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Digestive Disease Conference: Day Three

Alan Franciscus
Editor-in-Chief, HCV Advocate

Abstract 504
Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: Final Results.
Ira M. Jacobson, Furqaan Ahmed, Mark W. Russo, Robert S. Brown Jr., Edward Lebovics, Albert Min, Stephen Esposito, Norbert Brau, Hillel Tobias, Franklin Klion, Edmund Bini, Neil Brodsky, Deborah Rovner, Clifford Brass, NY PEG-Intron Study Group

Background:

Pegylated interferon (PEG IFN) has proven superior to standard interferon (IFN) as monotherapy for chronic hepatitis C and, more recently, in combination with ribavirin (RBV) in treatment naive patients.

Aim:

To compare the efficacy of two dose regimens of peginterferon alfa-2b plus ribavirin in patients with prior nonresponse to IFN monotherapy or combination therapy, or with relapse after combination therapy. We present final data from this study.

Methods/Patients:

Patients in the three categories were randomized to receive:

Peginterferon alfa-2b 1.0 µ/kg plus RBV 1000-1200 mg/d (Group 1), or Peginterferon alfa-2b 1.5 µ/kg plus RBV 800 mg/d (Group 2).

Prior therapy must have been stopped at least three months prior to entry. Three hundred twenty one patients were treated for 48 weeks with cessation of therapy if HCV RNA PCR (Roche Amplicor) was positive at 24 weeks.

Fibrosis scores—stage 2, group 1-18%; group 2-14% (p=ns); stage 3-4, group 1-5%; group 2-24% (p=0.03)

Results:

Of 321 patients enrolled in the study, 161 were randomized to Group 1 and 160 were randomized to Group 2. Overall, the sustained response (SR) rate was 15% across the three categories. SR rates for the different treatment groups are given in the table. Among the combination nonresponders, patients with genotype 1 had lower SR rates than non-genotype 1 patients (5-9% vs. 13-25%). Patients with normal ALT respond as well as those with an elevated ALT at onset of therapy (21% vs. 14%, p=0.54).

Patients with advanced fibrosis (Metavir stage 3-4) tend to do respond better with the higher dose of PEG IFN (25% vs. 5%, p=0.44)

Conclusions:

SR rates are highest in combination relapsers (range 32-47%) and lowest in genotype 1 combination nonresponders (range 5-9%).
Breakthrough and relapse are more common than in naive patients; the concept of treatment for more than 12 months warrants further study.
Higher dose of PEG IFN may be better in patients with fibrosis.
Normal ALT does not adversely affect response.
Lower treatment response results in African Americans than other groups

This study is supported by Schering-Plough Corporation.

Quantitative PCR <1000 cop/ml at follow-up week 24

	Week 24	Week 48	SVR
Comb NR- Group 1	20/114 (18%)	12/114 (11%)	7/114 (6%)
Comb NR- Group 2	31/105 (30%)	23/105 (22%)	10/105 (10%)*
Comb Rel- Group 1	18/25 (72%)	13/25 (52%)	8/25 (32%)
Comb Rel- Group 2	24/30 (80%)	23/30 (77%)	14/30 (47%)*
IFN NR- Group 1	10/22 (45%)	7/22 (32%)	6/22 (27%)
IFN NR- Group 2	13/25 (52%)	10/25 (40%)	4/25 (16%)*
*93% of Comb NR were genotype 1.p>0.05 Group 1 vs. Group 2**

Abstract 505
Epoetin alfa Treatment of Anemic HCV-infected Patients Allows for Maintenance of Ribavirin Dose, Increases Hemoglobin Levels, and Improves Quality of Life Vs Placebo: a Randomized, Double-blind, Multicenter Study
Nezam H. Afdhal, Douglas T. Dieterich, Paul J. Pockros, Eugene R. Schiff, Mitchell L. Shiffman, Mark S. Sulkowski, Teresa Wright, Zobair Younossi, Peter J. Bowers

Background:

Combination therapy for chronic HCV infection is ribavirin (RBV)/interferon a (IFN) or RBV/pegylated IFN a (PEG-IFN)—induces anemia that may compromise the ability to achieve a sustained virologic response (SVR) by prompting RBV dose reduction or cessation. Treatment (tx) adherence is critical for achieving an sustained virolocial response, and studies suggest that maintaining higher RBV doses (1000/1200 mg/day vs 800 mg/day) is more effective (Hadziyannis et al., EASL. 2002; Manns et al., Lancet. 2001; McHutchison, Hepatology. 2000).

We assessed whether epoetin alfa (EPO) treatment of anemic (Hb £12 g/dL) HCV-infected patients (pts) could maintain RBV dose, increase hemoglobin (Hb) levels, and improve quality of life (QOL).

Methods:

HCV patients (N=186) who developed anemia while being treated with RBV/IFN or RBV/PEG-IFN for an anticipated period of ³16 weeks were randomized to receive 40,000—60,000 IU, SC QW epoetin alfa or matched placebo (PL) with titration for 8 wks (double-blind phase [DBP]).

Following the double-blind phase, eligible patients received open-label epoetin alfa for the remainder of their HCV therapy. After HCV therapy cessation, patients were followed at 4, 12, and 24 weeks. The primary efficacy endpoint (assessed at the end of week 8) was RBV dose success—a week 8 RBV dose ³study entry RBV dose. Secondary efficacy endpoints assessed at Weeks 9 and 17 were RBV dose, change in Hb levels, and QOL self-assessments (Linear Analog Scale Assessment [LASA] and Medical Outcomes Study Short Form-36v2 [SF-36v2]).

Results:

By week: Patients (n=95 [EPO], n= 92 [PL]) had similar baseline (BL) characteristics. RBV dose success was achieved in 82 patients (88%) of patients on epoetin alfa versus 50patients (60%) on PL (P<.001). Mean RBV doses at the end of the double blinded DBP were 944 (+/-) 217 mg/day (EPO) and 855 (+/-)241 mg/day (PL) (P<.001). At 8 wks, 80% of EPO-treated pts had a RBV dose = the dose at the start of HCV therapy vs 49% of ptson PL (P<.0001). Mean Hb levels at the end of the double blinded phase were 13.0 (+/-) 1.3 g/dL (EPO) vs 10.8 (+/-) 1.0 g/dL(PL) (P<.001); mean changes from BL Hb were +2.2 (+/-) 1.3 g/dL (Epoetin) and 0 (+/-) 1.0 g/dL (PL). Mean scores on the LASA and selected SF-36v2 domains improved significantly from BL with EPO vs PL(P<.001—.003). Epoetin alfa appeared safe and well tolerated.

Conclusions:

In anemic HCV-infected patients on RBV/IFN or RBV/PEG-IFN, EPO maintains RBV dose and significantly improves anemia and QOL. Epoetin alfa has the potential to improve adherence rates, which may in turn improve sustain virological response rates.

Abstract 1204
Effect of Silybum Marianum on Serum ALT and Well Being in Chronic Hepatitis C
Adam Gordon, Daryl A. Hobbs, Andrew J. P. Francis, Stuart K. Roberts

Introduction:

Chronic hepatitis C (CHC) often causes significant morbidity in subjects via fatigue and impaired quality of life (QOL). Silybum marianum is a herbal preparation commonly used by subjects with CHC. However, limited information is available on its efficacy in improving liver chemistries and symptoms.

Aim:

Thus, the AIMS of this study are to assess the efficacy and safety of 600mg and 1200mg of silybum marianum on ALT levels and well being in patients with CHC.

Patients and Methods:

We enrolled 24 subjects with CHC into a randomized, double-blinded, placebo-controlled, cross-over study. Subjects received 12 weeks of both silybum (either 600mg or 1200mg/d) and placebo given in random order across the cohort, with treatment periods separated by a 4 week washout interval. Subjects were followed for 12 weeks after the second treatment phase. Baseline biochemical, virological, psychological and QOL Short Form 36 (SF36) tests were performed. Biochemical tests were repeated monthly, and QOL assessments were repeated at the end of both treatment periods. ALT results were blinded to subjects and clinicians during the study. Comparisons were made using the Student t test and ?2 analysis.

Results:

16 patients completed the trial, including 10 male subjects and 10 (63%) subjects with genotype 1 infection; this reflects the distribution of CHC in the Australia. The mean total SF36 score increased with silybum therapy compared to baseline (73.7(+/-)19.4 v 60.6(+/-)17.6; p=0.003) but not compared to placebo (p=0.74). Mean scores for individual SF36 domains and anxiety did not differ significantly between silybum and placebo. The mean ALT after treatment with silybum was not significantly different compared to placebo (87U/L(+/-)36 v 103U/L(+/-)60;p=0.10) and baseline levels (97U/L(+/-)46). Also, the mean change in ALT on silybum was not significantly different compared to placebo (+5U/L(+/-)32 v +5U/L(+/-)57; p=0.98). Three patients on silybum and 4 on placebo achieved a 25% reduction in ALT. The frequency of adverse events was similar with silybum and placebo (p=0.24). No significant adverse events occurred and no significant differences were seen with daily doses of 600mg and 1200mg silybum.

All P values=not significant

Change in liver chemistries in placebo and silybum marianum

Parameter ?Placebo ? S. marianum P value

ALT (u/l) 4 (+/-) 57 6 (+/-) 32 .90

Bilirubin (mol/l) 0 (+/-) 1 -1 (+/-) 3 .057

SGT (IU/l) 8 (+/-) 27 - 3 (+/-) 21 .09

ALP (U/L) -1 (+/-) 13 -4 (+/-) 17 0.26

Conclusion:

Silybum is safe and well tolerated in subjects with chronic hepatitis C. However, silybum does not significantly affect QOL, anxiety or ALT values compared to placebo, and hence appears to have little efficacy in CHC, but does result in a significant increase in STAI S-anxiety score.

Abstract 1206
Pegylated Interferon alpha 2b (PEG-IFN) plus Ribavirin (RBV) versus Pegylated Interferon alpha 2b for Chronic Hepatitis C in HIV Patients
Antonietta Cargnel, Elena Angeli, Annalisa Mainini, Guido Gubertini, Riccardo Giorgi, Giovanna Orlando, Piergiorgio Duca, Italian Coinfection Study Group ICOS

Background:

In HIV positive patients chronic hepatitis C has an aggressive course, and mortality for end stage liver disease is growing
The introduction of highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV infected individuals
In these conditions, treatment of chronic hepatitis C in co-infected patients becomes crucial
Little data is available concerning the use of PEG-IFN plus ribavirin in HIV/HCV coinfected patients
Because of the complexities of HAART, drug-drug interactions can occur

Objective:

To study the efficacy and tolerability of PEG-IFN plus ribavirin versus PEG-IFN alone

Methods:

HIV-HCV patients were randomized in an open, prospective, multi-center study
Inclusion criteria were: stable HIV-RNA <400 cp/mL and CD4+ cells > 300 cells/mm3
Clinical and laboratory monitoring were performed at regular intervals.

Treatment Schedule:

PEG-IFN 1.5 µg/kg qw plus ribavirin 800 mg/daily – Group A
PeG-IFN 1.5 µg/kg qw – Group B

Baseline characteristics

	PEG-IFN/ Riba (A)	PEG-IFN (B)
Gender	55 males 14 females	57 males 9 females
Age	39 (31-61)	38 (22-65)
HIV Epidemiology: IVDU Sexual Not available	51 14 4	58 7 1
Mean CD4+ cell/mm3	566 (300-1448)	617 (307-1429)
Mean ALT	142 (22-1000)	143 (24-543)
Mean HCV-RNA (log10 IU/ML)	5.9	5.9
Genotype 1/3; 2/3	37;32	31;33

Interim data 48 weeks

48 weeks

Virological response (negative PCR) in 12 patients (63.2%); 9/10 patients (90%) treated with PEG-IFN/RBV, 3/9 (33.3% with PEG-IFN; Fisher’s exact test p=0.019

Kinetics of HCV-RNA: 6th/12th Month of Treatment

A drop of more than 2 logs of HCV-RNA at month 2 is significantly related to virological response at month 6 (p=0.0004 Fishers exact test) and at month 12 (p=0.0018 Fisher’s exact test)

Potential Factors Influencing the Response to Anti-HCV Therapy

	Responders (24 weeks)	Non-Responders (24 weeks)
Mean age	38.8	37.7	n.s
Male/Female	22/4	38/8	n.s
IVDU/Others	20/6	38/8	n.s
Genotype 1, 4 Genotype 2,3	7 19	30 16	P= 0.0029
ECA Cirrhosis	26 0	34 8	P= 0.0199
Mean CD4+ (cells/ mm³)	599	138	n.s
Mean ALT (IU/mL)	168	138	n.s
Mean HCV-RNA (log10 IU/mL	5.9	6	n.s

Toxicity and Tolerablity (1):

CD4+ cell/mmD4+ cell counts decreased at week 24 (group A: 600 ® 453; group B: 621® 491 cells/mm3); an increase (2 log) of HIV RNA was observed in 2 patients
Therapy was discontinued in 51 (37.7%) patients, mostly during the first month (28/52 ® 54.9%) without a significant difference between the groups (group A:29/69; group B: 22/66, p = 0.37)
Reason for discontinuation were
- Trial violation (11 patients)
- Side Effects (33 patients, 24.4%)
- Compliance (7 patients)

Toxicity and Tolerablity (2):

PEG-IFN dose was reduced in 19 patients (14%) and RBV in 7 patients (10.1%)
The most frequently observed adverse events included: hematologic toxicity (11.8%), flu-like syndrome (8.9%), psychiatric disorders (2.9%), cutaneous rash (1.5%)
Three patients had a significant increase in ALT levels after 24 weeks of therapy; for one patient, it was related to the introduction nevirapine (NVP) in antiretroviral therapy.
Neither life threatening adverse events nor sever lactic acidosis occurred, independently from HAART regimen

Conclusion:

Preliminary results indicate that PEG-IFN plus ribavirin appears to be a promising choice for HIV/HCV coinfected patients
The high percentage of study discontinuations may be related to low awareness of early adverse events or lack of motivation of patients to continue treatment. Counseling is extremely important to improve compliance.
A drop of more than 2 logs of HCV –RNA after 8 weeks seems to be predictive of virological response at 24 and 48 weeks, but this finding needs to be confirmed by further results.

Abstract 1207
A Preliminary Study of Growth Factors Versus Dose Reduction for Peg Interferon Alfa-2b and Ribavirin Associated Neutropenia and Anemia in HIV/HCV Co-Infected Patients.
Preeti Golia, Andrew H. Talal, Ira M. Jacobson, Sandra Flynn, Piyush Golia

Background:

HIV/HCV co-infection is a major cause of liver-related morbidity and mortality. Pegylated interferon (IFN-a) and ribavirin (RBV) are commonly associated with neutropenia and anemia, leading to discontinuation in up to 27% of co-infected patients.

Aim:

We prospectively evaluated the safety of Peg IFN-a-2b/RBV and compared two management strategies for the treatment of medication-associated anemia and neutropenia in co-infected patients.

Methods:

Twenty-one HCV/HIV co-infected, therapy-naive subjects with hemoglobin (hbg) levels of > 11 mg/dL and absolute neutrophil counts (ANC) > 1,200/mm3 were treated with Peg-IFN a-2b 1.5mcg /kg/wk and RBV 13 2 mg/kg/day. Safety and tolerability were evaluated at Weeks 1, 2, 4, and monthly until Week 48 with serial CBC, CD4 T-cell counts, HIV and HCV RNA levels. Subjects whose hgb was =10 mg/dL were randomized to either receive recombinant human erythropoietin (epoetin alfa) 40,000 U/wk (Group A, n = 13) or RBV dose reduction to 10 mg/kg/d (Group B, n = 7). Subjects whose ANC was =750 cells/mm3 were randomized to either receive Granulocyte-Colony Stimulating Factor (G-CSF) 5 mg/kg/d BIW (Group A, n = 7) or to Peg-IFN dose reduction to 1.0 mcg/kg/wk (Group B, n = 3).

Results:

Twenty-one (17 male) patients with a mean age of 47.0 (range = 36 - 60) years, who have been followed for a mean of 20 (range = 6 - 42) weeks, had a baseline mean hgb = 14 mg/dL and mean ANC = 1935/mm3. During the study, one subject withdrew consent on day 5, an additional subject was withdrawn secondary to refractory anemia, and two subjects secondary to refractory neutropenia. At Week 4, 13/20 patients had a mean hgb decrease of 2.8 +/- 0.75 mg/dL that declined by a mean of 3.5 +/- 0.76 mg/dL by Week 12. In Group A, 7/13 patients had a mean hbg increase from 8.9 mg/dL to 9.7 mg/dL (p = 0.03) while in Group B, 4/13 patients had a mean hbg increase from 9.9 mg/dL to11.4 mg/dL (p = 0.02) within two weeks after the intervention. At Week 4, 10/20 patients had a mean ANC decrease of 1015/mm3 that declined by a mean of 1148/mm3 by Week 12. In Group A, 3/10 patients had a mean ANC increase from 571 to 1814/mm3 (p=0.15) while in Group B, 7/10 patients had a mean ANC increase from 553 to 2013/mm3 (p=0.16) within two weeks after the intervention.

The effect of dose reduction growth factor supplementation in therapeutic response (HCV RNA) will be determined upon study completion.

Results - Anemia
Characteristics:

Developed at an average of eight weeks
NADIR hgb at week 9
Mean baseline hgb Group A: 13.6 mg/dl
Mean baseline hgb Group B: 14.0 mg/dl

Mean hgb increase post 4 week of intervention

Group A (11/18) 9.3 mgl/dl to 106 mg/dl (P=.0003)
Group B (5/18) 9.6 mg/dl to 11.1 mg/dl (P=.002)

Outcome

Hgb response to each intervention dose does not differ significantly (P=0.29)

Results – Neutropenia Characteristics

Developed neutropenia at an average of 8.8 weeks
NADIR ANC at week 12
Mean baseline ANC Group A: 2,225 /mm3
Mean basline ANC Group B: 3,222 / mm3

Mean ANC increase post 3.6 weeks of intervention

Group A (4/12) 600 to 2,806 / mm3 (P=0.16)
Group B (5/12) 551 to 1,749/ mm3 (P=0.13)

Outcome

ANC response to each intervention does not differ significantly (P=0.33)

Conclusion:

Anemia and neutropenia are common side effects of Peg-IFN and RBV treatment. Growth factor supplementation and dose-reduction are effective for the management of neutropenia and anemia in HIV/HCV co-infected individuals.

Abstract 1208
Non-Invasive Assessment of Fibrosis Resolution/Progression in Chronic Hepatitis C Patients Who Received Anti-Viral Therapy
Yasushi Shiratori, Haruki Yamada, Yusei Ikeda, Masayuki Matsumura, Naoaki Hashimoto, Ryo Nakata, Masao Omata

Introduction:

Liver fibrosis is a dynamic process, with phases of either net matrix deposition or net degradation leading, respectively, to progression or regression of fibrosis. Recently, there are several reports indicating that fibrosis of the liver regressed in patients with sustained virological response. Fibrosis progression was also retarded in patients who received interferon therapy (Shiratori Y, Ann Intern Med 2000). Fibrosis regression stage could be assessed by repeated liver biopsy, but liver biopsy sometimes induces serious event of bleeding or death. Thus, it may be benefit for the patients to assess fibrosis regression state using blood only.

Methods:

To evaluate the dynamics of fibrosis progression/regression in chronic hepatitis C patients, thirty-seven patients who received a daily administration of 6 to 10 million unit (MU) of interferon-alfa 2b thrice weekly for 24-26 weeks were enrolled.

PIIIP levels, cytokines contributing to matrix production (PDGF, TGF-beta), and the enzymes regulating matrix degradation (MMP-1, TIMP-1) in serum were measured during therapy, at the completion of therapy, and 24, 48, and 72 weeks after the end of therapy.

Results:

When the patients were categorized according to sustained response state to interferon, PIIIP levels was markedly decreased in sustained responders during treatment and after the end of treatment, while it was not decreased in the non-sustained responders. Both TGF-beta and PDGF levels were markedly decreased in sustained responders during IFN therapy and shortly thereafter, but these values in non-sustained responders were not changed after the end of therapy. Although MMP-1 level was not changed in sustained responders as well as non-sustained responders during treatment and after the end of treatment, TIMP-1 level in sustained responder was significantly reduced after the end of treatment and thereafter, while that in non-sustained responders was not changed.

Conclusion:

These results suggest that there is an increase in matrix degeneration process which 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 matrix degradation even after the end of treatment. The present data may indicate that extracellular matrix degradation persists in sustained responders. By measuring these cytokines and enzymes, the process of degradation of matrix could be evaluated without liver biopsy.

Abstract 1209
Safety and efficacy of pegylated interferon (peg INF)-alfa-2b plus ribavirin (RBV) for the treatment of chronic hepatitis C in HIV-coinfected patients: 48 week results.
Esther Voigt, Christian Schulz, Gerd Klausen, Joachim Goelz, Stefan Mauss, Antonius Mutz, Franz A. Mosthaf, Elke Lauenroth-Mai, Juergen K. Rockstroh

Background:

The natural course of chronic hepatitis C is accelerated in HIV coinfected patients. Therefore specific treatment strategies are urgently needed. We evaluated long term efficacy and safety of peg INF-alfa-2b plus RBV for treatment of HCV in HIV-coinfected patients.

Methods:

Within this open label, uncontrolled, multicenter 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 patients have been enrolled so far. Follow up is still ongoing.

Results:

Here we present data on 52 patients who have completed 48 weeks. At baseline 52 patients (median age 38.5 years, range 23-58, 71% male, 62% i.v. drug users) showed a median HCV RNA of 5.93 log cps/ml (range 3.8-7.9). 52% were infected with HCV genotype 1, 33% with genotypes 2 or 3. Median HIV RNA was 326 cps/ml (range <50 to 76852 cps/ml), median CD4 cell count was 417/mul (range 150 to 1288/mul) at baseline, respectively.

Forty-eight percent of patients were receiving concomitant antiretroviral treatment. 23/52 patients (44%) showed an end of treatment response with HCV RNA below detection limit of 500 cps/ml, 26% of patients with genotype 1, compared with 87% with genotype 3.

Eight patients (15%) discontinued study treatment prematurely due to adverse events

4 due to psychiatric disorders,
2 due to blood count abnormalities.
21 (41%) patients discontinued due to virological non response.

CD4 cell count declined significantly at week 12 and 24. However, relative CD4 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 monoinfected patients. Overall, discontinuation rate is low. However, psychiatric disorders are a major problem in this cohort with a high proportion of former drug users.

Abstract 1210
Treatment With Pegylated Interferon Alpha 2B and Ribavirin Produces Significant Sustained Virologic Response Rates in HCV Infected Patients who Failed Prior Therapy
Paul J. Gaglio, Melissa Brown, David Zimmerman, James Choi, Larry Heller, Robert Brown Jr.

Introduction:

Eradicating HCV in the majority of infected patients remains an elusive goal, particularly in previously treated patients who failed or relapsed following prior therapy. We hypothesize that response rates in these patients who are re-treated with Pegylated interferon and ribavirin will be improved compared to standard interferon preparations with or without ribavirin. The present prospective study is designed to determine the efficacy and safety of treatment with PEG-Intron (pegylated interferon alfa-2b) and ribavirin in a group of patients who failed prior therapy with interferon with or without ribavirin.

Methods:

439 patients are presently enrolled in this multi-center study. The first 250 enrolled patients were treated with 1.5 mg/kg of PEG-Intron sc q week, and Ribavirin 800 mg po qd. The remaining patients received 1.5 mg/kg of PEG-Intron and weight based Ribavirin (800-1400mg). The intended duration of treatment is 48 weeks regardless of 24 week HCV RNA. 192 patients have been treated for 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 required in 22% of patients most commonly due to leukopenia and anemia. Permanent 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 abscess, cellulitis and multi-organ failure, cutaneous and pulmonary sarcoidosis, pneumonia, homicidal ideation, and suicide.

Conclusions:

Overall end of treatment response rate was 46% and the sustained virological response rate was 33%.
SVR was significantly higher in genotype non-1 patients and those who failed previous monotherapy
15% of G1 non responders to Rebetron achieved a sustained virological response rate (16% Caucasian, 12% Black) 4).

It is hoped that a weight based dose of ribavirin will be associated with lower relapse rates and improved sustained response rates particularly in G1 patients.

Study Entry (%)	Wk 48 (% HCV - )	Wk 72 (% HCV - )
Genotype 1 (83)	44	32
Genotype non 1 (17)	70	50
Previous Ifn/Riba (79)	44	29
Previous Ifn mono (21)	60	50
Genotype 1 combo NR (50)	27	15

Abstract 1214
Interleukin-11 In Patients With Chronic Hepatitis C And Advanced Liver Disease Who Have Been Nonresponsive To Antiviral Therapy
Eric J. Lawitz, Thomas Casey, Norma S. Cantu

Background

Those with advanced liver disease as a result of Hepatitis C are at risk for decompensation requiring liver transplantation or the development of hepatocellular carcinoma. Immune mediated injury is the primary mechanism of injury resulting in hepatic inflammation and fibrogenesis. It has been shown that there is a positive correlation between both gamma interferon and Interleukin (IL)-2 mRNA expression and the severity of both hepatic inflammation and fibrosis. IL-11 decreases the TH-1 cytokines such as gamma interferon and IL-2 (Keith, Cytokine Reference 2000, 565). In the setting of psoriasis, IL-11 has been shown to suppress the TH-1 response at doses as low as 2.5 mcg/kg/day, which is greater than ten fold lower than the currently approved dose for thrombocytopenia (Trepicchio, J Clin Invest 1999; 104(11),1527).

Aim

To evaluate the effect of IL-11 on the histologic activity index (HAI) in patients who have been nonresponsive to antiviral therapy yet have advanced liver disease.

Methods

A baseline liver biopsy was performed in those with advanced liver disease defined as a Metovir score of F3-F4. All participants were treated with rhIL-11 5.0mcg/kg/day subcutaneously daily for 3 months. At the completion of therapy a post therapy liver biopsy was performed. HCV-RNA was obtained at the initiation and completion of therapy.

Table 1. Baseline characteristics (N=20)

Age (mean) 50.5 years

Male/Female (%) 60/40

Weight (mean) 79.6 kg

HCV-RNA (mean) 5,595,600 copies/ml

HAI (mean) 7.0

Fibrosis stage 3 (%) 50

Fibrosis state 4 (%) 50

Results

Twenty adult participants with Metovir F3-F4 fibrosis with compensated liver disease were enrolled. The mean age is 50.5 years with a mean weight is 79.6 kg. Sixty percent were male. Mean baseline HCV-RNA 5,595,600 copies/ml. Mean baseline HAI is 7.0 with Metovir fibrosis scores of F3 in 50% and F4 in 50%.

Serum alanine transaminase (ALT) levels were found to decrease with administration of IL-11. In addition IL-11 caused an increase in platelets. Change in Knodell Histologic Activity Index (HAI) indicated that inflammatory activity was improved in 55% of patients. In 40% of patients, this improvement was significant. In only 10% of patients, inflammatory activity increased. Overall, IL-11 was well tolerated with no serious adverse events reported among patients. Lower extremity edema occurred in all patients but was not significant . One patient (5%) discontinued treatment because of extravascular fluid retention.

Figure 1. Change in HAI. Alternations in HAI indicated that inflammatory activity improved in 10% of patients, inflammatory activity increased.

Conclusion

IL-11 is well tolerated in patients with advanced liver disease. In most patients, inflammatory activity was improved, and in many patients this improvement was significant. Additionally, use of IL-11 caused ALT levels to decrease and platelets to increase. Further trials are needed to extend the duration of therapy and to evaluate the effect of IL-11 on fibrosis.

Abstract 1215
Early Virologic Response to Interferon and Ribavirin Treatment in Patients Co-infected with Hepatitis C Virus and Human Immunodeficiency Virus
Elana Maser, Ron Palmon, Douglas T. Dieterich

Background:

The prevalence of HCV infection in HIV patients ranges from 20-50%/ Patients with hepatitis C virus (HCV) infection who have a virologic response to interferon (IFN) and ribavirin (RBV) regimens usually respond within the first 12 weeks of therapy. We reviewed the virologic response rate to IFN and RBV regimens in patients co-infected with HCV and human immunodeficiency virus (HIV) who were predominantly HCV genotype 1.

Methods:

We conducted a retrospective chart review of 31 HIV/HCV co-infected patients from a New York City practice. All patients were treated with weight appropriate doses of IFN and RBV. The serum HIV and HCV RNA were detected using the polymerase chain reaction and were recorded approximately once per month.

Results:

Patient Characteristics:
- The majority of patients were HCV genotype 1 (74%) and male (84%).
- Mean HCV RNA at baseline was 2,733,774 IU/ml.
Treatment:
- 71% of patients were treated with PEG-IFN/RBV and 29% with IFN/RBV.
Baseline statistics:
- At baseline, the median CD4 count was 425/microl., 64% of patients had undetectable HIV viral loads, and 68% were on highly active antiretroviral therapy.

The median duration of treatment was 39 weeks. Twelve of 31 patients (42%) had an end-of-treatment 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 log 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.

Abstract 1216
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 Kallinowski, Claus Niederau, Hans Klinker, Peter R. Galle, Myrga Zankel, Stefan Zeuzem

Introduction:

In interferon (IFN) non-responders with chronic hepatitis C, retreatment with standard interferons combined with ribavirin showed sustained virologic response rates of 20-30%. Only limited data is available concerning the efficacy of antiviral retreatment in patients not responding to a previous treatment with standard interferons combined with ribavirin.

Aims:

The aims of the present trial were to evaluate efficacy and safety of a retreatment with pegylated IFN-alpa2b plus ribavirin.

Patients/Methods:

240 patients (162 males, 78 females, mean age 45.5 years) not responding to previous antiviral treatment with standard interferons combined with ribavirin.

Patients received pegylated IFN-alpha2b 100 µg/week s.c. for 8 weeks followed by 50 µg/week s.c. for 40 weeks in combination with ribavirin 800 mg/d for 48 weeks.

Treatment was discontinued in patients with detectable serum HCV-RNA after treatment week 24.

Results:

A virologic end-of-treatment response was achieved in 25/240 (10.4%) patients while after a follow-up period of 24 weeks a sustained virologic response was observed in 15/240 (6.3%) patients.

Patients infected with HCV genotype non-1 were more likely to respond to antiviral retreatment than patients infected with HCV genotype 1 (6.8% vs. 17%).

Conclusions:

In conclusion, antiviral retreatment with pegylated interferon-alpha2b 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 ribavirin. 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

Abstract 1217
Study in CHC Patients Comparing Three Different Combination Therapies with Interferon a-2b (IFN) and Ribavirin (Rebetol): Weekly PEG-IFN (Peg- Intron) Versus Daily IFN (Intron A Pen) Versus Standard Regimen of IFN (Intron A Pen).
Yves Horsmans, I. Colle, H. Van Vlierberghe, Ph Langlet, M. Adler, R. Brenard, P. Michielsen, N. Bourgeois, V. Lefèbvre, J. Henrion, X. De Koninck, L. Bruckers, on behalf of the Belgian Association for the Study of the Liver

Introduction:

The combination of PEG-interferon a-2b and ribavirin is considered to be the standard treatment for naive chronic HCV patients.

Aim:

A study was initiated to compare the sustained virological response and safety of daily Intron A versus PegIntron, both in combination with Rebetol .

Patients/Methods:

Three hundred seventeen naive chronic HCV patients were randomized in three groups with a ratio of 2:2:1.

Group A: daily interferon a-2b (4 MIU s.c. for patients > 65 kg or 0.06 MIU/ kg for patients < 65 kg) and ribavirin—130 patients
Group B: PEG-interferon a-2b (100µg s.c. weekly for patients > 65 kg or 1.5µg/kg weekly for patients < 65 kg) and ribavirin—119 patients
Group C (reference arm): interferon a-2b (3 MIU s.c. TWI) and ribavirin—68 patients

The duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period.

Results:

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 didn't show any statistical difference regarding age, gender, race, genotype and METAVIR score.

At week 24 on treatment, HCV RNA (Amplicor) was undetectable in 86% in group A, in 80% in 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 follow-up, these results were 60%, 52% and 29%, respectively.

When comparing the efficacy of the daily interferon (+ ribavirin) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.378).

78 patients withdrew before termination of the treatment:

30 patients in group A---43% due to adverse events
22 patients in group B—18% due to adverse events
26 patients in group C—19 due to adverse events

Regarding safety, no statistical difference was found for the drop-out rate in the daily interferon (+ ribavirin) regimen versus 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).

Conclusion:

In conclusion, daily weight based Intron A dosing and PEG-Intron weighed based dosing once weekly both in combination with ribavirin offer the same efficacy and safety rates.

Abstract 1218
Effect of therapy with pegylated interferon-alpha 2b 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-Radosavljevic

Objective:

Interferon alpha induced thrombocytopenia can become a limiting factor for therapy continuation. Platelet counts provide no information about platelet function. Quality of platelet function is crucial for the assessment whether a patient is at risk for bleeding or not. The present study was carried out to evaluate the effect of pegylated IFN-alpha administration on the expression of platelet activation markers and apoptosis in patients with chronic hepatitis C.

Methods:

10 patients with chronic hepatitis C (subtype 3a) received once a week 1 mcg/kg pegylated IFN-a2b (Peg-Intron (R), Schering, Vienna, Austria) subcutaneously over a period of 4 weeks, following by 180 mcg pegylated IFN-a2a once a week. Platelet counts, expression of P-selectin and GPIIb/IIIa receptor on platelets as markers of platelet activation and annexin V as a marker of apoptosis were measured by whole blood flow cytometry at baseline, day 1, day 3 and every other week over a period of 12 weeks.

Results:

Platelet counts dropped to a minimum of 70% of the baseline 4 weeks after begin of interferontherapy (p<0,01). There were no significant changes in P-selectin, GP/IIb/IIIa receptor or annexin V expression on platelets during the study period(p>0,05).

Conclusions:

Therapy with interferon alpha significantly decreases platelet count, but has no effect on platelet activation or apoptosis. Dose reduction or discontinuation of pegylated IFN-alpha due to moderate thrombocytopenia does not seem to be warranted based on our data regarding platelet activation but in vivo bleeding time was not assessed in this study. Apoptosis may not play an important role in the induction of IFN-alpha induced thrombocytopenia.

Abstract 1219
Efficacy of Daily Interferon in Combination with Ribavirin in Patients with Chronic Hepatitis C: Final Results of A VA Multicenter Study
Edmund J. Bini, Ayse Aytaman, Bhupinder S. Anand, Arun Samanta, Isabelita Cordoba-Rellosa, Bernard Nemchausky, Hector H. Trevino, Mitchell Mah'moud, Allan P. Weston, Neville R. Pimstone, Saray Stancic, Kyong-Mi Chang, Rosemary James

Background:

Hepatitis C is a major problem in U.S. veterans and the prevalence of infection is higher than non-veterans. Prior studies suggest that the SVR rates with IFN alpha and RBV may be lower than the general population. Furthermore, the optimal dose and duration of IFN + RBV therapy in this population is not known.

Aim:

The aims of this study were: 1) to determine the sustained virologic response to IFN alfa-2b (3 MU TIW) and RBV for 48 weeks in veterans with chronic HCV, 2) to evaluate whether 3 MU of daily IFN in combination with RBV for 24 weeks is superior to standard combination therapy, and 3) to determine the impact of HCV therapy on health-related quality of life (HRQOL).

Method:

158 IFN naive patients from 11 VA Medical Centers were randomized to receive either 3 MU of IFN alfa-2b QD plus RBV (1000 - 1200 mg/d) for 24 weeks (daily therapy group) or 3 MU of IFN alfa-2b TIW plus RBV (1000 - 1200 mg/d) for 24 weeks (genotype 2 & 3) or 48 weeks (genotype 1) (standard therapy group). HRQOL was measured using the Hepatitis QOL Questionnaire.

Results:

The proportion of patients with genotype 1 (78.2% vs. 80.0%, P = 0.78), number of patients with cirrhosis (10.3% vs. 10.0%, P = 0.96), mean HCV viral load (1.8 vs. 2.0 x 106 copies/ml, P = 0.41), and proportion of African American patients (26.9% vs. 35.0%, P = 0.27) did not differ significantly. The virologic response rates at the end of treatment in the daily IFN group were higher than in the standard group for all genotypes (46.2% vs. 23.8%, P = 0.003) and for those with genotype 1 (37.7% vs. 12.5%, P = 0.001), but did not differ for those with genotype 2 and 3 (76.5% vs. 68.8%, P = 0.71). Similarly, the sustained virologic response rates 24 weeks after treatment in the daily IFN group were higher than in the standard group for all genotypes (30.8% vs. 16.3%, P = 0.03) and for those with genotype 1 (19.7% vs. 6.3%, P = 0.03), but did not differ for those with genotype 2 and 3 (70.6% vs. 56.3%, P = 0.48). The proportion of patients who completed therapy did not differ between groups (82.1% vs. 80.0%, P = 0.74). Both daily and standard therapies were associated with significant improvements in several domains of HRQOL.

Conclusion:

The sustained virologic response to IFN alfa-2b 3 MU TIW and RBV in veterans with chronic HCV is lower than the response rates reported in non-veterans. Daily administration of 3 MU of IFN alfa-2b in combination with RBV for 24 weeks is superior to standard IFN alfa-2b 3 MU TIW and RBV for 48 weeks in veterans with genotype 1. In contrast, daily therapy was no better than standard therapy for patients with genotype 2 and 3. In our patient population, treatment with combination therapy was associated with significant improvements in HRQOL. Future studies to determine whether pegylated IFN + RBV can improve the SVR in veterans with chronic hepatitis C is warranted. This study was supported in part by a grant from Schering Plough Corp.

Abstract 1220
Early Viral Kinetics in Chronic Hepatitis C Virus Genotype 4 Infection
Wolfgang Jessner, Michael Gschwantler, Elisabeth Formann, Petra Steindl-Munda, Hanns Hoffmann, Christian Mueller, Peter Ferenci

Introduction:

In patients infected with hepatitis C virus (HCV) genotype 1, a decrease in HCV RNA levels of < 0.810 within 24 hours of a single dose of interferon alpha (IFN) predicts nonresponse to IFN/ribavirin with 100% specificity.

Similarly, a decrease in HCV RNA levels of < 0.7 log10 after a single 9 MU dose of IFN predicted nonresponse to peginterferon alfa-2a (40KD) plus ribavirin with 81% specificity in patients harboring HCV genotype 1. In contrast, the decrease in HCV RNA levels within 24 hours and 14 days after initiation of peginterferon alfa-2a (40KD) 180 µg/week, had no predictive value with respect to virological responses.

In common with genotype 1 infection, patients infected with HCV genotype 4 are considered “difficult-to-treat”, however, no data are available on the predictive value of the 24-hour virological response (24hVR) to IFN in patients infected with HCV genotype 4.

Objective:

Determine whether viral kinetic studies are of predictive value in HCV genotype 4 infection analogous to HCV genotype 1 infection.

Patients and Methods:

The study population comprised 33 consecutive, IFN-naïve patients with chronic hepatitis C infection attributable to HCV genotype 4. The population included 29 Egyptians and 4 Austrians. All patients were HCV RNA positive, had elevated ALT levels for = 6 months, and liver biopsy findings characteristic of chronic hepatitis C. HCV RNA levels were determined by COBAS AMPLICOR HCV MONITOR Test, v2.0, and COBAS AMPLICOR HCV Test, v2.0 (Roche Diagnostics). HCV genotypes were determined by line probe assay (Innogenetics N.V., Zwijnaarde, Belgium).

Patients received a single 10 MU dose of IFN on day-7 of the study. Between day 0 and 14, patients received IFN 5 MU/day. Subsequently, patients received combination therapy for 48 weeks comprised of FIN 5 MU three times weekly (n=6), PEG IFN alfa-2b 1.5 µg/kg/week (n=7), or peginterferon alfa-2a (40KD) 180 µg/kg/week (n=7) plus ribavirin 1 or 1.2 g/day.

Study End Points:

The primary end point was the virological response after 6 months of treatment with IFN/ribavirin or PEG IFN alfa-2B/ribavirin, or after 3 months of treatment with peginterferon alfa-2a (40KD)/ribavirin. Sustained virological responses as determined by qualitative PCR six months after completion of treatment was a secondary end point.

Result:

Patient characteristics according to virological response are presented in Table 1.

Table 1. Patient Characteristics According to Virological Response After 3 or 6 Months of Treatment

HCV RNA Negative
(n=26) HCV RNA Positive
(n=7)

Age (year) 39 (21-51) 41* (30-50)

Sex (M/F) 24/2 5/2*

Viral load (kIU/mL) 267 (16.4-1190) 403* (125-783)

ALT (IU/mL)/i>< /i>< /i>< /i> 41 (14-190) 58* (26-100)

Weight (Kg) 77 (61-93) < 71* (61-102)/td>
BMI 24.7 (20.7-30.4) 26.1* (21.1-32.2)

Fibrosis score 2 (1-4) 3* (1-4)

*Not Significant

The decrease in HCV RNA levels was more pronounced, both after a single IFN test dose and during 14 days of daily IFN therapy, in patients who achieved virological responses after 3 or 6 months of combination treatment, than in patients who did not achieve virological responses (Table 2)

Table 2. Mean Decrease in Log10 HCV RNA Levels After Single and Multiple Doses of FIN According to Response After 3 or 6 months of Combination Therapy

24 hours
10 MU IFN 24 hours
5 MU IFN 14 days
5 MU/day IFN

Repsonders (n=26) 1.37 (0.40-2.48) 0.99 (0.09-2.22) 2.4 (0.37-3.59)*

Nonresponders (n=7) 0.33 (0.08-0.57)* 0.16 (-0.12-0.46)* 0.16 (-0.13-0.74)*

*p = .0002 versus responders

The positive and negative predictive power of different tests is presented in Table 3.

Table 3. Prediction of Nonresponse to Combination Therapy with Single or Multiple Daily Doses of IFN

Decrease in HCV RNA levels (time period) and dose of IFN Sensi-tivity
(d=7) Sensi-tivity
(d=26) Positive Pred-ictive Value Negative Pred-ictive Value

< 0.06 log10 (24-hr) after IFN 10 MU 100% 92.3% 77.8% *(d=9) 100% (d=24)

< 0.5 log 10 (24-hr) after IFN 5 MU 100% 88.5% 70% (d=10) 100% (d=23)

< 0.8 log 10 (14-day) after IFN 5 MU/day 100% 84.6% 63.6% (d=11) 100% (d=22)

d = denominator

The HCV RNA response after single and multiple doses of IFN according to virological responses are presented in Table 4.

Table 4. Mean Decrease in Log 10 HCV RNA Levels After Single and Multiple Doses of IFN According to Virological Response to Combination Therapy

24 hours
10 MU IFN 24 hours
5 MU IFN 14 days
5MU/day IFN

Sustained virological responder (n=7) 1.54 (1.26-1.91) 1.17 (0.90-1.46) 2.86 (2.20-3.35)

Nonresponders (n=5) 0.44 (0.27-1.88)* 0.41 (0.13-1.77)** 0.43 (0.27-3.41)**

p=.062; ** p = 0.88

Summary:

The 24-hour decline in HCV RNA levels after a single 10MU dose of IFN has a high predictive value for the outcome of subsequent combination therapy in patients infected with HCV genotype 4.
A decease of < 0.6 log 10 identifies nonresponders with a sensitivity of 92%.

Conclusions:

Some patients with a poor response to IFN achieve on-treatment virological responses to pegylated IFN/ribavirin, although relapse is not uncommon after the end of treatment.
Pretreatment prediction of sustained virological response may help select patients for antiviral treatment, although the concept must be confirmed in larger studies.

Abstract 1221
Safety and Efficacy of Peginterferon Alpha-2b plus Ribavirin in Pre-Cirrhotic and Cirrhotic Patients with Chronic Hepatitis C
Frederic Marrache, Marie Pierre Ripault, Yann Consigny, Dominique Cazals Hatem, Nathalie Boyer, Michele Martinot, Claude Degott, Dominique Valla, Patrick Marcellin

Background:

In patients with chronic hepatitis C, peginterferon alpha-2b (PEG-IFN) plus ribavirin (RBV) is the most effective therapy. However its benefit remains unclear in pre-cirrhotic and cirrhotic patients. This group is minority in clinical trials, and tolerance has not been specifically assessed, especially regarding to initial blood count abnormalities commonly observed in these patients.

Objective:

The objective of this study was to assess tolerance and efficacy of therapy with PEG-IFN plus RBV in unselected pre-cirrhotic and cirrhotic patients.

Methods:

74 patients were treated with PEG-IFN (1.5 or 1 microg/kg/week) plus RBV (800-1200mg/day). Tolerance and safety were evaluated by the rate of treatment's discontinuation, and occurrence of serious clinical adverse events, respectively. Virological response was assessed by detection of serum HCV RNA (Amplicor, Roche Diagnostics) at week 12, at the end and six months after treatment. Histological response was assessed on liver biopsy performed the last week of treatment.

Results:

Among 74 treated patients, 41 % had cirrhosis and 59% bridging fibrosis. Child-Pugh score was five in all patients except three with a score of six, and three with a score of seven. Platelet count was below 100*10^9/L in 27 % and neutrophil count below 1.5*10^9/L in 7 % of patients. No serious clinical event was observed. Treatment was withdrawn in 19% of patients. Dose reduction was necessary in 8% of patients for PEG-IFN and in 23% patients for RBV. In a multivariate logistic regression, initial blood count abnormalities were not associated with cessation of treatment. Treatment was discontinued because of blood count abnormalities in only two patients. Overall sustained virological response rate was 32 %. Details are shown in the table. End of treatment liver biopsy was performed in 23 patients. Eleven had baseline cirrhosis. Regression of fibrosis was observed in eight patients and reversion of cirrhosis in three.

Conclusion:

Combination therapy with peginterferon plus ribavirin for chronic hepatitis C seems safe and effective in patients with bridging fibrosis or compensated cirrhosis. Heamatological tolerance is not a limiting factor.

Percentages of Patients with Undetectable HCV-RNA

Naive Prev-
iously IFN
treated Prev-
iously IFN
plus RBV
treated

Geno-types 1 or 4 n=13 Geno-types 2 or 3 n=15 Geno-types 1 or 4 n=14 Geno-types 2 or 3 n=7 Rela-psers n=6 Non-resp-onders n=19

End of treat
ment (EOT) 23 87 50 71 83 21

Six months after EOT 23 57 43 57 33 0

Abstract 1222
An Open Prospective Study of Adacolumn Granulocyte and Monocyte/Macrophage Adsorptive Apheresis in Combination with Interferon-Alpha and Ribavirin in 6 Refractory Patients with High Plasma HCV Viremia
Koji Sawada, Kunio Ohnishi, Ken Fukunaga, Tsuyoshi Kusaka, Yoshihiro Fukuda, Toshikazu Hada, Takashi Shimoyama, Abby Saniabadi, Ichiro Hirata

Objective:

Granulocytes and monocytes/macrophages are extra-hepatic sites for HCV replication and dissemination. This study was to investigate if granulocyte and monocyte adsorptive apheresis enhances the efficacy of INF-alpha and ribavirin combination therapy.

Methods:

Six patients, mean age 53.8 yr, range 46 to 65 yr were included. The inclusion criteria were chronic hepatitis and HCV-RNA greater than 100KIU/mL of genotypes 1b, 2a or 2b. Qualitative and quantitative analysis using Amplicor-PCR and alanine aminotransferase (ALT) were done to determine HCV-RNA level and liver function. All 6 patients were hitherto non-responders to a standard 24 week IFN-alpha therapy.

Leukocyte apheresis was done with Adacolumn which contains cellulose acetate beads as the adsorptive carriers for neutrophils and monocytes /macrophages; one session was 60 minutes at 30 mL/minute.

Interferon in combination with ribavirin was started after 5 consecutive Adacolumn sessions over 5 days. Daily 6 million units of IFN for 4 weeks and then every other day for 20 weeks were given together with ribavirin (600-800 mg/patient). Complete response (CR) was judged when plasma HCV-RNA did not become positive and liver function kept normal during the 6 months follow-up, without additional therapy. Partial response (PR) was judged when HCV-RNA became negative and liver function became normal during the therapy and then became positive during the follow-up.

Results:

All 6 patients completed the study without experiencing side effects from the leukocyte apheresis procedure. HCV-RNA became negative within one week in 3 patients (2 were genotype 1b and 1 was 2a), within 2 weeks in 2 patients (1b) and within week 12 in 1 patient (1b). Complete response was obtained in 4 of 6 patients (67%) which is a very impressive efficacy rate compared to IFN plus ribavirin, the other 2 achieved a partial. Response. Additionally, alternative pathway dependent active complement fragments, C3a, C5a and others were found to be high in the post column blood, by up to 10 fold relative to the column inflow.

Conclusions:

The results indicate that granulocyte and monocyte/macrophage adsorptive apheresis might be an effective adjunct to interferon plus ribavirin therapy for eradication of HCV. Further, at present, we have the impression that active complement in the post column blood which perfuses the liver contributes to the clearance of HCV.

Abstract 1223
High Dose Paroxetine and Quetiapine to Augment Interferon and Ribavirin Treatment in Chronic Hepatitis C Patients With Psychiatric Disease
Eric L. Altschuler, Richard E. Kast

Introduction:

Hepatitis C virus (HCV) is the most common viral cause of liver failure in the US. There is no current vaccine and prospects for development of one in the near future seem dim. While it appears that if patients are treated within six months of HCV infection cure rates are greater than 90%, in chronically infected patients and these are the vast majority and testing is not feasible, cure rates with the current best treatment-peginterferon alfa-2a (PEG INF) plus ribavirin (RBV) is only 56% and for the most common viral genotype type 1A only 46%. Given the potential severe neuropsychiatric symptoms from INF, including life threatening depression, psychiatric disease can be a relative, or even absolute, contraindication to HCV treatment.

Results:

We have found that adding high dose paroxetine (Paxil) (40mg BID) and quetiapine (300mg QHS) to INF and RBV has resulted in an excellent HCV cure rate, seven of nine treated patients (eight with type 1A genotype virus), with no suicide attempts or other major psychiatric decompensation. All of the patients had long standing mood disorders and six of the nine had concomitant psychotic illness. None of the patients were HIV+ or HBsAg+. Eight of the nine patients had genotype 1A virus, the other patient had genotype 3A. Eight of the patients had chronic HCV infection and one had more acute disease. Six of the eight patients with genotype 1A cleared the virus, as did the one patient with genotype 3A. Two patients were also taking olanzapine (Zyprexa).

Might these medicines also augment or boost the efficacy of INF + RBV? Indeed, while paroxetine is traditionally considered to be an antidepressant, and quetiapine an antipsychotic medicine these medicines have other pharmacologic properties that could be crucial in fighting HCV: paroxetine is a potent nitric oxide synthase (NOS) inhibitor, and quetiapine is a potent histamine receptor antagonist. (Olanzapine is also a potent histamine receptor antagonist.) As both nitric oxide and histamine are positive trophic factors for HCV, we believe that the paroxetine and quetiapine may augment INF and RBV by antagonizing these factors by lowering systemic or local levels of NOS and inhibiting histamine activity.

Conclusion:

Larger trials of high dose paroxetine and quetiapine to supplement INF and RBV in psychiatric and general patients with chronic HCV infection are warranted.

Abstract 1225
Pilot Study of Interferon Gamma for Chronic Hepatitis C
Alejandro Soza, Theo Heller, Edward Doo, Kittichai Promrat, Glen Lutchman, Lijun Mi, Yoon Park, Harvey Alter, Henry H. Hsu, Marc Ghany, Jake Liang, Jay H. Hoofnagle

Introduction:

There are currently no therapies of proven benefit for patients with chronic hepatitis C who fail to respond to interferon alfa-based therapies. Interferon gamma, a cytokine with no homology to interferon alfa, has marked antiviral effects in vitro in the hepatitis C virus (HCV) replicon system. The aims of this pilot study were to determine the antiviral effects and safety of recombinant interferon gamma-1b in patients with chronic hepatitis C.

Patient Characteristics:

11 Caucasians; 3 African Americans
9 men; 5 women
Mean age 50.4 ± 5 years
All genotype 1
6 patients had evidence of advanced fibrosis (ISHAK =3)
All patients had not achieved a sustained response to a previous course of therapy with interferon alfa with or without ribavirin (10 were non-responders and 4 were relapsers).

Methods:

Fourteen patients were randomly assigned to receive interferon gamma in a dose of either 100, 200 or 400 µg sc thrice weekly for 4 weeks. HCV RNA levels were measured 3 times before treatment, then at 6, 12, 18, 24, 48 hours and at 1, 2, 3, 4, 6 and 8 weeks after starting treatment.

Results:

There was no change in HCV RNA titer during therapy; no patient had more than a one log change during the 14 time points). Therapy was associated with significant reductions in neutrophil counts (mean reduction 41%), lymphocyte counts (11%), white blood cell count (28%) and hematocrit (5%). Platelet counts remained unaffected. Similarly, ALT levels were unchanged (mean pre = 80 ± 45 IU/ml, mean at 4 weeks = 72 ± 25 IU/mL, p=NS). There were no differences in response between the high and low dose groups or between previous non-responders and relapsers. Treatment was well tolerated in all patients, with minimal flu-like symptoms and no significant worsening in quality of life scores. No severe adverse events were noted.

Conclusions:

A 4-week course of conventional doses of interferon gamma as monotherapy in patients who had previously failed treatment with interferon alfa had no demonstrable effect on serum aminotransferase levels or HCV viral titer. Whether higher doses, longer duration or combination therapy are effective against HCV remains to be determined.

Abstract 1226
Thrombocytopenia (T) in Patients with Chronic Hepatitis C: Management with Interleukin 11
Charles L. Mendenhall, Abdur R. Shakir, Elizabeth A. Zoiss, Catrina Reese, Hai Bui, Stephen Goldberg, Gary A. Roselle

Introduction:

Of the 4 million people infected with HCV in the US it is estimated that treatment is interrupted or prevented in 1 million due to thrombocytopenia. In many instances this is the result of portal hypertension with secondary platelet pooling and destruction in the spleen. Peripheral platelet antibody destruction may also contribute even in the absence of severe liver injury. Once therapy is initiated the process is further exacerbated by bone marrow suppression associated with interferon therapy (IFN). These combination of events may result in life threatening thrombocytopenia.

Purpose:

Describe thrombocytopenia in the veteran population and indicate one corrective therapeutic action.

Results:

Thrombocytopenia (<120,000) was observed prior to treatment in 25% of 56 patients undergoing therapy for HCV. Therapy consisted of INF alfa 2b + ribavirin (R) (n= 20), Peginterferon alfa PEG IFN 2b (PEG IFN) (n= 12), and PEG IFN 2a (n=10). Platelet changes from baseline(% decrease)at time 2,12,26,48 weeks were -5.2%,-0.7%,-7.2%,-4.1% on R; -18.9%, -27%, -33.5%, -27.7% on PEG IFN 2b and were -27.4%, -38.1%, -23.4%,(week 48 in progress) on PEG IFN 2a. Of these, 25% needed Interleukin 11 (IL11) to prevent IFN dose reduction or discontinuation and 5% required IL11 prior to IFN to raise platelets to recommended safe IFN treatment levels. All patients responded to IL11. Only side effect observed was fluid accumulation in 5% of subjects, which was easily managed with diuretics.

Conclusion:

Thrombocytopenia is a common problem before and during HCV therapy with IFN. Management with IL11 permits continuation of IFN therapy without dose reduction.

Abstract 1246
Treatment of Acute Hepatitis C Virus with Recombinant Interferon Alpha 2b. Clinical Trial
Enrique R. Arus Sr., Luis Rivera Sr., Mirtha Infante Sr., Marlen Perez Sr., Grisel Soto Sr., Bienvenido Gra Sr., Guillermo Padron Sr., Pedro Lopez Sr.

Aim/Method:

A clinical trial was carried out aimed at evaluating the efficacy and safety of interferon in a group of 13 patients with acute hepatitis C. The diagnosis was made according to biochemical criteria (alanine aminotransferase 2 times the normal value), serological criteria (presence of anti hepatitis virus antibodies), virological criteria (presence of RNA-HCV by PCR) and histological criteria. Treatment with recombinant interferon Alfa 2b 3 000 000 IU was indicated 3 times a week during 12 weeks.

Results:

It was proved that 53.8 % finished the period of treatment with normal alanine aminotransferase and that at the end of follow-up 30.7% had a maintained biochemical and virological response. 4 patients (36.3%) of the 11 that concluded the follow-up had a normal histology in the evolutive hepatic biopsy and of them 2 had a maintained biochemical and virological response, which made us think they were cured.

Interferon was well tolerated and only 38.5% of patients showed secondary manifestations of toxicity. We observed a predominance of cephalalgia (headache), fever, myalgia and arthralgias.

Conclusion:

We concluded that interferon should be used in patients with acute hepatitis C.

Abstract 1256
Biopsy vs. Non-Biopsy: A Comparison of Cost of Treatment of a Biopsy vs. Non Biopsy Model in the Management of HCV Prisoners
Mark J. Marino, William Cassidy, Elizabeth Britton, Nancy Bailey, Anthony Tarver, Monica Prada

Objective:

Analyze cost effectiveness of histologic staging to determine which HCV infected prisoners to treat.

Methods:

HCV infected inmates at Louisiana State Penitentiary are evaluated per a treatment algorithim in which histologic stage determines treatment eligibility. Patients with Stage 0 or Stage 1 fibrosis with a fibrosis index (stage of fibrosis/number of years infected) <0.1 are not treated. Those with Stage 1 with fibrosis index > 0.1 or Stages 2, 3 or 4 (with compensated liver disease) are treated. This cost analysis compares using liver biopsies ("biopsy model") versus treating all patients without contraindications ("non biopsy model"). Patients with at least a 2-log decrease or a negative HCV RNA at week 12 continue treatment for 12 more weeks and if RNA is negative, continue for 24 more weeks. Cost of treating genotype 1 patients with interferon (pegylated and non) an ribavirin was analyzed.

Results:

501 patients were evaluated in the clinic. Liver biopsies were performed on 221 patients. After histological classification, 124 patients were treated with interferon alpha 2b and ribavirin. The actual cost(drug alone) per week of interferon alpha and ribavirin was $336 and the estimated cost of pegylated interferon and ribavirin(drug alone)was $397 per week. Cost of treating these 124 patients using the biopsy model was $15,159 per patient for a total cost of $1,879,716. In the non-biopsy model, 221 patients would have been treated at a cost of $12,659 per patient for a total cost of $2,797,706. A further analysis was performed using pegylated interferon and ribavirin for genotype 1 patients, which revealed a total cost of $2,082,415 for the biopsy model at $16,826 per patient treated and $3,295,739 for the non-biopsy model at $14,389 per patient treated.

Conclusion:

Management of HCV in the prison system is evolving. A protocol using liver biopsy to establish need for treatment balances cost and complies with current recommendations.

Abstract 1258
The Role of Triple Therapy with Amantadine Sulphate Plus Ribavirin and Interferon-Alpha2a on Chronic Hepatitis C Patients
Ashraf R. Abulfutuh, Mohammed Morsy, Abd El Ghany Solyman, Said El Hendawy, Mohammed El Desouky, Salwa El Hadad, Moemena Kamel

Background:

Controversial reports exist on the usefulness of the application of amantadine as an additional regime in the treatment of patients with chronic hepatitis C.

Methods:

We therefore conducted a study on 400 patients with histologically proven chronic hepatitis C receiving amantadine sulphate (100 mg bid , group 1) or a matched placebo ( group 2) together with IFN-alfa 2a induction therapy plus ribavirin (1000-1200 mg/day)for 48 weeks .The two groups showed similar demographic , biochemical and virological baseline characteristics .

Results:

IFN and ribavirin dose reduction was necessary because of side effects in 15% and 16%, and 41% and 33% of the amantadine and placebo group, respectively. Amantadine /placebo dose was reduced in 1% and 5%. Based on intention-to-treat analysis, a sustained virological response after 24 weeks follow-up was observed in 52% of the amantadine group and in 43% of the placebo group (p=0.055).The treatment response rate at week 24 was significantly higher in the amantadine group(70%) as compared to the placebo group (59%) (p =0.02).Baseline factors significantly associated with sustained response to HCV (p=0.0001), GGT (p=0.001), ALT (p=0.008), age (p=0.004), fibrosis stage >2 (p=0.015) and body weight (p=0.05).

Conclusions:

Triple therapy with amantadine plus IFN-alfa2a induction and ribavirin led to a significant higher on treatment response and also slightly improved sustained virological response rate (p=0.055) when compared to combination therapy with interferon alpha-2a induction plus ribavirin. Thus, amantadine seems to have an additional antiviral effect in patients with chronic hepatitis C.

Abstract 1259
Hepatitis A Prevalence in Intravenous Drug Users and Blood Product Infected Hepatitis C Patients.
Fraser Cummings, Shelia O. Cameron, Sharon Hutchinson, Peter R. Mills, John Morris

Introduction:

Some studies of hepatitis A (HAV) superinfection in patients with previous hepatitis B or hepatitis C (HCV) have suggested a poor outcome. In order to develop an anti-HAV vaccination strategy, the number of patients at risk of HAV superinfection needs to be ascertained. No previous studies have looked at the route of HCV infection and the risk of HAV superinfection.

Objective:

The objective of this study was to look at HAV IgG seroprevalence in patients who are at risk of or who already have HCV.

Methods:

IgG anti-HAV were measured in 4 groups: 1) 109 HCV positive IVDU 2) 107 HCV negative IVDU 3) 90 HCV positive patients infected by blood products (BPG) 4) 100 HCV negative blood donors.

Results:

The BPG was significantly older than the other 3 groups. Overall HCV positive patients were more likely to be HAV positive than HCV negative patients (56.3% vs. 36.2% p<0.01). There was no significant difference in HAV IgG seroprevalence between HCV positive IVDU and BPG patients. Sub-group analysis demonstrated male HCV positive IVDU were more likely to be HAV positive than the control group or HCV negative IVDU (51.5% vs. 33.3%, p<0.05 or 31.9%, p<0.05). There were no differences between female groups. Data was also analyzed on the basis of age (<30 or >30). IVDU <30, regardless of their HCV status, were more likely to be HAV positive than controls (29.2% vs. 3.7%, p<0.001) but had significantly lower prevalence than those >30 (60.4%, p<0.001). There were no significant differences between patients in the >30 groups.

Discussion:

Our data show that HCV patients are more likely to have been exposed to previous HAV infection; especially if male IVDU. However young IVDU, regardless of HCV status, would be an appropriate group to target for HAV vaccination.

Abstract 1262
Mutagenic effect of ribavirin in NS5A and NS5B regions and response to interferon/ribavirin combination therapy in patients with chronic hepatitis C
Yasuhiro Asahina, Namiki Izumi, Ken Ueda, Kazunari Inoue, Yuki Nishimura, Kaoru Tsuchiya, Kosei Hamano, Jun Itakura, Osamu Noguchi, Masakatsu Uchihara, Shozo Miyake, Nobuyuki Enomoto, Mamoru Watanabe

Background/Aim:

Mechanisms involving antiviral effect of ribavirin against HCV have not been fully elucidated in vivo. To determine the mutagenic effect of ribavirin on clinical response to IFN/ribavirin combination therapy, NS5A and NS5B regions of HCV genome were serially sequenced in chronic hepatitis C patients.

Methods:

Thirty-four patients infected with HCV genotype 1b, which had no or only 1 aminoacid mutation in interferon sensitivity determining region (ISDR), were received 600 to 800 mg of daily oral ribavirin monotherapy for 4weeks, after which 6MU of IFN and ribavirin combination therapy was given for additional 24 weeks. NS5A including ISDR and NS5B regions were amplified by RT-PCR from sera obtained before and after ribavirin monothreapy, and serial mutations were determined by direct sequencing. Correlation between mutagenic effect and clinical response to subsequent IFN/ribavirin combination therapy was evaluated. Patients in whom HCV RNA could not be detected for 6 months following the termination of IFN/ribavirin therapy were defined as sustained viral responders (SVR). Patients in whom HCV RNA become negative at the end of combination therapy but reappeared were considered as transient responders (TR), and patients who did not became negative were considered to be non responders (NR).

Results:

Sustained viral response was achieved 4 of 34 patients. Remaining 17 patients were TR and 13 were NR. After 4-week ribavirin monotherapy, sequential nucleotide mutations were found at a rate of 1.6 x 10-3. Nucleotide mutation rate was significantly higher in SVR than TR and NR (5.51 x 10-3 vs. 9.59 x 10-4 and 8.42 x 10-4, respectively). G to A and C to T mutations were frequently detected at a rate of 1.8 x 10-4 and 3.0 x 10-4, respectively. Although non-synonymous mutation was rarely found (10%), non-synonymous mutation in NS5A was more frequent in SVR than in TR and NR. Especially, 3 of 5 patients in whom aminoacid mutation in ISDR increased after ribavirin monotherapy achieved sustained viral response. In contrast, only 1 SVR was found in 29 patients who had no increased mutation in ISDR (p<0.006). No significant relation was found between serum ribavirin concentration and a mutation rate.

Conclusion:

Our results suggest that clinical response to IFN/ribavirin combination therapy correlates with mutagenic activity of ribavirin in patients with genotype 1b. Ribavirin may act by promoting IFN sensitive HCV RNA mutation rate in some responders.

Abstract 1267
Significant Percentage of Normal ALT Values seen in Chronic HCV infected patients at a VA Medical Center
Venkat Rangaraj

Background:

HCV is an RNA virus and is the leading cause of liver disease in the United States. It affects about 4 million not including the military personnel. Chronic infection with HCV has been known to lead to cirrhosis in approximately 20% of patients and is an ongogenic virus associated with the development of hepatocellular carcinoma (HCC) in 10% of patients. Acute infection is most often null or asymptomatic hence most cases are not diagnosed at the onset. Of all the HCV infected patients, 85% of these go on to develop chronic infection with approximately 15% undergoing “spontaneous clearance”.

Often the diagnosis of HCV infection is confirmed after abnormalities are seen in biochemical tests for liver injury, i.e. ALT (alanine aminotransferase). Serum ALT levels and liver biopsy have been used to assess disease activity. Most, but not all agree that liver biopsy is the more preferable way to determine the degree of liver damage.

In the beginning PCR was too variable between labs and commercially expensive ($200-$250 per test) so ALT levels have been the only lab test readily available to follow patients with chronic hepatitis. Some have proposed that a normal ALT indicates minimal or no liver injury. This is difficult to determine in a disease, which is characterized by slow non-linear progression. ALT testing is non-invasive. Normal ALTs are defined as = 50 IU/L and reports range that 26-30% of patients being treated for chronic hepatitis C have normal ALT levels. ALT levels alone are not an adequate way to assess progression.

Aim:

This study was undertaken to further clarify the significance of normal ALT in veterans with active chronic HCV infection.

Methods:

Eighty seven HCV positive outpatients referred for treatment at the VA Medical Center Cincinnati were studied prospectively. Pre-treatment laboratory tests included ALT levels, viral genotypes and HCV-RNA loads were obtained on every patient. Patients with established disease were treated with interferon alpha 2b or Pegylated interferon alpha 2b in combination with Ribavirin using generally accepted protocols. Serum HCV-RNA levels were obtained at 0, 3, 6, 12 months after initiating treatment and again at 18 months (6 months post treatment). Pre-treatment liver biopsy to stage the fibrosis was performed on every patient. Treatment was not initiated on any patient if consumption of alcohol was observed in the preceding 3 month period. We then compared the following 7 variables (race, age, virology genotype, nutrition, biopsy result and response to treatment) of each of the two clinical groups, (normal vs elevated ALT levels).

Results:

From a pool of 87 patients (85 males, 2 females), we identified 29 patients (33.33%) with normal serum ALT (<50 IU/L) and 58 patients (66.67%) with >50 IU/L serum ALT at baseline. On liver biopsy, 9 of the 29 patients (34.48%) with normal ALT had cirrhosis or incomplete cirrhosis. (stage 2.5 to stage 4). In patients with elevated ALT, the prevalence of cirrhosis/incomplete cirrhosis was seen in 50% of the population. Differences in histological injury seen on liver biopsy (p<0.09) and nutritional status (BMI) (p<0.08) showed a trend towards significance (p>0.05 < 0.10). We noticed no significant differences in race, age, virology, or response to therapy. (p>0.05). Fisher exact test was used to compare the characteristic data. Linear regression analysis however showed a significant (p = 0.05) linear relationship between ALT and liver fibrosis on biopsies.

Discussion:

At baseline just prior to the initiation of treatment with IFN alpha 2a and RBV, normal ALT serum level (0-50 IU/L) was observed in 33.33% (29/87) of the subjects. If one examines past records for results of prior ALT test of liver injury over a six month period the % of persistently normal ALT values is reduced to 21-25%. This is comparable to that previously reported. Using the VA computerized data retrieval system (CPRS), ALT levels measured prior to baseline could be easily retrieved back 10 years.

One contributing factor for the high incidence of normal ALTs may be a high occurrence of alcoholism. In our population prior alcohol abuse was recorded in over 90%> It has long been recognized that both ALT and AST are lower in alcoholic liver disease than might be anticipated particularly with evidence of alcoholic liver present. This is especially true of the ALT so that the ration of AST:ALT becomes elevated. Indeed a ration value of >2 has been used for diagnosis purposes to differentiate alcoholic verses viral etiologies.

It is noteworthy that all our patients were required to exhibit sobriety for at least 3 months prior to treatment. Whether 3 months sufficient time to lose the alcohol effect is remains to be established. The more important question is the clinical significance of normal ALT at baseline.

Our studies indicate that a normal ALT did not preclude more severe liver injury since 34.48% (9/29) of our normal ALT patients had cirrhosis or incomplete cirrhosis which would have been unrecognized in the absence of histological conformation. None the less, the ALT relationship to liver pathology showed the best correlation.

Patients with elevated ALTs had the higher prevalence of cirrhosis/incomplete cirrhosis seen in 50%. Regression analysis confirmed this relationship showing a significant linear correlation between ALT levels and the range of pathology (stages 1 to 4) p<0.05. None of the other 6 variables analyzed showed a significant relationship (p>0.05)

Conclusion:

Our studies indicate that a normal ALT (0-50 IU/L) did not preclude more severe liver injury in a significant percent of cases. Therefore, the use of ALT in patients with HCV infection is not a predictable indicator of significant underlying liver disease.

Abstract 1269
Steatosis as a Predictive Factor for Treatment Response in Patients with Chronic Hepatitis C
Ivan Antunez, Nestor Aponte, Alberto Fernandez, Doris H. Toro, Federico Rodriguez-Perez

Background:

Hepatic steatosis has been described in 31-72% of chronic hepatitis C (HCV) liver biopsies. It has been related to disease progression and suggested as a predictor of treatment response in chronic HCV.

Aim:

This study aims to evaluate the presence and degree of steatosis in liver histology of patients with chronic HCV prior to combination therapy with interferon (INF) and ribavirin (RBV), and how it influences treatment response.

Methods:

The hospital records of patients with chronic HCV who received treatment at the San Juan VA Medical Center from 1998 to 2002 were reviewed. All patients completed therapy, had a pre-treatment liver biopsy, genotype determination, and pre & post treatment HCV-RNA levels. Patient's age, sex and body mass index (BMI) were examined. Pre-treatment liver biopsy slides were reviewed and graded for steatosis by a double-blinded hepatopathologist. Steatosis was graded by the presence of fat in total biopsy area as: mild (<33%), moderate (33-66%), severe (>66%) or absent. Treatment response was defined as virological clearance measured by HCV RNA at the end of treatment and 24 weeks after completion of treatment. The presence of steatosis was compared to BMI, HCV genotype and treatment response.

Results:

46 records met the inclusion criteria. All patients were male of Hispanic origin. Mean age: 52.2 years (range: 40-68). Mean BMI: 27.5 kg/m2 (range: 21.1-35.9). HCV genotype 1 was equally distributed in all groups with an overall prevalence of 75%. 82.6% (38/46) of the patients had hepatic steatosis: 29 (63%) mild, 7 (15%) moderate and 2(4%) severe. 16.6% (8/46) of the biopsies did not show steatosis. Overall, the response rate for those with steatosis was 31.6% (12/38) : 10/29(34.5) mild, 1/7 (14.3%) moderate and 1/2(50%) of severe. 75% (6/8) of those without steatosis responded to treatment. This difference (31.6% vs.75%) was statistically significant (p=.042). The mean BMI of both groups was similar (27.7 kg/m2 steatosis and 26.6 kg/m2 no steatosis). This difference was not statistically significant (p=.308).

Conclusion:

The results of our study show a high prevalence of steatosis in the liver histology of patients with chronic HCV. The presence and degree of steatosis in our HCV patients appears to be unrelated to either genotype or BMI. Furthermore, the response to therapy is negatively influenced by the presence of steatosis regardless of genotype. Hepatic steatosis, either mild, moderate or severe, appears to be an independent predictor of poor response to therapy.

Abstract 1272
Nonlinear HCV and linear ALT Dynamics in serum during high dose Interferon
Gerond Lake-Bakaar,