Interferon alpha-2b alone or combined with recombinant granulocyte-macrophage colony-stimulating factor as treatment of chronic hepatitis C

Category 6: Viral hepatitis: clinical aspects

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MONONUCLEAR CELLS CYTOKINES AND INTERFERONOTHERAPY RESULTS PROGNOSING IN CHRONIC VIRAL HEPATITIS

Natalya Geyvandova, Mexandre Yagoda. Department of Internal

Diseases, State Medical Academi, Stavropol, Russia The purpose was to investigate possibilities ofinterferonotherapy outcomes prognosing in chronic viral hepatitis (CVH) on the basis of data about interferon-alpha (IFN-alpha), IFN-gamma, interleukine-4 (IL-4), IL-6, IL8 and tumor necrosis factor-alpha (TNF-alpha) synthesis in mononuclear cells (MNC). Subjects were 89 patiens: 65 - CVH C, 24 - CVH B. Spontaneous and FGA-induced cytokines production was studied before and 4.5 hours after the first injection of 3 mln CU of IFN-alpha. MNC were incubated in medium for 24 h at 37 C and assayed for cytokines by ELISA. Treatment was conducted within 6 months (9 mln CU of IFNalpha weekly - in CVH C and 15-18 mln CU - in CVH B). Predictors of interferonotherapy efficiency in CVH: normal spontaneous and induced IFN-alpha synthesis; growth of spontaneous IFN-gamma production and ratio of IFN-gamma/IL-4 (more than in 2 times in CVH C) after the first injection of IFN-alpha; spontaneous IL-6 production by MNC not superior 1.5 ng/2*106; spontaneous IL-8 synthesis not superior 11 ng/2*106 in CVH B and no more 10.5 ng/2*106 in CVH C; spontaneous TNF-alpha synthesis by MNC - not higher than 2.2 ng/2*106 in CVH C; increased spontaneous TNF-alpha production after the first injection of 3 mln CU of IFN-alpha in CVH B. Conclusions: The level of cytokines production by MNC in CVH and its change after the first injection of IFN-alpha can be used as predictors of interferonotherapy efficiency

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SINGLE NUCLEOTIDE POLYMORPHISM IN TUMOR NECROSIS FACTOR PROMOTER: ASSOCIATION WITH DISEASE PROGRESSION IN HEPATITIS C VIRUS INFECTION

A. Goyal 1'2, S.N. Kazim 1, M.K. Parvez 1, S. Wakil 1, N. Arora 2, S.K. Sarin I . ]Dept. of Gastroenterology, G.B. Pant Hospital; 2Centrefor

Biochemical Technology, Mall Road New Delhi, India Background: Pathogenesis of Hepatitis C virus infection remains an enigma. Immune gene polymorphism due to single nucleotide polymorphism such as TNF may influence disease progression and response to therapy in HCV infection. These inherited polymorphisms may result in variable levels of cytokine production TNF alpha production depends on SNP in TNF alpha promoter which are inherited. TNF beta activates NF kappa-B, which stimulates pro-inflammatory cytokines like TNF alpha Objective: To study whether single nucleotide polymorphism in TNFalpha and TNF-beta locus, influences, the progression of HCV infection Patients and Methods: Fifty Two Patients (mean age 41, male:female 38:14) with histologically proven chronic HCV infection, raised ALT (1.5X ULN) and HCV RNA positive were studied. Genotyping o f - 308 promoter variant and NcoI marker was done by sequence specific primers followed by restriction digestion with NcoI enzyme. Hundred and eleven healthy controls were included in the study. Results: The mean ALT was 105, histological active index was 9.0 and fibrosis score of 1.6. In patients, TNF-alpha - 308 GA allele frequency was higher compared with controls, R.R. of 1.4. TNF-beta AA allele also had a R.R. of 1.8. A strong genetic association was seen between TNF-alpha GG and TNF-beta AA, with R.R. of 6, indicating possible linkage between TNF beta AA allele and the TNF-alpha GG allele Conclusions: Immunogenetic factors, such as SNP in TNF-alpha (GA allele) and TNF beta (AA allele) may have a significant role in the course of HCV infection in viral persistence and disease progression.

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~-]HCV INFECTION SCREENING AND TREATMENT IN DRUG USERS FOLLOWED IN AN ADDICTION OUT PATIENT UNIT Veronique Grando l , Pierre Goisset 2, Frederic Sorge 2, Jean Claude Trinchet 1, Laurent Castera I , Dominique Roulot I , Veronique Sitruk I , Michel Beaugrand I . 1Service d'hepatologie, Hopital

Jean Verdier, Bondy; 2La Mosaique, SDPST 93, Montreuil, France Aim: to investigate efficiency of HCV screening and treatment of drug abusers (mostly heroin IV) enrolled in an addiction out patient program. Methods: all patients followed in an addiction unit were offered HCV ab testing; further evaluation and treatment if indicated, were proposed to positive patients. Results: between July 1997 and September 2000, 404 consecutive patients (310 men; mean age: 32; 94 per cent in substitution program) were included. 66 per cent of patients agreed for HCV ab testing: 83.6 per cent had positive test. Among them, 68 per cent accepted to perform ALT serum measurement and HCV mRNA. 120 had indication for liver biopsy, 32 patients declined. 88 liver biopsies were performed, showing severe fibrosis (Metavir score F3 or F4) in 20 cases. Ethanol intake (over 50 g per day in 51 per cent of patients) was significantly correlated to fibrosis. Antiviral treatment was indicated (Metavir score F2, F3 or F4) in 47 patients but was initiated only in 27 due to patient refusal (7) or contraindication (13). Treatment had to be discontinued in 12 cases because of psychiatric side effects (depression: 3; delirium: 3; severe irritability: 3; relapse in heroin addiction: 3). Finally, 12 patients completed the treatment by either interferon (4) or interferon and ribavirin (8). Only 4 were sustained responders. Conclusion: despite the high rate of indication for antiviral therapy, treatment benefit was low due to high drop out rate. Ethanol withdrawal must be the highest priority in these patients.

~8-7-] INTERFERON ALPHA-2b ALONE OR COMBINED WITH RECOMBINANT GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AS TREATMENT OF CHRONIC HEPATITIS C Karin Groenhaek I , Henrik Krarup 2, Helmet Ring-Larsen ~, Ove Schaffalitzsky de Muckadell 3, Axel Moeller 4, Poul Schlicting 5, Mogens Vyberg 6. 1Department of Hepatology, Rigshospitalet,

Copenhagen; 2Department of Clinical Biochemistry, Aalborg Hospital, Aalborg; 3Department of Medical Gastroenterology, Odense University Hospital, Odense; 4Department of lnfectious Diseases, Skejby University Hospital, Aarhus; 5Department of Medical Gastroenterology, Herlev University Hospital, Herlev; 6Department of Pathology, Aalborg Hospital, Aalborg, Denmark Aim: To compare the effect of interferon-alpha (INF-alpha) + granulocytemacrophage colony-stimulating factor (GM-CSF) to INF-alpha alone in the treatment of chronic hepatitis C. Methods: 45 patients with chronic hepatitis C were randomized to 1) INFalpha + GM-CSF for three months followed by INF-alpha alone for nine months (n = 23) or 2) INF-alpha for 12 months (n = 22). Both drugs were administered three times weekly in doses of 3 mU (INF-alpha) and 50-100 micrograms depending on body weight (GM-CSF). Results: After 12 months, more patients treated with GM-CSF + INFalpha compared to INF-alpha alone had normalized ALT (65 vs 32%, p = 0.03), but there was no difference in viral clearance (48 vs 32%, p = 0.27). After 6 months follow-up, the biochemical response had declined to 35% in the combination therapy group and to 23% in the monotherapy group (p = 0.37), viral clearance had declined to 22 vs 27% (p = 0.67) and the overall sustained response rate was 22 and 23% respectively (p = 1.00). One patient, from the monotherapy group, had the dose of INF-alpha tranciently reduced due to neutropenia. Conclusions: Although INF-alpha + GM-CSF had significantly better effect on the biochemical response during treatment compared to INF-alpha alone, the sustained biochemical and virological response was not increased. Thus, GM-CSF hardly plays any role in the future treatment of

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Poster Sessions

chronic hepatitis C, except for treatment of INF-alpha induced neutropenia.

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QOL BENEFITS OBSERVED AS EARLY AS WEEK 2 WITH PEGINTERFERON ALFA-2a (40KD) (PEGASYS) IN COMBINATION WITH RIBAVIRIN (RBV) VERSUS INTERFERON ALFA-2b PLUS RBV

T.I. Hassanien 1, W.G.E. Cooksley 2, M. Sulkowski 3, C. Smith 4, G. Marinos 5, M.-Y. Lai 6, G. Pastore 7, R. Trejo-Estrada s, A. Horta E. Vale 9, N.S. Winfield lo, M. Neary lo, j. Green 10.1 UCSD Liver Center, San Diego, CA; 2Royal Brisbane Hosp., Brisbane, Queensland; ~Johns Hopkins Univ., Baltimore, MD; 4Minn. Clin. Res. Ctr., St. Paul, MN; Sprince of Wales Hosp., Randwick, Australia; 6Natl. Taiwan Univ. Hosp., Taipei, Taiwan, ROC; r Univ. Policlinico, Bari, Italy; 8Centro Medico Nacional Siglo XXI, Mexico DE Mexico; 9Clinica Diagnostico Medico Integral, Vila Nova De Gaia, Portugal; l°Hoffmann-La Roche Inc., Nutley, NJ, USA Objective: To determine the relationship of time-on-therapy to QoL during treatment with peginterferon alfa-2a (40KD) + RBV versus IFN + RBV. Methods: Patients were treated for 48 weeks with peginterferon alfa-2a (40KD) + RBV or IFN + RBV and followed for an additional 12 weeks. QoL was assessed using the SF-36 and Fatigue Severity Scale (FSS). Scores were analyzed with a repeated-measures mixed-model ANCOVA. Results: For both treatment groups, QoL scores declined from baseline to week 2, declined further by week 12, and then remained stable through week 48. QoL was better for the peginterferon alfa-2a (40KD) + RBV group at week 2 on all scores, at week 12 on 6 SF-36 domains and FSS, and at weeks 24 and 48 on all scores. Differences were statistically significant at week 2 for Role-Physical and FSS, and at weeks 2 and 24 for Bodily Pain, Vitality, and Social Functioning. Consistent with improved QoL, patients in the peginterferon alfa-2a (40KD) + RBV group reported fewer complaints of pain and fatigue interfering with activities including work compared with the IFN + RBV group. Conclusion: Advantages in QoL favoring peginterferon alfa-2a (40KD) + RBV emerge as early as week 2 and continue throughout therapy. These results are consistent with lower rates of flu-like symptoms and depression for peginterferon alfa-2a (40KD) + RBV. More favorable QoL should reduce premature discontinuation.

(p < 5 10-5). Main non treatment reasons were normal ALT (42.4%) and contraindication to treatment (18.3%); differences according to the gender were found, particularly alcohol consumption and drug addiction more frequent in males than in females (p = 0.001 and p = 0.04). This study showed that in a general population one patient out of six remained out of healthcare progression. It revealed differences in management according to gender which need further investigations.

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Sidhartha Hazari 1, Subrat Panda I , Subrat Acharya 2. 1Department of Pathology, AIIMS, New Delhi; 2Department of Gastroenterology, AIIMS, New Delhi, India Background: All consensus recommendation for therapy in HCV suggests HCV RNA positivity as an important prerequisite. Concordance between anti HCV positivity and HCV RNA among patients with elevated ALT has been reported to be quite high. Therefore we evaluated the frequency of HCV RNA positivity among patients with elevated ALT and anti HCV positive and compared with similar frequency among anti HCV positive healthy blood donors without elevated ALT. Method: A total of 1785 healthy blood donors without any overt clinical disease with normal ALT and 116 patients with elevated ALT (more than 1.5 times) and anti HCV positivity were included. We also included patients with elevated ALT without anti HCV positivity. All these three groups of patients were screened for HBV, HAV, HEV infection. There were 65 blood donors, 116 patients with raised ALT and anti HCV positivity, and 30 patients with raised ALT but without any serological markers of hepatitis viral infection including anti HCV. HCV RNA was detected in 8/65 of blood donors, 110/116 among patients having anti HCV positive and raised ALT and 29/30 among patients having only raised ALT Coclusion: 97 percent patients with raised ALT without B, A and E had HCV RNA positivity and 97 percent patients with raised ALT and anti HCV positive had HCV RNA positive where as only 12 percent of patients had HCV RNA positive despite having anti HCV positive with normal ALT.

~-] ~80"] INEQUALITIES IN ACCESS TO HEALTHCARE OF HEPATITIS C PATIENTS IN A GENERAL POPULATION Cyril Hatem ], Anne Minello 1, Anne Claire Gossard 2, Valerie Jooste I , Philippe Evrard 2 Benedicte Obert 2, Emmanuel Rassiat I , Chantal Milan I , Elisabeth Monnet 2, Jean Philippe Miguet 2, Solange Bresson Hadni 2, Patrick Hillon 1. I Registre des Hepatites Virales de Cote d'Or - 7 bd, Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex; ZRegistre des Hepatites Virales du Doubs - Service d'Hepatologie - CHU Jean Minjoz - 25030 Besancon Cedex, France Our aim was to study the management of patients after hepatitis C diagnosis in a 1,006,171 inhabitants French population. A questionnaire was sent to practitioners who had pointed out hepatitis C cases to obtain complementary information. Between 1994 and 1999, 1508 HCV cases were diagnosed, of which 1251 were eligible for the study. A total of 201 (16.1%) patients did not have specialized medical care after diagnosis; among them 55.2% had normal ALT, 58.2% had risk factors related to lifestyle (drug addiction, sexual risk) and 22.4% were current alcoholics. Amongst the 1050 other patients, 441 (42.0%) had a liver biopsy and 263 (25.1%) were treated. Multivariate analysis showed that treatment was more often carded out in males than in females (p = 0.003), in patients under 65 than in older patients (p = 0.0002), in patients diagnosed by general practitioners or by gastroenterologists than by another specialist (p -- 0.0002), in non alcoholics patient or in former alcoholics than in current alcoholic patients

CONCORDANCE BETWEEN ANTI HCV AND HCV RNA AMONG PATIENTS WITH AND WITHOUT BIOCHEMICAL EVIDENCE OF LIVER DISEASE

SUSTAINED ANTIVIRAL RESPONSE AND LACK OF VIRAL RESISTANCE WITH LONG TERM ADEFOVlR DIPIVOXlL (ADV) THERAPY IN CHRONIC HBV INFECTION

Elizabeth Heathcote 1, Lennox Jeffers 2, Robert Perrillo 3, Teresa Wright 4, Morris Sherman 5, Hamid Namini 6, Shelly Xiong 6, Craig James 6, Victoria Ho 6, John Fry 6, Carol Brosgart 6. 1West Division, The Toronto Hospital, Toronto; 5Toronto General Hospital, Toronto, Ontario, Canada; 2Center for Liver Disease, University of Miami, Miami, Florida; 3Gastroenterology Department, Ochsner Medical Center, New Orleans, Louisiana; 4GI Unit, San Francisco VA Medical Center, San Francisco, California; 6Clinical Research, Gilead Sciences, Foster Oty, California, USA

Objective: To evaluate long-term safety, antiviral activity, and viral resistance in a Phase II, open-label, extension study. Methods: 39 patients (28 HBeAg+ and 11 precore mutants) who completed Phase II ADV studies were enrolled. Patients initially received 30 mg daily, but were dose reduced to 10 mg daily for chronic therapy. Results: At baseline, median age: 41, male: 85%, Asian: 51%, precore mutants: 28%, median HBV DNA: 8.02 logl0 copies/mL (Roche PCR), median ALT: 83 IU/L. To date, 21 patients continue ADV with median duration of ADV, 88 weeks (range 4-136). Median HBV DNA reductions of 3.40 (p < 0.0001, N = 33) and 3.36 (p < 0.0001, N = 23) logl0 copies/mL observed at Week 48 and 100, respectively. By Week 100, HBV DNA was undetectable (<400) in 70% of patients. Median ALT reductions of 36 (N -- 30) and 48 IU/L (N = 22) observed at Week 48 and 100, respectively. By