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High dose of interferonα (IFN) plus ribavirin (RIBA) for 6 or 12 months in non responder (NR) patients with chronic hepatitis C (CHC): Results of a randomized trial
Viral hepatitis: clinical aspects
[
P/C06/73
]
BONE MASS AND CHRONIC VIRAL HEPATITIS M. Auletta ~, V. Nuzzo, E Fonderico, M.R. Fittipaldi, S. Antoniello u, G. Lupoli IDepartment of Clinical Medicine and Cardiovascular Sciences, and Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy. The liver plays a central role in bone metabolism. Several studies reported low bone mineral density (BMD) in chronic liver disease especially cholestatic, alcoholic, corticosteroid-treated chronic hepatitis, bemochromatosis. Aim of the present study was to examine the prevalence of osteoporosis and/or osteopenia in a consecutive series of patients affected by chronic viral hepatitis. Twenty five male patients, aged 41-59 years, affected by biopsy-proven chronic hepatitis correlated to C virus were studied. Exclusion criteria were: body mass index (BMI) <20 and >25 Kg/m2, hyperbilirubinemia, advanced liver cirrhosis, cholestatic and alcoholic liver disease, previous therapy or disease affecting bone mass. BMD was evaluated by dual energy X-ray absorptiometry (DEXA) at lumbar spine (LI-IA) and femural neck (FN) using a hologic QDR 1000 densitometer. The results are expressed as BMD (g/cm2), T score (SD from the mean value obtained in 30-years-old subjects) and Z score (SD from the mean value obtained in subjects of the same age and sex). Serum calcium, phosphorus, ALP, gonadotropins, testosterone, thyroid hormones, cortisol, PTH, urinary calcium and hydroxyproline were evaluated. A complete clinical, biochemical and ultrasonographic evaluation of liver desease was performed. The results showed an alteration of bone mass in 16 out of 25 patients (64%): in fact, T score resulted <-1 SD in 11 (44%), and <-2.5 SD in 5 patients (20%). Moreover an inverse correlation (p< 0.05) was found only among BMD at lumbar spine, serum calcium and duration of liver disease. At femoral neck a direct correlation between BMD and BMI (p<0.05) and an inverse one between BMD and cortisol (p<0.05) were found. No correlation was found with patient's age. The reduction of BMD in patients with non advanced viral liver disease suggests that more attention should be paid to BMD in patients without eholestasis, alcoholic consumption, malnutrition, and/or factors affecting bone metabolism.
P/C06/74
]
I
HIGH DOSE OF INTERFERONa (IFN) PLUS RIBAVIRIN (RIBA) FOR 6 OR 12 MONTHS IN NON RESPONDER (NR) PATIENTS WITH CHRONIC HEPATITIS C (CHC): RESULTS OF A RANDOMIZED TRIAL P. Andreone, C. Cursaro, A. Gramenzi, M. Margotti, E. FerrL S. Talarico, L. Di Giammarino, R. Carella 1, A. D'Errico l, M. Spinosa2, P. Spagnuolo, M. Bernardi Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, University of Bologna, Italy. tDipartimento di Anatomia Patologica, University of Bologna, Italy. 2Dipartimento di Centro Trasfusionale, Ospedale di Termoli, Italy. Background: the ~ e m e n t o f pts with CHC NR to IFN monotherapy remains a problem. The results o f retreatme~t with a standard re~imen o f IFN plus RIBA for 6 mo are disappointing. Aim: to evaluate the efficacy and the tolerability o f high IFN dose and prolonged time o f combined treatment in NR HCV-positive pts. Methods: 85 pts with CHC NR after one or more courses o f IFN monotherapy were retreated with IFN-a2b (5 MU fiw) plus RIBA (1-1.2 g daily). Forty-four were randomized to receive 6 mo (group A) and 41 12 mo (group B) o f combination therapy. Complete response was defined as ALT normalization and serum HCV-RNA cleurance by PCR at the end o f treatment and 6 mo after stopping therapy. Resuits." intent-to-treat analysis is reported in the table. 15/41 (37%) Ns 7/41 (17%9 Ns Eleven pts of group A (25%) and 13 o f the group B (32%) discontinued treaonent for side effects. A statistically significant reduction o f the Histological Activity Index was observed in both group (group A: 9.2:~3 vs 7.9+_.3.7, p=0.03; group B: 9.6.+_2.9 vs 7.6:£-4.4, p=0.02). Conclusions: this study demonstrates that a certain number o f NR pts can beneficiate o f high dose o f IFN plus RIBA but a 12 mo course is not more efficacious than 6 mo. However a high proportion o f pts does not tolerate this treatment schedule.
EEnn~d °offfot~l~wt~-utp
18/44 (39%) [ 8,44 (18%)
P/C06/76 ]
MODULATION OF TH-lrFH-2 SERUM CYTOKINE PROFILES AND TNF-RECEPTOR RESPONSE IN PATIENTS WITH CHRONIC HEPATITIS C DURING INTERLEUKIN-12 (IL-12) TREATMENT G. Teuber 1, S. Rossol 2, J.H. Lee I, C.E Dietrich I, W.E Caspary I, S. Zeuzem ~ 1Universit~itskliniken, Frankfurt, Germany. 2Universit~tskliniken, Mannhelm, Germany.
IL-12 exerts several antiviral activities in vitro including the enhancement of cytolytic lymphocyte response, the promotion of Thl-type helper cell responses and induction of interferon# (IFN~) production. In the present study, potential antiviral effects of IL-12 were investigated in 11 patients with chronic hepatitis C (8 males, 3 females, mean age: 45.7 yrs), treated with recombinant human IL-12 within 3 different dosage groups (0.03, 0.1, 0.5 mg/kg) once weekly s.c. for 10 weeks. Serum concentretlons of IL12, IL-12-p40, IFN~, IL-2, tumor necrosis facfor-~ (TNF~), TNFR-p55 and -p75 were determined by EIAs before treatment, at days 3, 5, 8, 10, 12, 15, 17, 22 and thereafter once weekly during the treatment period and at the end of the 12 weeks follow-up period. HCV-RNA was determined by quantitative HCV-RNA (Amplioor Monitor 2.0). Significant, transient increases of serum IL-12, IL-12-p40, IFN-x and TNFR-p55 ¢oncenrations ware observed 2-3 days after IL-12 administration decreasing to pretreatment levels before the next IL-12 injections. A significant sustained increase during the entire treatment period was found for TNFR.p75 serum concentrations. The observed increase of these cytokines were more pronounced in patients treated within the higher dosage groups. There was a trend towards higher IL-12 serum concentrations in patients with a decline of serum HCV-RNA levels. However, serum IL-2, TNF-cz and 11.-10profiles fluctuated during IL-12 treatment. In conclusion, once weekly administration oflL-12 leads only to a transient increase of IL-12, IL-12-p40 and of Th-1 cytokines serum levels. The lack of a sustained induction:of Th-1 cytokine response may be a possible explanation for the reported poor clinical efficacy of IL-12 in patients with chronic hepatitis C.
115
[
P/C06/73
]
BONE MASS AND CHRONIC VIRAL HEPATITIS M. Auletta ~, V. Nuzzo, E Fonderico, M.R. Fittipaldi, S. Antoniello u, G. Lupoli IDepartment of Clinical Medicine and Cardiovascular Sciences, and Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy. The liver plays a central role in bone metabolism. Several studies reported low bone mineral density (BMD) in chronic liver disease especially cholestatic, alcoholic, corticosteroid-treated chronic hepatitis, bemochromatosis. Aim of the present study was to examine the prevalence of osteoporosis and/or osteopenia in a consecutive series of patients affected by chronic viral hepatitis. Twenty five male patients, aged 41-59 years, affected by biopsy-proven chronic hepatitis correlated to C virus were studied. Exclusion criteria were: body mass index (BMI) <20 and >25 Kg/m2, hyperbilirubinemia, advanced liver cirrhosis, cholestatic and alcoholic liver disease, previous therapy or disease affecting bone mass. BMD was evaluated by dual energy X-ray absorptiometry (DEXA) at lumbar spine (LI-IA) and femural neck (FN) using a hologic QDR 1000 densitometer. The results are expressed as BMD (g/cm2), T score (SD from the mean value obtained in 30-years-old subjects) and Z score (SD from the mean value obtained in subjects of the same age and sex). Serum calcium, phosphorus, ALP, gonadotropins, testosterone, thyroid hormones, cortisol, PTH, urinary calcium and hydroxyproline were evaluated. A complete clinical, biochemical and ultrasonographic evaluation of liver desease was performed. The results showed an alteration of bone mass in 16 out of 25 patients (64%): in fact, T score resulted <-1 SD in 11 (44%), and <-2.5 SD in 5 patients (20%). Moreover an inverse correlation (p< 0.05) was found only among BMD at lumbar spine, serum calcium and duration of liver disease. At femoral neck a direct correlation between BMD and BMI (p<0.05) and an inverse one between BMD and cortisol (p<0.05) were found. No correlation was found with patient's age. The reduction of BMD in patients with non advanced viral liver disease suggests that more attention should be paid to BMD in patients without eholestasis, alcoholic consumption, malnutrition, and/or factors affecting bone metabolism.
P/C06/74
]
I
HIGH DOSE OF INTERFERONa (IFN) PLUS RIBAVIRIN (RIBA) FOR 6 OR 12 MONTHS IN NON RESPONDER (NR) PATIENTS WITH CHRONIC HEPATITIS C (CHC): RESULTS OF A RANDOMIZED TRIAL P. Andreone, C. Cursaro, A. Gramenzi, M. Margotti, E. FerrL S. Talarico, L. Di Giammarino, R. Carella 1, A. D'Errico l, M. Spinosa2, P. Spagnuolo, M. Bernardi Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, University of Bologna, Italy. tDipartimento di Anatomia Patologica, University of Bologna, Italy. 2Dipartimento di Centro Trasfusionale, Ospedale di Termoli, Italy. Background: the ~ e m e n t o f pts with CHC NR to IFN monotherapy remains a problem. The results o f retreatme~t with a standard re~imen o f IFN plus RIBA for 6 mo are disappointing. Aim: to evaluate the efficacy and the tolerability o f high IFN dose and prolonged time o f combined treatment in NR HCV-positive pts. Methods: 85 pts with CHC NR after one or more courses o f IFN monotherapy were retreated with IFN-a2b (5 MU fiw) plus RIBA (1-1.2 g daily). Forty-four were randomized to receive 6 mo (group A) and 41 12 mo (group B) o f combination therapy. Complete response was defined as ALT normalization and serum HCV-RNA cleurance by PCR at the end o f treatment and 6 mo after stopping therapy. Resuits." intent-to-treat analysis is reported in the table. 15/41 (37%) Ns 7/41 (17%9 Ns Eleven pts of group A (25%) and 13 o f the group B (32%) discontinued treaonent for side effects. A statistically significant reduction o f the Histological Activity Index was observed in both group (group A: 9.2:~3 vs 7.9+_.3.7, p=0.03; group B: 9.6.+_2.9 vs 7.6:£-4.4, p=0.02). Conclusions: this study demonstrates that a certain number o f NR pts can beneficiate o f high dose o f IFN plus RIBA but a 12 mo course is not more efficacious than 6 mo. However a high proportion o f pts does not tolerate this treatment schedule.
EEnn~d °offfot~l~wt~-utp
18/44 (39%) [ 8,44 (18%)
P/C06/76 ]
MODULATION OF TH-lrFH-2 SERUM CYTOKINE PROFILES AND TNF-RECEPTOR RESPONSE IN PATIENTS WITH CHRONIC HEPATITIS C DURING INTERLEUKIN-12 (IL-12) TREATMENT G. Teuber 1, S. Rossol 2, J.H. Lee I, C.E Dietrich I, W.E Caspary I, S. Zeuzem ~ 1Universit~itskliniken, Frankfurt, Germany. 2Universit~tskliniken, Mannhelm, Germany.
IL-12 exerts several antiviral activities in vitro including the enhancement of cytolytic lymphocyte response, the promotion of Thl-type helper cell responses and induction of interferon# (IFN~) production. In the present study, potential antiviral effects of IL-12 were investigated in 11 patients with chronic hepatitis C (8 males, 3 females, mean age: 45.7 yrs), treated with recombinant human IL-12 within 3 different dosage groups (0.03, 0.1, 0.5 mg/kg) once weekly s.c. for 10 weeks. Serum concentretlons of IL12, IL-12-p40, IFN~, IL-2, tumor necrosis facfor-~ (TNF~), TNFR-p55 and -p75 were determined by EIAs before treatment, at days 3, 5, 8, 10, 12, 15, 17, 22 and thereafter once weekly during the treatment period and at the end of the 12 weeks follow-up period. HCV-RNA was determined by quantitative HCV-RNA (Amplioor Monitor 2.0). Significant, transient increases of serum IL-12, IL-12-p40, IFN-x and TNFR-p55 ¢oncenrations ware observed 2-3 days after IL-12 administration decreasing to pretreatment levels before the next IL-12 injections. A significant sustained increase during the entire treatment period was found for TNFR.p75 serum concentrations. The observed increase of these cytokines were more pronounced in patients treated within the higher dosage groups. There was a trend towards higher IL-12 serum concentrations in patients with a decline of serum HCV-RNA levels. However, serum IL-2, TNF-cz and 11.-10profiles fluctuated during IL-12 treatment. In conclusion, once weekly administration oflL-12 leads only to a transient increase of IL-12, IL-12-p40 and of Th-1 cytokines serum levels. The lack of a sustained induction:of Th-1 cytokine response may be a possible explanation for the reported poor clinical efficacy of IL-12 in patients with chronic hepatitis C.
115