was undetectable in 86% in group A, in 80% m group B and in 67% in group C. At the end of treatment, 69% 70% and 55% respectively, had a negative PCR result. At week 24 of tbllow-up, these results were 60%, 52% and 29%, respectively. When comparing the efficacy of the daily interferon ( + ribavirm) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.378). 78 patients withdrew before termination of the treatment: 30 in group A, 22 group B and 26 in group C. In group A, 43% of drop-outs were due to adverse events compared to 18% in group B and 19% in group C. Regarding safety, no statistical difference was found for the drup-out rate in the daily interferon (+ ribavirin) regimen verstts the PEG-interferon ( + ribavirin) arm (p = 0.420). In contrast, a statistical higher rate of drop out was observed in the old standard therapy (group C) versus group A (p = 0,024) and versus group B (p = 0.004). In conclusion, daily weight based lntronA dosing and PEG Iutron weighed based dosing once weekly both in combination with Ribavirin offer the same efficacy and safety rates.
# Of ParUcipants 1 3 3 1 1
T1215 Early ViroLogic Response to Interferon and Ribavirin Treatment in Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Eiana Maser, Ron Pahnon, Douglas T. Dieterich Background. Patients with hepatitis C virus (HCV) int)ection who have a virulogic response to interteron (IFN) and ribavirm (RBV) regimens usually respond within the first 12 weeks of therapy. We reviewed the virologjc response rote to IFN and RBV regimens in patients co-infected with HCV and human immunodeflciency virus (HIV) who were predominantly HCV genoty~ 1. Methods. We conducted a retrospeetive chart review of 31 HPT/HCV coinl~'cted panents from a New Ymk City practice. All patients were treated with weight appropriate doses of 1FN and RBV. The serum HIV and HCV RNA were detected using the polynmmse chain reaction and were recorded approximately once per month. Results The majority of patients were HCV genoty2ae 1 (74%) and rnala (84%). Mean HCV RNA at baseline was 2,733,774 iUknl 71% of patients were treated with PEG-IFN/RBV and 29%
AASLD
Abstracts
T1218
Effect of therapy with pegylated interferon-a on platelet activation and apoptosis in patients with chronic hepatitis C. Monika Homoncik, Wolfgang Sieghart, Wolfgang Jessner, Elisabeth Formann, Alfred Gangl, Peter Ferenci, Markus Peck-Radosavljex4c OBJECTIVE: interferon alpha induced ffirombocytopenka can become a limiting factor/~ therapy continuation. Platelet counts provide no information about platelet function. Quali~" of platelet function is crucial for the assessment whether a patient is at risk for bleeding or
3.-768
required in 22% of pts most commonly due to leukopenia and anemia Penn,anent discontinuation of therapy was required in 8% most often due to: depression or anxiety Serious adverse events: (1.8% of 439 pts) Included one patient each with neutropenia/MRSA sepsis, optic neuritis with monocular blindness, perirectal abg:'ess, cellulitis and multi-organ failure, cutaneous and puhrmnary sarcoidosis, pneumonia, homicidal ideation, and suicide. Conclusions: 1) Overall ETR was 46% and SVR was 33%. 2) SVR was significantly higher in genotype non-1 patients and (nose Who failed previous monotherapy 3) 15% ot G1 I~on responders to Rebetrmr achieved an SVR (16% Caucasian, 12% Black) 4) It is hoped that a weight based dose of Ribavirin "~qll be associated with lower relapse rates and improved sustained response rates particularly in G1 pts.
Non-lnvasive Assessment of Fibrosis Resolution/Progression in Chronic Hepatitis C Patients Who Received Anti-Viral Therapy Yasushi Shiraton, Haruki Yamada, Yusei lkeda, Masayuki Matsumura, Naoaki Hashimoto, Ryo Nakata, Masao Oraata Liver fihros~s is a dynamic process, '4th phases of either net matrk,: deposition or net degradation leading, respectively, to progression or regression of fibrosis. Recently, there are several ~*'ports indicating that fibrosis of the liver regressed in patients with sustained virological response Fibrosis progression was also retarded in patients who received IFN therapy (Shiratori Y, Ann Intern Med 2000) Fihrnsis regression stage could be assessed by repeated liver biopsy, but liver biopsy sometimes induces serinns event of bleeding or death. Thus it utay be benefit tbr the patients to assess fibrosis regression state using blood truly. (Methods) To evaluate the dynamics of fibrusis progressinn/regression in chronic hepatitis C patients thmy-seven patients who received a daily administration of 6 to 10 million unit (MU) of interteron-alla 2b thrice weekly for 24-26 weeks were enrolled. PIIIP levels, cytokines contnhuting to matrix production (PDGF, TGF-beta), and the enzymes regulating matrix degradation (MMP-1 TIMP-1) in ~:rum were measured &ring therapy, at the completion ot therapy, and 2 4 48, and 72 weeks after the end of therapy. (Resuhs)Ve2qen the patients were categorized according to sustained response state to interterou, PIIIP levels was markedly decreased in sustained msponders during treatment and after the end of treatment, while it was not decreased in the non-sustained responders. Both TGE-beta and PDGF levels ",*,'ere markedly decreased in sustained responders dunng IFN therapy and shordy thereafter, but these values in non-sustained responders were not changed afier dre end of tberapy. Although MMP-1 level was not changed in sustained responders as well as non-sustained responders dunng treatment and after the end of treatment, TIMP-1 level in sustained responder was sigmficandy reduced after the end of treatment and thereafter, while that in non-sustained responders was not changed. (Concluslon)Tbese results suggest that there is an increase in matrix degeneration prOCeSswbich may be associated with a decrease in the level of TIMPs. Once the source of liver injury could be removed, it is possible to restore effective extracellular mamx degradation even after the end of t*vatment. The present data may indicate that extracdlnlar mamx degradation persists m sustained responders. By measuring these cy~okines and enzymes, the process of degradation of mamx could be evaluated w~thout lwer biopsy
s t ~ F..at,1,~ )
Wk4~HCV-)
............
GI (83)
44
32
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7'0
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Prey Ifn/Riba (/9) Prey Ifn mono (21) G1 combo NR (50)
44 60 27
50 15
T1211 Prospective Evaluation of The 24 Hour Interferon-Induced Dedine in Hepatitis C Virus Genotype 1 Load to Predict Response to Peginterteron-Alfa2a/Ribavirin Courbination Therapy Peter Ferenci, Gschwantler Michael, Hermann Laferl, Harald Brunner, Wollgang Jessner, Franz Hackl, Elisabeth Formann, Rudolf Stauber, Rainer Hubmann 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 unresponsiveness to standard IFN/ribavirin therapy (a decrease in viral load of <0.8 log predicted nonresponse with 100 pe~'ent 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 40kDPEG-1FNalf:a2a/rihavirin therapy. Aim of this study was to nivestigate the value of 24hVR prospectively. Methods: In an ongoing prospective trial which compares amaraadine and placebo in addition to treatment with 180 microg 40KDPEGqFNalla2a (PEGASYS, Roche, Basel, CH)/week + 1-1.2g ribavimr/d in chronic hepatitis C (genotype 1) patients are stratified according to the 24hVR at randomization (stratum A: >1.5 log decrease in '%aI load within 24 hrs; stratum B: 0.8-1.49; stratum C: < 0.8). All patients had a hver biopsy and none had received an antiviral therapy, before signing an intbrmed consent Currently all planned 220 patients were recruited, and 131, 101, and 35 completed 12,24, and 48 weeks of treatment, respectively In these patients the 24h\~ was compared with the 12 week EVR, the 24 week and end of treatment response (each ddlned as HCV-RNA neg). Analysis was done without knownrg to which treatment group a patient was assigned The 24hVR was pertormed 2 weeks prior randomization and was calculated from the decrease in viral load 24 hours following a single dose of 9 MU IFNalfa2a (Roche, Basel, CH). Viral load was determined by the Cohas Amplicor Mointor HCV Test, v20 (Roche Diagnostic Systems, USA). Results: The table below summarizes the data. Conclusion: The 24hVR is a good predictor of the response to PEGASYSlribavirin therapy. Patients with predicted poor response to standard-lFN/ribavirin therapy may still achieve a virologic response on PEGASYS/ribavirin therapy.
T1209 SafeLy and Efficacy"of Pegylated Interferon (peg lNF)-Alfa-2b Plus Ribavirin (RBV) tot The Treatment of Chronic Hepatitis C in HlV-Cointected Patients: 48 Week Results Esther Voigt Christian Cx'hulz, Gerd Klausen, Joachim Goelz, Stefan Manss, Antonius Mutz, Franz A. Mosthaf, Elke Lauenroth-Mai, Juergen K Rockstrnh Background: The uatural course of chromc hepatitis C is accelerated in HIV coinfected patients Therefore specifm treatment strategies are urgently needed We evaluated long term efhcacy and satety ot peg INF-alta-2b plus RBV tbr treannent of HCV in HIV-coint)cted patients Methods: Within this open label, uncontrolled, muhicenter trial patients received peg INF 1,5 mug/kg plus 800 mg RBV per day over 48 weeks with HCV genotypes 1 or 4, and 24 weeks with genotypes 2 or 3. Quantitative HCV RNA, HIV RNA and CD4 cell count as well as blood count and liver enzymes were assessed at baseline and at weeks 4, 12, 24, 48 105 panents have been enrolled so far Follow up is still ongoing. Hem we presem data on 52 patients who have completed 48 weeks Results: At baseline 52 patients (median age 3 8 5 years,range 23-58 71% male, 62% t.v drug users) showed a median ttCV RNA of 5 9 3 log cps/ml (range 3.8-79) 52% were int;ected with HCV genot)qpe 1, 133% with genotypes 2 or 3 Median HIV RNA was 326 cpsJml (range <50 to 76852 cps/ ml), median CD4 cell count was 417/nml (range 150 to 1288/mul) at baseline, respectively 48% of patients were receiving concomitant antimtro'viral treatment. 23/52 patients (44%) showed an end of treatment l~slxmse with HCV RNA below detection limit of 500 cps/ml, 26% ot patients with genotype 1, compared with 87% with genoty-pe 3 8 patients (15%) di~-ontinued study treatment prematurely due to adverse events, 4 due to psychiatric disorders, 2 due to blood count abnormalities. 21 (41%) patients discontinued due to ,;qrological uon response CD4 cell count declined significantly at week 12 and 24. However, relative C[N count remained stable as well as HIV RNA. Conclusions: Antiviral efficacy of peg INF plus RBV appears to be lower in HIV/HCV coinfected compared with HCV nronointi:cted patients. Overall, discontinuation rate is low However, psTchiatric disorders are a major problem in this cohort with a high proportion of tbrmer drug users
Virologic on treatment responseIN HCV RNA neg/N total) Stratum
week 12
week 24
A B C p (A/B; A/C; B / C }
27129(9&t%) 23/24 (95.8%) 35/49(71.4%) 37/44 {84.1%) 'U/52 {32.7%) 24143{55.8%) 0.04;0.00001;0.0002 024;0.0016;0,008 treatedper protocolanalysis,* only HCV-RNAneg pats.at week24.
end of Tx*
8..'9 17/17 7.~,
T1212 Beneficial Effects of Antiviral Therapy in Advanced Chronic Liver Disease Due to HCV Infection: A Pilot Study' Rakesh Kumar, Sudhir Kumar, Jagdeep Singh, Brijesh C Sharma, Shlv K. Sarm Background: Antiviral therapy is an effective treammm lor chronic hepatitis and cirrhosis due to HCV infection. However, limited data on antiviml tberapy is a'ailable in advanced chronic liver disease due to HCV infection (ACI.D-C) Aim: To study- the totembility and efficacy of antiviral therapy in patients with ACI_D-C Patients & Methods: HCV RNA positive patients of ACLD-C with ascites or Childs score greater than or equal to 7 were treated ,,'ith escalating dose of interferon (1FN) and ribavirin (R) starting from l MIU/d and 200 nrg/d respectively, up to 3 MIU/d and 600 mg/d respectively. The therapy was continued for a maximum of 4 years or till 3 m o alter HCV RNA loss. ,4n interim analysis of patients completing at least 6 mo follow-up was done. Results: Twenty patients (18 male) wvre analyzed. All patients had ascites and 6 (30%) had bled. Their median age, Childs score and serum albumin were 51 y (19-75), 8 [Childs B (n= 17), Childs C (n=3)] and 2 9 g/ dl (2.1-3.8) respectively. "11lepatients t~ceived IFN 1.5 MIU/d (range 1-3 MIU/d) and R 400 mg/dl (range 200-600 mg/d) for 10.3 mo. ( range 1- 36 too.) and 6.5 m o (range 0.5-14 tno.) respectively. 1>mng Mlow-up, serum albumin and Childs score improved significantly from baseline levels (3 0 plusminus 0.5 g/dl vs. 3.6 plusminus 0.4 g/dl; p = 0.01 ) and (8.2 plusminus 1.3 vs. 7.4 plusminus 1.8; p=0.03) respectively. HCV RNA loss ,was seen in 8 (40%) patients at 12 mo. (range 6-20 mo.) with sustained viral response in 4 (20%) patients. Drug discontinuation requiring permanent withdrawal was needed in 3 (15%) patients. TemporaB,- withdrawal and dose modification were required in 9 (45%) and 7 (35%) patients respectively. One or the other adverse event occurred in 19 (95%) patients, namely leucopenia in 12 (60%); thrombocytopenia in 6 (30%); anemia and SBP in 2 (10%) patients each; and pulmonary" TB, diarrhea and orbital cellulins in 1 (5%) patient each. Death on therapy occurred in 1 (5%) patient due to orbital cellulins The median duration of tbllow-up was 12 mo. (range 6- 62 mo). Conclusion: Antivirai therapy in
TI210 Treatment With Pegylated Interferon Alpha 2B and Ribavirin Produces Significant Sustained Virologic Response Rates in HCV Infected Patients who Failed Prior Therapy Paul J Gaglin, Melissa Brown, David Zimmemlan, James Choi, Larry Heller, Robert Brown Jr. Imroduction: Eradicating HCV in the majority of infected patients remains an elusive goal, particularly in previoudy treated patients who iailed or relapsed tollowing prior therapy. We hypothesize lhat response rates in these patients who are re-treated with Pegylated Interferon and I~abavirin will Ix- improved compared to standard interferon preparations with or vmhout Rihavirirc The pre~nt prospective study is designed to determine the efficacy and satety of treatment with PEG-Intmn (pegylated interterun alla-2b) and Ribavirin in a group of patients who laiied prior therapy with Interferon with or without Ribavirin. Methods: 439 patmnts are presendy enrolled in this muhi-cemer study. The first 250 enrolled patients were treated with 15 mg/kg of PEG-lntron sc q week, and Ribavirin 800 mg po qd. The remaniing patients received 15 mg/kg of PEG-Intron and weight based Ribavirin (8001400rag) The intended duration of treatment is 48 weeks regardless ot 24 week HCV RNA. 192 patients have been treated t0r at least 48 weeks and SVR data at week 72 is available in 98 patients, all treated with 800mg Ribavirin/d Adverse events: Dose reduction was
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Abstracts
advanced chronic liver disease due to HCV intection achieves significant improvement in hepatic synthetic flanction and Cfiilds score v,ath sustained virological response in l/5th of the patients Adverse events are common necessitating dose monitoring.
with IFN/RBV. At baseline, the median CD4 count was 425/microL, 64% of patients had undetectable HIV viral loads, and 68% were on highly active antiretroviml therapy. The median duration of treatment was 39 weeks. Twelve of 31 patients (42%) had an end-oftreatment response (defined as the absence of detectable HCV RNA at cessation of therapy). Of those twelve responders, HCV RNA was <400 copies/ml in nine patients (77%) by week 12. Of the remaining three responders, two patients had a 2 log decrease in viral load within 12 weeks, and one had a 2 hog decrease in HCV viral load by 24 weeks. Conclusions: In patients with predominately genotype 1 HCV and HIV infection, the response to therapy almost always occurs within 12 weeks. If patients do not have at least a 2 log decrease in HCV viral load by 12 weeks, discontinuation of therapy should be considered
T1213 Study of Vitamin E Response on Chronic Hepatitis C Patients Under Inter Feron Plus Ribavirin Therapy Ashraf R Abulfutuh, Mohammed Morsy, Al~d El Ghany Solyman, Said El Hendawy, Mohammed El Desouky, Salwa El I-ladad, Moemena Kamel Background:Interferon-alpha plus Ribavirin is the treatment of choice in patients with chronic hepalitis C(CHC); un{brtunately , t~uly- a minority of patients have a sustained response .Aim and Methods:We conducted a randomised-placebo control study to evaluate the effect of \fltamin E after IFN-alpha plus Ribavirin therapy on the durability, of the biochemical and virological response Serum HCV-RNA , ALT and Vitamin E were determined every two months lor 48 weeks The 126 CHC patients enrolled were treated with 6MU recombinant 1FN-alpha2a thrice/week plus Ribav~irin (1,200 my/day) for 6 months. Results :after six momhs of antiviral therapy , 66 patients were non responders and 16 patients presented intolerance to therapy ; the remainders 44 responder patients randomly received either Vitamin E (900 mgJday) or placebo tot 6 months .in the Vitamin E group, 20 out of 22 patients (91%) showed the persiste~me of complete response m therapy, one patient had serum HCV-RNA but normal AI_T at the tiourffi month and one patient relapsed at the second month .In the Placebo group subjects presenting a complete sustained response were oNy 13 (59%), 7 patients relapsed after 2 month from antiviral therapy and 2 patients showed HCV-RNA but normal ALT, Conclusion : a long-term Vitamm E administration significantly (p<0,05, Fisher test) improves the durability of antiviral therapy .These data support the hypothesis that Vitamin E may play a role in modulating the immunological response in chronic viral hepatitis.
T1216
Retreatment with Pegylated Interferon-Alpha2b Plus Ribavirin in Patients with Chronic Hepatitis C Not Responding to a Previous Antiviral Treatment with Standard Interferons Combined with Ribavirin Gerlinde Teuber, Birgit KaUinowski, Claus Niederau, Hans Klinker, Peter R. Galle, Myrga Zankel, Stefan Zeuzem In interferon (IFN) non-responders with chronic hepatitis C retreatment with standard interferons combined w/th ribavirin showed sustained virologic response rates of 2040%, Concerning the efficacy of antiviral retreatment in patients not responding to a previous treatment with standard interferons combined with ribavirin only limited data with conflicting results are available. Therefore, the aims of the presem trial were to evaluate efficacy and safety of a retreatment with pegylated IFN-alpa2b plus ribavirin in 240 patients (162 males, 78 females, mean age 45.5 years) not responding to previous antiviral treatment with standard mterferons combined with ribavirin. Patients received pegylated IFN-alpha2b 100 pg/week s.c. for 8 weeks followed by 50 pg/week s.c. for 40 weeks in combination with ribavirin 800 mg/d for 48 weeks, Treatment was discontinued in patients with detectable semm HCV-RNA after treatment week 24. A virologic end-of-treatment response was achieved in 25/240 (10.4%) patients while after a followmp period of 24 weeks a sustained virologic response was observed in 15/240 (6.3%) patients. Patiems infected with HCV genot)~ non-1 were more Likely to respond to antiviral retreatment than patients infected with HCV genotype 1 (6.8% vs. 17%). In conclusion, antiviral retreatment with pegylated interferonalpha2b plus ribavirin in this flat and low dose showed only a limited therapeutic efficacy in patients with chronic hepatitis C not responding to previous treatment with standard interferons and ribavlrin. In these patients, virologic response rates may be improved by administering pegylated interferon-alpha2b and ribavirin bodyweight adapted or by the addition of other antiviral agents.
T1214 interleukin-ll In Patients With Chronic Hepatitis C And Advanced Liver Disease 'Who Have Been Nonresponsive To Antiviral Therapy Eric J Lawilz, Thomas Casey, Norma S. Cantu Backgruund: Those with advanced liver disease as a result of Hepatitis C are at risk for decompensation requiring liver trausplamation or the development of hepatocellular carcinnma hnmune mediated injury is the primary mechanism of injury resulting m hepatic inflammation and fibrogenesis It has been shown that there is a positive correlation between both gaomla interleron and lntefleukin (IL)-2 mRNA expression and the severity of both hepatic inflamnlation and fibrosis IL-11 decreases the TH-] cytokines such as gamma interteron and IL-2 (Keith, Cytokme Reference 2000, 565) In the setting of psoriasis, ILl i has been shown to suppress the THd response at doses as Iow as 2.5 mcg/kg/day, which is greater than ten told lower than the currently approved dose for thrombocylopenia (Trepicchio, ,J Cfin Invest 1999; i04(11),1527). A1M: To evaluate the effect of IL-11 on the histologlc actmty index (HAl) in patients who have been nonrespousive to antiviral therapy yet have advanced liver disease. Methods: A baseline liver biopsy was pertbrmed in those with advanced liver disease defined as a Metovir score of F3-F4 All participants "were treated with rhlL-115.0mcg/k~/day subcutaneously daily Jbr 3 momhs. At the completion of therapy a post therapy hver biopsy" was perfocmed. HCV-RNA was obtained at the initiation and completion of therapy. Results: IM'enty adult participants with Metovtr F3-F4 fibrosis with compensated liver disease were enrolled The mean age is 50.5 years with a mean weight is 7 9 6 kg. Sixty percent were male. Mean baseLine HCV-RNA 5,595,6CK) copies/ml. Mean baseline HAl is 7 0 with Metovir fibrosis scores of F3 in 50% and F4 m 50%. Fourteen participants have completed 8 weeks and 9 have completed therapy. Mean baseline AkT was 144 which was reduced to 56 after 12 weeks of therapy Mean baseline platelet count was 140 which rose to 210 after 12 weeks of therapy The effects of 12 weeks of therapy on HAl are seen in the chart below The therapy has been well tolerated to date with scant pretibial edema in 19/20 responsive to bydrochlorothiazide One participant (1/20) discontinued medication early due to significant fluid retention Conclusion: rfilL-11 is well tolarated at a dose of 5.0mcWkg/day in participants with advanced liver disease. Fifty six percent of treated participants have a 2 point or greater reduction in HAl to date. Further study is warranted to extend the duration of therapy to evaluate the elfect on fibrosis. HAl Point Reduction 0 d -2 -3 4
T1217
Study in CHC Patients Comparing Three Different Combination Therapies with Interferon a-2b (fiN) and Rihavirin (Rebetol): Weekly PEG-IFN (Peg- lntron) Versus Daily IFN (lntron A Pen) Versus Standard Regimen of 1FN (Intron A Pen) , Yves Horsmans, I. Coil< H. Van Vlierberghe, Ph Langlet, M Adler, R. Brenard, P. Michielsen, N. Bourgeois, V. Lef~bvre, J. Henrion, X De Koninck, L Bruckers, on behalf of the Belgian Association for the Study of the Liver The combination of PEG-interferon a-2b and nhavirin is considered to be the standard treatment for naive chronic HCV patients. A study was initiated to compare the sustained virological response and safety of daily lntronA ~versus Peglntron ~, both in combination with Rebetol ~. Naive chronic HCV patients were randomized in three groups with a ratio of 2:2:1. Group A: daily interferon el-2b (4 MIU s.c. for patients > 65 kg or 0.06 MIU/kg for patients < 65 kg) and ribavirin, group B: PEG-interferon a-2b (100~g s.c. weekly for patients > 65 kg or 15~g/kg weekly' for patients < 65 kg) and ribavirin arid group C (reierence arm): interferon ix-2b (3 MIU s.c. TWI) and ribawrin. ]'he duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period. 317 patients were enrolled: 130 in group A, 119 in group B and 68 in group C. We are presenting the results of an interim analysis performed on the available patient data. Demographic data, PCR results and reasons for early withdrawal have been statistically analysed. At baseline, the 3 groups didfft show any statistical difference regarding age, gender, race, genotype and METAVlR score. At week 24 on treatment, HC~' RNA (Amplicor) was undetectable in 86% in group A, in 80% m group B and in 67% in group C. At the end of treatment, 69% 70% and 55% respectively, had a negative PCR result. At week 24 of tbllow-up, these results were 60%, 52% and 29%, respectively. When comparing the efficacy of the daily interferon ( + ribavirm) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.378). 78 patients withdrew before termination of the treatment: 30 in group A, 22 group B and 26 in group C. In group A, 43% of drop-outs were due to adverse events compared to 18% in group B and 19% in group C. Regarding safety, no statistical difference was found for the drup-out rate in the daily interferon (+ ribavirin) regimen verstts the PEG-interferon ( + ribavirin) arm (p = 0.420). In contrast, a statistical higher rate of drop out was observed in the old standard therapy (group C) versus group A (p = 0,024) and versus group B (p = 0.004). In conclusion, daily weight based lntronA dosing and PEG Iutron weighed based dosing once weekly both in combination with Ribavirin offer the same efficacy and safety rates.
# Of ParUcipants 1 3 3 1 1
T1215 Early ViroLogic Response to Interferon and Ribavirin Treatment in Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Eiana Maser, Ron Pahnon, Douglas T. Dieterich Background. Patients with hepatitis C virus (HCV) int)ection who have a virulogic response to interteron (IFN) and ribavirm (RBV) regimens usually respond within the first 12 weeks of therapy. We reviewed the virologjc response rote to IFN and RBV regimens in patients co-infected with HCV and human immunodeflciency virus (HIV) who were predominantly HCV genoty~ 1. Methods. We conducted a retrospeetive chart review of 31 HPT/HCV coinl~'cted panents from a New Ymk City practice. All patients were treated with weight appropriate doses of 1FN and RBV. The serum HIV and HCV RNA were detected using the polynmmse chain reaction and were recorded approximately once per month. Results The majority of patients were HCV genoty2ae 1 (74%) and rnala (84%). Mean HCV RNA at baseline was 2,733,774 iUknl 71% of patients were treated with PEG-IFN/RBV and 29%
AASLD
Abstracts
T1218
Effect of therapy with pegylated interferon-a on platelet activation and apoptosis in patients with chronic hepatitis C. Monika Homoncik, Wolfgang Sieghart, Wolfgang Jessner, Elisabeth Formann, Alfred Gangl, Peter Ferenci, Markus Peck-Radosavljex4c OBJECTIVE: interferon alpha induced ffirombocytopenka can become a limiting factor/~ therapy continuation. Platelet counts provide no information about platelet function. Quali~" of platelet function is crucial for the assessment whether a patient is at risk for bleeding or
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