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The Liver Meeting— 54th Annual Meeting of The American Association for the Study of Liver Diseases, October 24 - 28, Boston, MA—Day 1

Alan Franciscus
Editor-in-Chief, HCV Advocate


Lawrence M. Blatt, Hua Tan, Jin Hong, Jena Derrick, Scott Seiwert, InterMune, Brisbane, CA; Craig Day, John Morrey, Utah State University, Logan, UT; William M. Grosse, Corneliu Sanda, Milton Taylor, Indiana University, Bloomington, IN.

Treatment of chronic Hepatitis C patients with type 1 interferon (IFN-alpha) and ribavirin leads to a sustained virologic response in ~50% of patients. The elimination of serum HCV RNA in an individual patient displays biphasic kinetics with the first order attributed to the direct antiviral effects of IFN-alpha and the second order attributed to an immune mediated clearance of infected cells by induction of TH1 cytokines, primarily IFN-gamma (type 2 IFN). We have postulated that the direct antiviral effects as well as the TH1 response of current therapies may be enhanced by the addition of type 2 IFN (IFN-gamma). To study this hypothesis, we examined the activity of a type 1 IFN, Infergen; (IFN-alfacon1) in combination with a type 2 IFN, Actimmune; (IFN-gamma 1b) in preclinical models of HCV. These included an infectious flavivirus system (West Nile Virus) and the HCV replicon. In addition, global transcriptional profiling was examined utilizing the HG-U133A Genechip; (Affymetrix, Santa Clara, California) system. Effective Concentration (EC) studies of the 1 effects of IFN-alfacon1, IFN-gamma 1b and the combination against the West Nile Virus and the HCV replicon are shown below:

  IFN-alfacon1 IFN-?1b Combination
EC50 0.03 ng/mL 2.8 ng/mL 1.1
ng/ML IFN alfacon1
0.001 ng/mL IFN-γ 1b
HCV Replicon      
EC 50 0.002 ng/mL 0.025 ng/mL 0.0002 ng/mL IFN-alfacon1

0.0025 ng/mL
IFN-γ 1b
EC 90 02 ng/mL 0.25 ng/mL 0.002 ng/mL IFN-alfacon1

0.025 ng/mL IFN-γ1b

Analysis of synergy for the combination of IFN-alfacon1 and IFN-gamma 1b in the HCV replicon using the Chau-Talalay methodology demonstrated very strong synergistic effects for a range of doses (C1<0.1 for all observations). Initial statistical analysis (PV<0.001; Fold Change > 1.2) of global transcriptional profiling revealed that treating HCV replicon containing cells with IFN-alfacon1 up-regulated 156 transcripts, while 61 transcripts were significantly down-regulated. IFN-gamma 1b treated cells had 109 transcripts up-regulated and 32 down-regulated transcripts. Most significant was the finding that several transcripts were up-regulated by the combination of IFN-alfacon1 and IFN-gamma 1b that were not up-regulated by either IFN alone. These transcripts were involved in cell-cycle regulation, antigen presentation, apoptosis and immuno-activation. In addition, several known interferon stimulated genes were highly elevated by the combination when compared to the monotherapy treatments. These results demonstrate synergistic effects of the combination of type 1 and type 2 IFNs for the treatment of chronic Hepatitis C both on a cellular and molecular level. Further study in HCV infected patients is warranted.

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Heiner Wedemeyer, Medizinische Hochschule Hannover, Hannover, Germany; Andreas Erhardt, Universitätsklinikum Duesseldorf, Duesseldorf, Germany; Wolff Schmiegel, Ruhr Universitaet Bochum, Bochum, Germany; Holger Hinrichsen, I Medizinische Universitätsklinik Kiel, Kiel, Germany; Ricardo Chaves, Boehringer Ingelheim, Biberach, Germany; Chan-Loi Yong, Boehringer Ingelheim, Ridgefield, CT; Gerhard Nehmiz, Gerhard Steinmann, Boehringer Ingelheim, Biberach, Germany.

BILN 2061 is a potent and specific inhibitor of the HCV serine protease in-vitro and in patients infected with HCV genotype 1 (GT 1). In previous studies, no safety issues were found in patients with minimal and advanced fibrosis who were treated with BILN 2061 for 2 days. In a first exploratory trial, the effect of a 2-day oral treatment with BILN 2061 was investigated in patients with liver cirrhosis who were infected with HCV GT 1.

In a randomized, double-blind group comparison, 10 patients with HCV GT 1(InnoLiPA) and liver cirrhosis (Child’s A) were treated with 200 mg BILN 2061 or placebo (randomized 8:2) given b.i.d. over 2 days in an oral solution. Virus load (VL) was measured as HCV RNA by Cobas Amplicor HCV Monitor v2.0.

The study was performed as a randomized, double-blind trial, according the principles specified in the Note for Guidance on Good Clinical Practice for Trials on Medical Products in the European Community , January 17th 1997.

Ten patients with HCV genotype 1 infection and liver cirrhosis (Child’s A) received 200 mg BILN 2061(0,1,2,24 and 36 hours) or placebo (randomized 8:2), administrated b.i.d. (twice a day) over two consecutive days in polyethylene-glycol drinking solution.

Eight of the ten patients were male, including two in the control group. The patient age was 52.5 years. Nine patients had previously been treated with anti-HCV therapy; including all 8 active-treated patients. The mean duration of infection was 10.4 (SD 3.7)years in the control group.

Viral efficacy
Viral load (VL) was primarily measured by HCV RNA by Cobas Amplicor HCV Monitor v2.0 (Roche) (15) and secondarily with the quantitative Bayer B assay. If the reduction in viral load exceeded the limits of the Amplicor assay (lower limit of quantification: 1500 RNA copies/ml), the samples was also analysed with the qualitative Bayer TMA (transcription mediated amplification) assay.

Safety monitoring was conducted throughout the study and follow up period. These included monitoring of changes in vital signs (heart rate, blood pressure), routine laboratory tests and resting ECG assessment. Liver function was monitored by measuring alanine aminotransferease (ALT) and aspartate aminotransferase (AST) plasma levels.

All adverse events, serious and non-serious, that occurred during the course of the study were fully documented.


All patients completed the study and were followed up for 12-2 days post treatment. Patient compliance was excellent and there were no clinically relevant deviations from protocol. Pharmacokinetic data did not disclose any deviation from the treatment schedule.

As expected, due to the short-term treatment with BILN 2061, the viral infection was not completely eradicated. In all cases in which the viral load was below the level of detection, the qualitative TMA assay revealed that the virus was still present. As the viral load reduction was not permanent, the secondary efficacy parameters, AST and ALT, remained unchanged.

Viral load decrease
Amplicor (copes/ml) (n=8)
Bdna (copies/ml)
≥ 1 log 10 copies /ml
≥ 2 log 10 copies /ml
≥ 3 log 10 copies /ml

*The range of quantitation was restricted to the interval from 1,500 to 1,250,000
Thus, a reduction ≥ 3 log 10 copies/ml was not possible

An oral dose of 200 mg BILN 2061 b.i.d. oral solution over a two day period was effective and well tolerated in patients infected with HCV genotype 1 and who had liver cirrhosis. Viral load reductions of up to 3 log 10 copies/ml were achieved in the BILN 2061-treated patients, who had failed to respond to previous anti-HCV therapies. These observations are identical to the efficacy of the same dose of BILN 2061 in patients with no or varying degrees of liver fibrosis.

No safety issues were identified during the study; in particular, there was not indication of liver damage. All laboratory parameters of specific interest to patients with hepatic impairment (e.g. albumin, alkaline phosphatase) remained unchanged.

Few incidences of drug-induced adverse reactions were reported. Further patients need to be studied to investigate whether the reported mild constitutional and gastrointestinal symptoms may be related to BILN 2061 administration.

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Eva Herrmann, Universität des Saarlandes, Homburg/Saar, Germany; Thomas Berg, Universitätsklinikum Charité, Campus Virchow-Klinikum, Humboldt-Universität, Berlin, Germany; Holger Hinrichsen, Medizinische Universitätsklinik I, Christian-Albrechts-Universität, Kiel, Germany; Tilman Gerlach, Klinikum Großhadern, Ludwig-Maximilians-Universität, München, Germany; Ulrich Spengler, Medizinische Universitätsklinik, Bonn, Germany; Tobias Goeser, Medizinische Klinik IV, Universität zu Köln, Köln, Germany; Stefan Zeuzem, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.

The influence of absolute dose and dose in mg per kg body weight of ribavirin on sustained virologic response (SVR) in interferon-based combination treatment of chronic hepatitis C as well as the influence of dose reduction is still controversial.

Here, we address this problem by reanalyzing data of 343 previously untreated patients with chronic hepatitis C from a multicenter trial who were treated with interferon alfa-2a plus ribavirin and amantadine or interferon alfa-2a plus ribavirin (Berg et al, Hepatology 2003, 37, 1359-1367) and completed therapy. Thereby, we used a multivariate approach to account for correlations of the dose of ribavirin with body weight and body mass index (BMI) and known predictor variables from this data set which are low baseline HCV RNA, high platelet counts, high pretreatment ALT, and low γ glutamyl transpeptidase (GGT) as well as HCV genotype non-1.

Because per protocol dosage of ribavirin was weight-adjusted (1000 mg for body weight below 75 kg and 1200 mg for body weight 75 kg or more) and body weight was positively correlated with GGT and negatively correlated with platelet counts (Spearman rank correlation, p<0.01% and p=0.2%), respectively, we used a stratification with respect to genotype (GT 1 vs. non-1), GGT, and platelet counts in the analysis of ribavirin dose. When comparing body weight, BMI, the absolute intention to treat (ITT) ribavirin dose as well as the ITT dose of ribavirin measured in mg per kg body weight and the respective ribavirin doses at the end of treatment (EOT), a significant association with SVR was found for the EOT ribavirin dosage (mg per kg body weight) and BMI (p=1.8% and p=3.0%, respectively).

For predicting SVR, a weight-based ribavirin dosage threshold of 13.75 mg/kg was calculated using receiver operating characteristics (ROC) curves. The SVR rate was 66% (112/169) in patients with a ribarivin dose of more than 13.75 mg/kg as compared with 46% (79/172) in patients receiving equal or less than 13.75 mg/kg ribavirin at EOT (odds ratio 2.3; 95% CI 1.5-3.6; p=0.1%).

The analysis of ribavirin dosage motivates new considerations of weight-adjustments of the ribavirin dosage to further increase SVR in HCV-infected patients treated with combination therapy.

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Markus Schwaiger, Maurice Pich, Leonora Franke, Florian van Boemmel, Thomas Berg, Martin Schaefer, Charite, Humboldt-University, Berlin, Germany.

Hepatitis-C-infection (HCV) is associated with an increased incidence of the chronic fatigue syndrome and depressive mood changes. Beside immunological changes the modulation of the serotenergic system might be related to these psychiatric syndromes. IFN-a was also shown to modulate the central serotenergic transmission in rats and cell cultures by lowering the 5-HT concentration in the frontal cortex, midbrain and striatum and increasing transcription of the serotonin transporter. Moreover lower tryptophan concentrations were found during adjuvant IFN–a treatment in patients with malignant melanoma and the decrease was associated with depressive mood changes. Serotonin concentration, 5-HT uptake and the activity of the enzyme MAO-B in platelets are useful peripheral parameters to monitor serotenergic activity and function in patients with a chronic hepatitis C (cHC).

In a prospective controlled study serotenergic biochemical measurements of 85 patients with chronic HCV were compared to 22 healthy subjects. Measurements included assays of 5-HT concentration and 5-HT uptake activity at a low physiological substrate concentration in platelets as well as MAO-B activity. Furthermore the effect of interferon-alpha treatment on serotenergic parameters was evaluated in 47 patients before and during treatment.

The mean serotonin platelet concentration did not differ between controls and HCV-infected patients. However, 5-HT-uptake and the MAO-B activity were significant lower in patients with HCV-infection (p<0.001 respectively, t-test, two-tailed). Interferon-treatment did not influence the 5-HT reuptake (P=0.01), but led to a highly significant increase of MAO-B activity (p<0.01) and to a significant decrease of serotonin and tryptophan concentrations (p<0.01). HCV infected patients have significant changes in platelet serotenergic metabolism which maybe associated with the known increased prevalence of depression and fatigue during HCV infection. The decrease of serotonin concentrations during HCV infection was possibly compensated by a decrease in re-uptake and reduced metabolism by lowered MAO-B activity. Treatment with IFN-a may finally lead to a ‘decompensation’ of those mechanisms by increasing the MAO-B activity and 5-HT reuptake. On that account IFN treatment induces a serotenergic deficit in platelets, which is possibly a good marker for the risk to develop depressive mood changes. However, peripheral platelet changes do not necessarily reflect changes in the CNS and therefore the question remains: If depressive symptoms and serotenergic changes show a correlation, this correlation has to be investigated in future trials

Our results support recent results, suggesting that pre-treatment with anti-depressants may prevent patients from developing a serotonergic deficit, resulting in significant reduction of the incidence of IFN associated depression.

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Kazumoto Murata, Yukiko Saito, Tomoyuki Kawakita, Kazushi Sugimoto, Katsuya Shiraki, Mie University School of Medicine, Tsu, Japan

Recent large prospective trials demonstrated that the combination therapy of interferon (IFN)-alpha/ribavirin significantly increased the ratio of a sustained virological response in patients with chronic hepatitis C in comparison with IFN monotherapy, especially in patients with high HCV-RNA titer and genotype 1b. However, the mechanism of beneficial effect of ribavirin is still unknown. On the other hand, interleukin 18 (IL-18), originally termed IFN-γ inducing factor, is one of proinflammatory cytokines, which acts on Th-1 cells and strongly induces intrahepatic NK or NKT cells as well as activated T cells to produce IFN-γ. To clarify the effect of ribavirin in combination with IFN, special emphasis on IL-18, we examined the correlation between serum IL-18 level and anti-viral effect, and compared it with IFN monotherapy in patients with chronic hepatitis C.

Patients and Methods
All patients in this study are biopsy proven chronic hepatitis C with high HCV-RNA titer (HCV-RNA>100 kcopies/ml before therapy) and serotype 1 (Genotype 1a or 1b). Forty-two patients were treated with IFN alpha-2b (6 MU) in combination with ribavirin (600-800 mg) daily for 2 weeks, following 22 weeks with IFN alpha-2b (6 MU) 3 times a week (the combination group). Another 40 patients who were treated with IFN alpha-2b alone between 1998 and 1999 (before introduction of ribavirin in Japan) with the same schedule are used as control (the monotherapy group). Serum samples were taken before, 2 weeks after administration and 12 weeks after cessation of therapy. Serum IL-18 are examined by enzyme linked immuno-sorbent assay (ELISA), using human IL-18 ELISA kit (MBL, Nagoya, Japan). The IL-18 ratio is defined as serum IL-18 level before administration divided by serum IL-18 level 2 weeks after administration. HCV-RNAs are quantitatively examined before and 2 weeks after administration. Sustained viral responses are confirmed 12 weeks after cessation of administration by RT-PCR.

There are no differences in the background of patients between the combination group and the monotherapy group. In the combination group, the decline of HCV-RNA level highly correlates with the IL-18 ratio in patients with higher viral titer (HCV-RNA>500 kcopies/ml before therapy) despite no correlation is observed in patients with lower viral titer (HCV-RNA<500 before therapy). Similarly, the HCV-RNA level 2 weeks after administration controversially correlates with the IL-18 ratio in the higher titer group despite no correlation in the lower titer group. Interestingly, serum IL-18 level itself does not correlate with the decline of HCV-RNA level in both the higher and lower HCV-RNA titer group. On the contrary, in the monotherapy group, the level of up-regulation of serum IL-18 is lower than that of the combination group. Furthermore, although the decline of HCV-RNA also correlates with the IL-18 ratio in the higher titer group, the level of a correlation coefficient is lower than that of the combination group. However, the sustained viral clearance 12 weeks after cessation of treatment is not correlated with the IL-18 ratio. It suggests that ribavirin enhances the up-regulation of serum IL-18 level in combination with IFN therapy and the effect of ribavirin is critical for the early anti-viral response during therapy, not for sustained viral response.

Ribavirin may contribute to the antiviral effect through up-regulation of IL-18 in the combination with IFN therapy for patients with chronic hepatitis C, especially in the early therapeutic viral response.

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Stephan Kaiser, Holger G Hass, Michael Gregor, University of Tuebingen, Tuebingen, Germany

Treatment with pegylated interferon alfa and ribavirin has an efficacy in genotype 1chronic hepatitis C patients of about 50%. However, response in genotype 1 patients with high viral load is lower. Thus further studies to improve response rates in these difficult-to-treat patients are needed. Consensus interferon (CIFN) is an interferon that has shown a 2 log10 or greater in vitro antiviral efficacy than pegylated interferons. The present study examines the effect of daily dosing of CIFN in this patient group. 253 patients were treated with either daily or TIW dosing as control group together with ribavirin for 48 weeks. All patients had a histologically proven hepatitis infection, increased ALT levels and viremia as determined by repeated HCV RNA PCR testing. The average weight was approximately 80kg

Patients were treated with CIFN dosages of 27 or 18 ug QD for 4 weeks, followed by 18 or 9 ug QD for 8 weeks, respectively. Treatment was continued with CIFN at 9 ug QD with ribavirin (7.5 or 15 mg/kg/d) for another 36 weeks.

CIFN 27/18µg (n=104)
CIFN 18/9µg (n=110)
Ishak Score
Body Weight

At 48 weeks therapy an undetectable HCV-RNA was observed in 79 % and 72 % in the CIFN 27/18 and 18/9 ug groups, respectively. Data regarding sustained response rates showed 64 % and 58 % for CIFN 27/18 and 18/9 ug groups, respectively. Due to side effects CIFN had to be dose reduced in 11% and discontinued in 6% of patients. Addition of ribavirin potentiated the effect of consensus interferon in a dose-dependent manner as has been shown for other interferons previously. When viral response rates were related to the initial viral load, in the genotype 1 / low viral load group, SR rates of 71 and 74% were obtained for the CIFN 27/18 and 18/9 ug groups (diff. n.s.). In contrast, genotype 1 / high viral load patients showed SR rates for the CIFN 27/18 and CIFN 18/9 ug groups of 41 and 49% (diff. sig.), respectively. The viral response rates obtained with daily dosing of CIFN were significantly higher than an independently run control arm using CIFN at 9 ug TIW with ribavirin irrespective of the initial viral load. Four patients (2%) experienced grade III thrombocytopenias, while no grade IV neutropenias or thrombocytopenias were observed. The overall tolerability in the CIFN 18/9 ug QD arm was comparable to standard therapy with pegylated interferon a2b and ribavirin, while the CIFN 27/18/9 ug arm was less tolerable during the high dosing period. However, the withdrawal rates were not significantly affected by the higher dose of CIFN.

Side Effects:
CIFN 27/18µg (n=104)
CIFN 18/9µg (n=110)
CIFN Dose Reduction
RBV Dose Reduction
Early Termination
Neutropenia <750
Thrombocytopenia <40,000
Initial ALT Increase

CIFN daily dosing / induction therapy in combination with ribavirin thus shows significant response rates with the highest response rates in genotype 1 patients seen to-date. The sustained response rates for genotype 1 / high viral load patients are higher than the ones demonstrated in the PEG Interferon and ribavirin registration trials. These data suggest that for difficult-to-treat genotype 1 / high viral load patients CIFN with daily and higher initial dosing may be a worthwhile alternative to standard combination therapy with pegylated interferons.

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Nezam H Afdhal, Beth Israel Deaconess Medical Center, Boston, MA; Betty Goon, Kevin Smith, Ortho Biotech Products, LP, Bridgewater, NJ; Zobair Younossi, Inova Fairfax Hospital, Falls Church, VA; on behalf of the PROACTIVE Study Investigators

Decreases in hemoglobin (Hb) levels are a major side effect of combination therapy for HCV infection (interferon/RBV or pegylated interferon/RBV). 29-36% of IFN/RBV treated patients develop anemia as a side-effect. Mean Hb decreases reported with PEG-IFN/RBV combination therapy in 2 large clinical trials were 2.5g/dl and 3.7g/dl. In a recent study 54% of patients on combination therapy experienced Hb decreases > 3g/dl. Prescribing information advises that the RBV dose should by reduced if Hb < 10g/dl and discontinued of Hb < 8.5g/dl. Additionally anemia was the reason for RBV dose modification in 22% of the patients and for discontinuation of therapy in 36% of patients in recent studies.

Decreases in health-related quality of life (HRQL) are coming during HCV treatment. Decreased HRQL during treatment is associated with treatment discontinuation. HRQL correlates directly with Hb levels in cancer patients receiving chemotherapy and measures to increase Hb levels in these patients improve HRQL.

In HCV infected patients, the relationship between HQRL and Hb levels has not been fully explored.

(1) To descriptively correlate changes in Hb with changes in HRQL in anemic (Hb<12g/dl) HCV infected patients receiving combination therapy
(2) To analyze the independent relationship of Hb to HQRL in this patient population

Study Design
Randomized, placebo-controlled, multicenter clinical trial with an 8-week double-blind phase (DBP) and an 8 week open-label phase (OLP) evaluating epoetin alfa versus placebo in anemic (Hb< 121g/dl) HCV-infected patients receiving combination IFN/RBV

HRQL scores were obtained from 185 anemic HCV-infected patients (mean Hb 10.8 ± 0.9 g/dL) who had been receiving IFN/RBV for 12-14 weeks (study population) (Afdhal et al., DDW 2003). During the double-blind phase (DBP), patients were randomized to receive EPO 40,000 U SC QW or placebo (PL) for 8 weeks. Following the DBP, both EPO and PL patients were allowed to receive EPO for the 8-week open label phase (OLP). HRQL was assessed at baseline and weeks 9 and 17 using two instruments, the Medical outcomes Survey Short Form-36 (SF-36) and the Linear Analog Scale Assessment (LASA). The SF-36 is an accepted and validated tool that measures 8 domains of HRQL, and the LASA measures constructs of energy, activity and overall quality of life. To minimize bias, patients were kept blinded to Hb, hematocrit, liver function tests, and HCV viral load results until all study procedures were completed for the visit. The baseline HRQL scores of the study population were compared with age- and gender-matched data from the general population, as well as with patients with congestive heart failure, diabetes, clinical depression, and untreated chronic HCV infection (SF-36 Health Survey Manual and Interpretation Guide; Bonkovsky et al., Hepatology. 1999). All baseline comparisons were completed using independent sample t-tests.

Categorical analysis of HRQL change from baseline to the end of the DHP by Hb level (independent of study drug received) involved patients placed in the following groups:
• Hb decrease from baseline to end of DBP
• Hb increase from 0 to < 2g/dl from baseline to end of DBP
• Hb increase>2g/dl from baseline to end of DBP
The relationship between Hb levels and HRQL at the end of the DBP (independent of study drug received) was also assessed using regression analysis to determine whether increased Hb levels in HCV-infected patients are associated with improved HRQL. The regression model controlled for age, gender, Hb level at baseline, HRQL domain at baseline, fibrosis status, RBV dose change, duration of HCV therapy and HCV RNA level.

Patients who had the greatest Hb increases from randomization to the end of the DBP, also had the largest increases in HRQL.
• Mean Hb of the study population at baseline = 10.8 ± 0.9g/dl
• At baseline, patients in the epoetin alfa and placebo groups had been on HCV therapy for an average of 12 and 14 weeks respectively
• Patients with Hb increases > 2g/dl had greater improvements in HRQL on both the SF-36 and the LASA than patients with Hb increases from 0 to <2g/dl
•Patients with Hb decreases had decreases in HRQL from baseline to the end of the DBP on the RE (role emotional), MH (mental health), GH (general health), VT (vitality) and RP (role physical) domains of the SF-36 and on the activity domain of the LASA. Only modest increases were found on the remaining HRQL domains
• Hb change from baseline to the end of the DBP was a significant independent predictor of HRQL on all domains of the LASA and 6 of 8 domains of the SF-36

Regression Analyses: Change in HRQL by change in Hb from baseline to end of DBP: SF-36

HRQL domain
Parameter estimate*
Physical Functioning
Role Physical
Bodily Pain
General Health
Social Functioning
Role Emotional
Mental Health

• *Increase in HRQL domain scores corresponding to 1g/dl increases in Hb as estimated by the regression model

Regression Analyses: Change in HRQL by Change in Hb from Baseline to End of DBP: LASA

HRQL Domain Parameter estimate * P- value
Activity 4.34 <0.0001
Energy 4.48 <0.0001
Overall 3.95 0.0004

• *Increase in HRQL domain scores corresponding to 1g/dl increases in Hb as estimated by the regression model

Hb improvement is a strong independent predictor of HRQL improvement in anemic HCV infected patients receiving combination therapy. Because administration of epoetin alfa increases Hb in anemic HCV patients, these data suggest that epoetin alfa treatment may improve HRQL in this patient population.

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Myron Tong, Huntington Memorial Hospital Liver Center, Pasadena, CA; Tarek Hassanein, UCSD Medical Center, San Diego, CA; William Van Antwerp, Medtronic MiniMed, Northridge, CA; Elizabeth Olek, Brian Murphy, InterMune, Inc., Brisbane, CA.

Pegylation of interferon-alfa results in an improved pharmacokinetic profile by maintaining constant blood levels, resulting in higher sustained response rates (SVR). However, modification of interferon-alfa by pegylation also reduces biologic potency. Delivery of a bio-optimized alpha interferon in an unmodified form (consensus interferon, Infergen®) by continuous infusion can be expected to provide sustained and constant levels of a fully potent protein. We hypothesize that such an approach may potentially result in greater antiviral activity and improved tolerability by avoiding wide swings in interferon levels. The viral kinetic profile for patients who have been previously non-responsive to therapy with either IFN-a + RBV or pegylated IFN-a + RBV maybe alterable if constant and sustained levels of IFN along with RBV are achieved. Thus, the demonstration of a dramatic decrease or the disappearance of HCV-RNA levels on therapy is important in individuals who have had a previous pattern of decline and maybe an advance for recalcitrant non-responders.

We conducted a phase 2 pilot study to assess the safety, tolerability and viral kinetics of Infergen (12 µg/day) by continuous infusion using a subcutaneous infusion device (Medtronic MiniMed® pump) in combination with ribavirin (1000 mg or 1200 mg daily). Based on extensive experience with insulin administration in the diabetic patient population, the pump method of delivery was considered a good option for the treatment of chronic HCV in those patients who have exhausted other treatment options. HCV RNA viral levels were measured at days 1, 3, 7, 10, 14, 21, 28 and then at weeks 6 and 12.

For patients receiving 12-24 weeks of therapy (n=9), 7 non-responder patients showed a = 2 log10 decrease in HCV-RNA level on therapy (78%) by NGI Superquant PCR (limit of detection = 30 IU/ml). Among non-responders (n=123), 1 patient showed HCV-RNA levels below the level of detection at week 24 (8%). Of all non-responder patients enrolled (n=12) only 1 patient had a 2 log10 in HCV-RNA on prior therapy (mean was 0.9 log10 on prior therapy) and as expected has shown a response to the current therapy regimen. 2 patients have required the addition of erythropoietin. 4 patients have had local injection site infection requiring oral antibiotic therapy and 3 patients discontinued within the first 2 weeks on therapy due to inability to acclimate to the pump. No serious side effects were reported.

Among non-responders receiving up to 12-24 weeks of Consensus interferon therapy administered by continuous delivery via the Medtronic MiniMed pump, 7/9 (78%) showed = 2 log10 decrease in HCV-RNA.

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Juan Armendariz-Borunda, University of Guadalajara, OPD Hospital Civil de Guadalajara, Guadalajara, Jal. Mexico, Mexico; M. Cristina Islas-Carbajal, Eduardo Meza, Ana Rosa Rincon, University of Guadalajara,, Guadalajara, Jal. Mexico, Mexico; Arnulfo Alvarez, University of Guadalajara, Guadalajara, Jal. Mexico, Mexico; Zachary D. Goodman, Armed Forces Institute of Pathology, Washington, DC; A.Soledad Sandoval, University of Guadalajara, Guadalajara, Jal. Mexico, Mexico; Amador Covarrubias, Hospital Civil Juan I Menchaca, Guadalajara, Jal. Mexico, Mexico; Gil Arechiga, University of Guadalajara, Guadalajara, Jal. Mexico, Mexico; Leonel García, University of Guadalajara, OPD Hospital Civil de Guadalajara, Guadalajara, Jal. Mexico, Mexico.

Pirfenidone (PFD) is an orally bioavailable pyridone derivative that affects a variety of cytokines, including inhibition of TGF-beta, TNF-alpha, PDGF, and EGF. PFD has been shown in clinical studies to improve physiologic parameters in patients with pulmonary fibrosis. We have previously shown that PFD decreased hepatic fibrosis in two different rat models of cirrhosis (J of Hepatology 37: 797-805, 2002). Our objective in this pilot clinical study was to evaluate the safety and preliminary activity of PFD in patients with cirrhosis of varying etiologies.

All patients had histologic and/or clinical evidence of cirrhosis. PFD was given orally at a dose of 400 mg TID for 12 months. Physical examination and labs including ALT, AST, bilirubin, albumin and prothrombin time, platelet count were assessed at baseline and on monthly basis. HCV RNA levels were measured in patients with chronic hepatitis C (Cobas Amplicor HCV Monitor v2.0). Liver biopsies were obtained at baseline and after 12 months of treatment and were read independently by two hepatopathologists who were blinded to the biopsy sequence. Modified Histological Activity (HAI) Index of Knodell and Ishak fibrosis stage were used to assess changes in necroinflammatory scores and fibrosis stage, respectively. Change in steatosis was also assessed.

A total of 26 patients with cirrhosis due to hepatitis C (15), ethanol (8), amyloidosis (1), autoimmune disease (1) and Budd-Chiari syndrome (1) were included. The mean age was 57 years (range, 29-75) with 13 males. Liver biopsies at end of therapy showed a 2-point or greater reduction in the HAI necroinflammatory score in 41% of the patients. Steatosis decreased in 33% of the patients, was unchanged in 42% and worsened in 25%. While there was no significant reduction in the Ishak fibrosis stage, improvement in interstitial fibrosis was noted. Evidence of cell regeneration was seen in some patients.

HCV RNA levels were measured in 15 patients with chronic hepatitis C. At 6 months, 9 patients had a decrease in viral load, 2 patients remained unchanged and 4 patients displayed an increase in viral load compared to baseline. No patient had a sustained virologic response. 4 out of 15 (27%) HCV patients had normalization of ALT, 7 out of 15 (47%) had decreased ALT values, 1 did not change (7%) and 3 patients showed a modest increase in ALT (20%). PFD was well tolerated with the predominant drug-related adverse events being nausea, photosensitivity rash, and itching occurring in 15% of the patients and which improved after 2 to 3 months of therapy.

In this pilot study, treatment of cirrhotic patients with pirfenidone for one year was well tolerated. A significant reduction in necroinflammation (= 2-point reduction in HAI grade) and steatosis was observed in a substantial proportion of patients. A subset of patients with chronic HCV infection showed on-treatment reduction in HCV RNA levels. Longer treatment duration or a less cirrhotic patient population may be needed to demonstrate effects on fibrosis. These data support conducting clinical studies to evaluate a potential role of PFD in the treatment of steatosis, or in combination therapy for chronic hepatitis C. This work was supported by Grants of Marnac, Inc and InterMune, Inc.

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John B. Gross, Terry M. Therneau, Stephanie M. Johnson, Mayo Clinic, Rochester, MN; Paul Y. Kwo, Indiana University, Indianapolis, IN; Nezam H. Afdhal, Beth Israel Deaconess, Boston, MA; Steven L. Flamm, Northwestern University, Chicago, IL; RENEW Trial Investigators, National Network, Rochester, MN.

Ten percent of interferon/ribavirin non-responders treated with conventional doses of peginterferon + ribavirin have a sustained virological response. The current trial was designed to see if better results could be achieved by retreating with higher doses of peginterferon alfa-2b (PEG2b) + weight-based ribavirin.

To compare the efficacy, safety and tolerability of three different doses of PEG2b + weight-based ribavirin among interferon/ribavirin non-responders.

Patients were randomized to 1 yr of treatment with PEG2b 0.5, 1.5 or 3.0 mcg/kg/wk, plus ribavirin 12-15 mg/kg/day. Treatment assignment was stratified for sex, race, HCV genotype and histologic fibrosis. Treatment was stopped at 24 wk if PCR(+). Doses were reduced by 33% for toxicity; growth factors were not allowed.

Patients: Enrollment took place between February 2001 and November 2002, with 963 patients recruited from 100 centers; data forms have been received on 794 thus far. Enrollment was stopped in the low-dose group after FDA approval of higher doses of PEG2b. The study population is 32% female, 16% African-American, 93% genotype 1, 64% F2/3/4, Age (yrs) 47+7 and BMI 29+6. The anticipated final analysis is expected 5/31/04.
Efficacy: On-treatment virological response rates were dose-related at 24 wk but less so at 48 wk (see table). This was partly due to a higher rate of discontinuation after a satisfactory response at 24 wk on the higher dose. On-treatment response rates were lower among African-Americans and patients with more advanced fibrosis.

On treatment Viral Clearance Rates

Dose of Peg 2b (mcg/kg/wk)
  0.5 1.5 3.0
24 weeks 16% 30% 39%
48 weeks 10% 19% 20%
72 weeks 4% 7% 11%

African American versus Other

24 weeks
24 weeks
African American

Response Rates were independent of BMI

24 weeks BMI > Median = 36%
24 weeks BMI < Median = 29%
48 weeks BMI > Median = 23%
48 weeks BMI < Median = 20%

Overall Rates of Dose Reduction (by dose of Peg 2b mcg/kg/wk)

0.5 32%
1.5 33%
3.0 45%

Overall Rates of Neutropenia (by dose by Peg 2b mcg/kg/wk)

0.5 24%
1.5 31%
3.0 35%

Neutropenia Less than 750 million/L (by dose of Peg 2b mcg/kg/wk)

0.5 8%
1.5 10%
3.0 11%

Most Common Adverse Events

Dose of Peg 2b (mcg/kg/wk)
  0.5 1.5 3.0
Fatigue 47% 54% 54%
Fever 26% 25% 29%
Headache 23% 30% 32%
Leukopenia 12% 21% 23%
Neutropenia 24% 31% 35%

Serious Adverse Events (by dose of Peg 2b mcg/kg/wk)

0.5 — 8 patients
1.5 — 22 patients
3.0 — 24 patients

Dyspnea – 10 patients
Elective Surgery – 8 patients
Chest Pain – 4 patients
Neutropenia – 4 patients
Suicidal Thoughts – 4 patients
Suicide Attempt – 2 patients
Abdominal Pain – 2 patients
Retinal Bleed or Tear – 2 patients
Rectal Bleeding – 2 patients
DKA – 2 patients

30-40% of IFN/RBV non-responders achieved initial viral clearance on peginterferon alfa 2b + RBV. The higher dose of 3.0µg/kg resulted in a higher initial viral clearance rate by a similar rate of SVR due in part to a higher rate of dose reduction. There was no serious difference in safety or tolerability between 1.5 and 3.0µg/kg. Predictors of response were similar to those previously observed for treatment naïve patients

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Thomas Berg, Charité, Campus Virchow-Klinikum, Berlin, Germany; M von Wagner, Universitätskliniken des Saarlandes, Homburg/Saar, Germany; H Hinrichsen, Christian-Albrecht-Universität, Kiel, Germany; T Heintges, Heinrich-Heine-Univeristät, Düsseldorf, Germany; P Buggisch, Universitätsklinik Eppendorf, Hamburg, Germany; T Goeser, Universität zu Köln, Cologne, Germany; J Rasenack, Medizinische Universitätsklinik, Freiburg, Germany; G R. Pape, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, Germany; W E. Schmidt, Medizinische Universitätsklinik, St. Josefshospital, Bochum, Germany; B Kallinowski, Universitätsklinik Heidelberg, Heidelberg, Germany; H Klinker, Klinikum der Universität Würzburg, Würzburg, Germany; U Spengler, Medizinische Einrichtung der Rh. Fr. Wilhelms Universität, Bonn, Germany; B Klapperich, Roche, Grenzach, Germany; M Popescu, Roche, Basel, Switzerland; S Zeuzem, Universitätskliniken des Saarlandes, Homburg/Saar, Germany; German PEGASYS+COPEGUS Genotype 1 HCV Study Group.

Treatment of patients infected with hepatitis C virus (HCV) genotype 1 (G1) remains a challenge necessitating innovative strategies to improve treatment outcome. Viral kinetic studies have shown that turnover of hepatocytes infected with HCV G1 is slower than in other genotypes. This implies that more aggressive antiviral treatments are required in patients infected with HCV G1. Extending the treatment duration beyond 48 weeks is one strategy that may improve response rates in these difficult-to-treat patients.

To compare the efficacy and safety of 48 weeks versus 72 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) in combination with ribavirin (COPEGUS®) in treatment-naïve patients infected with HCV G1.

Multicenter, national, randomized, open-label parallel group study conducted in accordance with local and international GCP guidelines. Treatment-naïve patients infected with HCV G1, aged >18 years with CHC infection, HCV RNA levels >1000 copies/mL, elevated ALT levels, liver biopsy findings consistent with a diagnosis of CHC, and compensated liver disease (Child-Pugh grade A) were eligible for the study.
After screening and signing of informed consent forms, patients were randomized to treatment with peginterferon alfa-2a (40KD) (PEGASY®) 180 µg once weekly plus ribavirin (COPEGUS®) 800 mg/day (400 mg BID) for either 48 weeks or 72 weeks. Patients were followed for an additional 24 weeks after the end of treatment. Virological response was defined as undetectable HCV RNA (<50 IU/mL by COBAS AMPLICOR® HCV Test, v2.0, Roche Diagnostics) at the end of follow-up.

To date 459 patients have been enrolled in the trial and 256 have completed follow-up. The two treatment groups were comparable with regard to baseline characteristics. The results of the study, presented as intent-to-treat, and per protocol (PP) analysis are shown below. The primary endpoint, a sustained virological response at the end of a 24 week follow up period was observed in 50.6% of the 48 week treatment group and in 50.9% of the 72 week group in the ITT population. The per protocol analysis showed a trend in favor of the 72 week treatment duration, although not significant with an SVR of 68.5% vs. 78.5% and a reduction in the relapse rates from 27.5% to 18.8% in the 48 week versus 72 week regimen respectively.

Reductions in the dose of peginterferon alfa 2a were required in 19.5% and 17.3% of patients in the 48 week and 72 week treatment groups, respectively. Reductions in the dose of ribavirin were required in 10.4% and 15.1% of patients in these groups respectively. Doses of peginterferon alfa 2a and ribavirin were reduced in 3.0% and 4.0% of patients in the 48 week and 72 week treatment groups respectively.
Therapy was discontinued prematurely in 14.2% and 28.0% of the patients in the 48 week and 72 week treatment groups (p <0.05). The overall discontinuation rate was also higher in the 72 week treatmewnt group (see table); however there was no difference in discontinuation rates during the first 48 weeks of treatment (24.2% vs. 23.9%).

ITT (intention to treat population) = all patients who took at least one dose of the study medication and had at least one HCV RNA evaluation post baseline;
PP (per prtocol population) = all patients who completed 48 or 72 weeks of treatment according to the protocol and had HCV RNA evaluations at the end of the 24 week follow-up period.


The combination of peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) was safe and effective in patients with HCV genotype 1. Despite the use of a dose of ribavirin (800 mg/day) that is lower than the recommended dose for patients infected with G1 (1000/1200 mg/day), approximately half of the patients in the study achieved an SVR. Because the study could not be blinded, a bias might have influenced the outcome of the study as suggested by the unequal discontinuation rate. Indeed, per protocol analysis demonstrasted a beneficial effect of 72 weeks of treatment in reducing the relapse rate. Nevertheless, our data do not support the concept of generally extending treatment duration in HCV type-1 infected patients to achieve higher SVR rates.

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Martin Schaefer, Markus Schwaiger, Thomas Berg, Charite, Humboldt-University, Berlin, Germany

It has recently reported, that pretreatment with paroxetine, an selective serotonin reuptake inhibitor (SSRI), prevents patients with malignant melanoma from interferon-alpha (IFN-alpha) associated depression.

In an open and prospective trial we investigated, if a pre-treatment with citalopram as an SSRI can reduce the frequency of IFN-associated depression in hepatitis-C-infected psychiatric risk patients during methadone substitution. 36 patients with a chronic hepatitis C were treated with pegylated interferon-alpha 2b and ribavirin according to body weight. Eleven patients without any psychiatric history (group A) were compared to 25 patients during methadone substitution. The methadone substituted patients were separated into two groups: the first group (group B, n=11) were only treated with IFN-alpha and ribavirin and the second group (group C, n=14) received a two week pre-treatment with citalopram (20mg/day) before combination treatment with IFN-alpa and ribavirin was started. Antidepressant treatment was continued over the study period of four months. The Hamilton Depression Rating Scale (HAMD, 17-item) was used and major depression defined as great than 20 points. Patients were followed over the first 4 treatment months. Group differences were calculated with ANOVA for parametric and chi²-test for non-parametric scales.

HAMD scores at baseline were significantly higher in the psychiatric groups as compared to the controls (p=0.010). A major depression during 4 months of IFN-alpha treatment was diagnosed in 15 of the 36 patients (42%). While group B and controls did not differ significantly in the development of major depression (64% vs. 55%), patients with citalopram pre-treatment (group A) developed significantly less depressive episodes (14%) (p=0.028). In case of depressive episodes during treatment, HAMD-scores for depression were significantly higher in psychiatric patients as compared to controls (p=0.018).

This study demonstrates for the first time that an anti-depressant pre-treatment with citalopram is highly effective in preventing interferon induced depression even in psychiatric risk patients with addiction.

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Laurent L. ALRIC, Jacques Izopet, Sophie Metivier, CHU Purpan, Toulouse, France; Jean Tkaczuck, Bernard Pipy, CHU Rangueil, Toulouse, France; Jean-Pierre Vinel, CHU Purpan, Toulouse, France.

Patients with severe liver disease, genotype 1 infection (100%), high viral load and no response to primary IFNa-ribavirin therapy have poor predictive factors of response to antiviral therapy. The aim of this randomized prospective study was to assess the efficacy and the safety of a triple therapy by IFNa2a- ribavirin- IL-2 in these difficult to treat patients.

20 HCV patients (men16/.women4), Age 48.9 ± 1.8 without HIV co-infection who were previously non-viral responders to IFNa (3 millions IU 3 times a week) and ribavirin (1000-1200 mg daily) were included. All eligible patients had : genotype 1 infection, high viral load > 200 000 IU/ mL (Amplicor Monitor Roche) and Metavir fibrosis score >= 2. Each patient was re-treated intensively by IFNa2a (3 millions IU every 2 days) combined to ribavirin (800-1000 mg daily) during 24 weeks. Patients were randomized to receive 4 cycles of subcutaneous injection of IL-2 (3 millions IU daily, 5 days a week every 3 weeks) during either the 12 first weeks (group 1, n=10) or the 12 last weeks (group 2, n=10) of IFNa2a-ribavirin combination therapy.

On the liver biopsy performed within 12 months before the start of triple therapy, Metavir fibrosis score was 3.3 +/- 0.7 and 10 patients had cirrhosis (50%). Baseline viral load was 788 650 IU/mL. In group 1, at the end of treatment (week 24), a decrease (p< 0.05) of viral load (298 538 ± 94 406 IU/mL)was observed as compared to baseline values (932 300 ± 689 509 IU/ mL). No significant difference was observed in group 2. At the end of tri-therapy, a viral response was observed in 4 of 20 patients (20%) : 2 in each group. A viral relapse occured in all cases within 12 weeks after tri-therapy discontinuation. No serious adverse effect was observed during treatment.

In patients with poor predictive factors of response, intensification of antiviral therapy could be associated to a viral response. A careful monitoring of viral load kinetic in group 1 and in group 2 before and under IL-2 therapy will determine the influence of IL-2 on these results. Such triple therapy is well tolerated in out patients. The combination of IL-2 with Peg-IFN ribavirin or during a longer period needs to be tested.

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Kazuko Iwata, Mie University Hospital, Tsu City, Mie, Japan; Motoh Iwasa, Masahiko Kaito, Masaki Takeo, Jiro Ikoma, Yukihiko Adachi, Mie University School of Medicine, Tsu City, Mie, Japan.

It is important to maintain reduced serum alanine aminotransferase (ALT) levels in cases with chronic hepatitis C (CH-C) that do not respond to interferon (IFN) and in those with no indication of IFN therapy. We reported previously that dietary restriction of iron intake reduces serum ALT levels in such patients. We evaluated CH-C patients treated with iron-restricted diet for two or more consecutive years, mainly focusing on the balance of energy intake, physical examination, and changes in hematological indices of nutrition.

Twenty-two patients with CH-C (males, 18; females, 4; mean age, 56 year-old) that consulted our outpatient department were enrolled in this study. The inclusion criteria were as follows: 1) elevation of ALT levels above the upper normal limit for 3 months or more; 2) positive tests for HCV-antibody and HCV-RNA; 3) absence of other causes of CH (alcoholic liver disease, drug-induced liver injury, hemochromatosis) and negativity for hepatitis B surface antigen and for serum anti-nuclear and anti-mitochondrial autoantibodies. Twenty cases had received IFN therapy for more than 12 months before the beginning of the study; none of them responded to IFN therapy. Dietary prescriptions included iron intake 7 mg/day or less, energy intake 30 kcal/kg/day, protein intake 1.1-1.2 g/kg/day, and a fat energy fraction of 20%. Nutritional balance was evaluated based on meal records, and instructions was given when necessary.

The average energy intake before dietary prescription was 2184 kcal (36.7 kcal/kg)/day, and it was significantly reduced to 1655 kcal (28.5 kcal/kg)/day (p < 0.01), and then maintained stable at 30 kcal/kg/day. The average protein intake before dietary prescription was 85.7 g (1.45 g/kg)/day and it was reduced to 1.1-1.2 g/kg/day after the prescription. The average fat intake of 66.5 g (1.1 g/kg)/day and the average fat energy fraction of 27% before the dietary prescription were significantly decreased to 30.8 g (0.52 g/kg)/day; p < 0.01 and 16% (p < 0.001), respectively, after dietary instructions. The fat energy fraction was maintained at a level of 20% or less. Carbohydrate intake did not change remarkably during the observation period, although the carbohydrate energy fraction significantly (p < 0.001) increased. The average iron intake decreased significantly (p < 0.001) from 9.6 (before) to 6.1, 5.2, 5.1, 5.2, and 5.1 mg/day 6, 12, 18, and 24 months after dietary prescription, respectively. Body mass index (BMI) before diet prescription was 23.9 on average; BMI had no significant change throughout the course. The body fat percentage was 24.6% on average before the diet instructions, and it significantly decreased after the diet. The average values of aspartate aminotransferase and ALT before diet prescription were 65 IU/l and 66 IU/l, respectively, and they were significantly reduced to 48 IU/l and 49 IU/l, respectively, after 24 months (p < 0.01). Serum iron levels significantly decreased after 18 (p < 0.01) and 24 (p < 0.05) months, while unsaturated iron binding capacity tended to increase. The average serum ferritin levels were 376, 210, 189, 189, 141 ng/ml before and 6, 12, 18, and 24 months after diet, respectively; there was a significant reduction (p < 0.01) in the values measured before and after the diet instructions. The average levels of hemoglobin, albumin and cholinesterase did not change significantly during the follow-up period.

Restriction of iron intake is safe and well tolerated for a long period. The results of our present study suggest that decreased dietary intake of iron may constitute an important adjuvant therapy in patients with CH-C.

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Charles L. Raison, Sherry D. Broadwell, Andrey S. Borisov, Amita K. Manatunga, Bobbi J. Woolwine, Emory University, Atlanta, GA; Ira M. Jacobson, Weill Medical College of Cornell University, New York, NY; Charles B. Nemeroff, Andrew H. Miller, Emory University, Atlanta, GA.

Interferon (IFN)-alfa plus ribavirin is an effective treatment for chronic hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders. To determine whether increased depressive symptoms during IFN alfa/ribavirin therapy were associated with reduced clearance of HCV, a prospective cohort design was used to evaluate HCV-infected patients at baseline and after 4, 8, 12 and 24 weeks of pegylated IFN-alfa-2b/ribavirin therapy.

The sample was derived from patients enrolled in a larger multi-center, randomized clinical trial of pegylated IFN-alfa-2b plus fixed-dose versus weight-based ribavirin. 102 HCV-infected subjects who volunteered to participate and completed 24 weeks of IFN alfa/ribavirin treatment followed by viral load testing were included. Severity of depressive symptoms was measured by the Zung Self-Rating Depression Scale (SDS). Viral clearance was defined as polymerase chain reaction (PCR) negative (less than 29 HCV IU/ml) at 24 weeks.

Increased depressive symptoms during IFN-alfa/ribavirin therapy were associated with reduced viral clearance (P=0.006). Only 34% of subjects with a 20-point or greater increase in SDS Index (N=29) were HCV PCR negative at 24 weeks, compared to 63% of patients without a 20-point increase (N=73)(crude OR, 3.2; 95% confidence interval (CI), 1.3-8.0; P=0.009). These results remained significant after adjusting for ribavirin dose assignment, viral genotype, age, antidepressant usage, IFN-alfa/ribavirin dosage reduction and knowledge of viral load status during treatment (adjusted OR 4.1; 95%CI 1.5-11.5). Cumulative depressive symptoms over the 24 weeks of IFN-alfa/ribavirin therapy also predicted failure to clear virus (P=0.026).

HCV patients who experience significant increases in symptoms of depression during IFN-alfa/ribavirin therapy are less likely to clear virus, highlighting the potential importance of identifying and treating depressive symptoms in this patient population.

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Charles L. Raison, Andrey S. Borisov, Sherry D. Broadwell, Emory University, Atlanta, GA; Amita K. Manatunga, Emory University Rollins School of Public Health, Atlanta, GA; Bobbi J. Woolwine, Emory University, Atlanta, GA; Ira M. Jacobson, Weill Medical College of Cornell University, New York, NY; Charles B. Nemeroff, Andrew H. Miller, Emory University, Atlanta, GA.

Interferon (IFN)-alfa plus ribavirin is the only FDA approved treatment for hepatitis C (HCV) infection.Unfortunately, IFN-alfa/ribavirin therapy is associated with depression in a high percentage of patients. To further examine the development of depression during treatment for HCV and the risk factors involved, we conducted a 24-week prospective cohort study of patients receiving pegylated IFN-alfa-2b (PEG IFN) and ribavirin for the treatment of HCV.

The study sample was derived from a larger multi-center, randomized clinical trial designed to compare the efficacy of standard versus weight based dosing of ribavirin plus PEG IFN. 150 patients from this trial volunteered to participate in our study, completed 24 weeks of treatment with PEG IFN/ribavirin and were included in data analysis. Subjects were evaluated at baseline (prior to start of PEG IFN/ribavirin) and following 4, 8, 12 and 24 weeks of therapy. At baseline, subjects were screened for past or current major depression and substance abuse by telephone. Subjects also completed the Zung Self Rating Depression Scale (SDS), a 20-item self-report instrument widely used to evaluate depressive symptoms in the medically ill. The development of clinically relevant depressive symptoms was considered to have occurred if patients developed an SDS score equal to or greater than 60 (consistent with the presence of moderate to severe depression) at any point during the 24 week treatment period.

Mean SDS score at baseline for the study sample as a whole was 41.8 (SD 10.0). During 24 weeks of IFN-alfa/ribavirin treatment, mean maximum SDS score for the group as a whole increased to a maximum of 55.6 (SD 10.2), with the majority of the increase from baseline occurring in the first 4 weeks of treatment. Thirty eight percent of patients developed SDS scores equal to or greater than 60 during treatment, while 11% of patients met criteria for major depression. In a univariate analysis, factors that correlated with the development of clinically significant depressive symptoms included weight-based dosing of ribavirin (Odds ratio [OR] 2.43, 95% CI 1.22-4.82) and past history of major depression (OR 3.3, 95% CI 1.35-8.24). Weight-based ribavirin dosing continued to predict the development of depressive symptoms after adjustment for age, gender, past history of depression, antidepressant use at baseline or during treatment, history of substance abuse and baseline SDS score (OR 3.0, 95% CI 1.3-7.0). Past history of major depression did not predict the development of depressive symptoms after adjustment for these factors (OR 1.20, 95% CI 0.26-4.0), suggesting that the effect of past major depression may be mediated in part by an increased likelihood of patients with a history of depression having elevated SDS scores at baseline. Consistent with this, patients with a past history of major depression had significantly higher baseline SDS scores. Baseline SDS score predicted the development of significant depressive symptoms (OR for each 5 point increase in baseline SDS = 2.0, 95% CI 1.52-2.6).

Results from this study suggest that the development of clinically significant depressive symptoms, but not major depression, is common in patients receiving pegylated PEG IFN plus ribavirin for HCV infection. Moreover, while PEG IFN has traditionally been viewed as the causative agent for depression during combined therapy, these data indicate that ribavirin may also contribute to the development of depressive symptoms, and that the effect may be dose related. Finally, the association between past depression and the development of depressive symptoms during treatment appears to be mediated by the increased likelihood for patients with a past history of depression to demonstrate increased depressive symptoms just prior to commencing IFN-alfa/ribavirin therapy. This finding highlights the importance of evaluating a patient’s mood status prior to commencing treatment for HCV.

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Steven L. Flamm, Northwestern University Medical School, Chicago, IL; Charles Mendenhall, Cincinnati VA Hospital, Cincinnati, OH; David Johnson, Carl T. Hayden VA Hospital, Phoenix, AZ; Maher Azzouz, G.V. "Sonny" Montgomery VA Hospital, Jackson, MS; Lawrence Lumeng, Richard L. Roudebush VA Hospital, Indianapolis, IN; Vivek Huilgol, Overton Brooks VA Hospital, Shreveport, LA; Helen Wong, Central California VA Hospital, Fresno, CA; Anastasios Mihas, McGuire VA Hospital, Richmond, VA; Frederic Regenstein, New Orleans VA Hospital, New Orleans, LA; Axel Feller, North Chicago VA Hospital, North Chicago, IL; Richard Jaszewski, John D. Dingle VA Hospital, Detroit, MI; Christina M. Bromley, Ronald L. Bromley, BioStat Solutions, Damascus, MD.

Chronic hepatitis C virus (HCV) infection is a common problem in the VA population. Although PEG IFN a 2b + ribavirin yield sustained response rates (SVR) of 54% in registration trials, VA patients have been noted on an anecdotal basis to have high medication drop-out rates and lower SVR. Furthermore, African Americans (AA) comprise a higher proportion of the VA population with HCV and have been reported to have lower SVR than the Caucasian (C) population. The reasons for lower antiviral response rates in the VA population in general and AA population in particular are unknown.

We sought to examine the psychosocial dynamics of the VA population eligible for antiviral therapy within the context of a randomized, controlled, multicenter, national trial. Differences between AA and C populations were determined.

Eligible patients with chronic HCV (+ HCV RNA) presenting for antiviral therapy from 12 national VA centers were evaluated within the context of a randomized, controlled treatment trial. Patients were enrolled if inclusion criteria were met. An extensive 48 question survey that measured epidemiological risk factors was administered prior to commencing medical therapy. The results of this questionnaire are reported for AA and C populations.

292 patients were enrolled in the treatment trial. Results of the survey were available in 239 patients (34% AA, 59% C and 7% other ethnicities). Results are reported for AA and C patients. Although 53% of VA patients attended or completed college or graduate school, the majority (58%) have incomes less than $25,000 annually (18% did not report income data). 72% of patients were Vietnam veterans and the majority (79%) served four or fewer years in the military. 57% had history of intravenous drug use and 22% have a history of a blood transfusion. 48% of patients have been incarcerated at least once. The majority of patients answered one or more of the CAGE questions in the affirmative. 44% had sex with prostitutes (13% did not answer). Significantly more AA have children and have more children than C (79% vs. 64%)*. Significantly more AA have genotype 1 (75/81 (93%) vs. 84/135 (62%) respectively)*. *p<0.05.

1) HCV patients in the VA population have significant psychosocial comorbidities including significant substance abuse history, incarceration history, history of depression and low income which suggests that antiviral medical therapy with a high side-effect profile would be difficult to maintain. 2) AA and C were similar in regards to psychosocial comorbidity with the exception of higher reported rates of depression, children and genotype 1 prevalence in the AA population. 3) Poor SVR in the AA population in comparison to the CC population is likely related to genotype profile rather than psychosocial issues. 4) Providing social support and counseling to HCV patients in the VA population may improve adherence rates and consequently improve SVR.

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Jason M. Hui, Storr Liver Unit, Westmead Hospital, Westmead, NSW, Australia; Archana Sud, Geoffrey C. Farrell, Priyanka Bandara, James G. Kench, Storr Liver Unit, Westmead Hospital, Westmead, Australia; Geoffrey W. McCaughan, AW Marrow Gastroenterology and Liver Centre, Camperdown, NSW, Australia; Jacob George, Storr Liver Unit, Westmead Hospital, Westmead, Australia.

Chronic hepatitis C virus (HCV) infection is associated with an increased prevalence of type 2 diabetes mellitus, which is known to accelerate fibrosis in NASH. We hypothesized that viral-induced insulin resistance (IR) may be a mechanism for fibrogenesis in chronic HCV infection.

Methods and Results
1. To assess the influence of HCV infection on IR independent of any effect of hepatic fibrosis, 121 HCV subjects with minimal (stage 1) or no (stage 0) fibrosis were compared with 137 healthy volunteers matched by gender, body mass index (BMI) and waist/hip ratio. Although the HCV subjects were younger than the healthy volunteers (P=0.004), they had significantly higher levels of markers of IR including fasting glucose (P=0.01), insulin (P=0.002), c-peptide (P<0.001) and HOMA-IR (P=0.002).

2. In 260 HCV patients (fibrosis stage 0 to 4), e examined the viral and disease-related factors (portal/periportal & lobular inflammation, viral genotype) which may be involved in the pathogenesis of IR in a multivariate model, controlling for other demographic and biochemical variables. By multiple linear regression analysis, independent predictors of HOMA-IR included BMI (P&lt;0.001), failed previous antiviral treatment (P&lt;0.001), portal inflammatory grade (P&lt;0.001) and genotype 3 status (P=0.01). Genotype 3 cases had significantly lower HOMA-IR than other genotypes at each stage of hepatic fibrosis. The adjusted difference in HOMA-IR between genotype 3 and non-genotype 3 was –0.58 (95% CI: -0.13 to –1.02; P=0.01).

3. We then assessed if IR was associated with increased fibrotic severity. By multiple ordinal regression analysis, independent predictors for the stage of fibrosis in the 260 HCV subjects were HOMA-IR (OR: 1.3, P&lt;0.001), portal inflammatory grade (OR: 5.3, P&lt;0.001), past alcohol intake (OR: 1.7, P&lt;0.001), age (OR: 1.1, P &lt;0.001), ALT (OR: 1.0, P=0.04), platelet count (OR: 0.93, P&lt;0.001), and serum cholesterol level (OR: 0.65, P=0.001). As cirrhosis is known to cause IR, a separate multivariate analysis was performed for the 236 non-cirrhotic subjects. The independent predictors for fibrosis were unaltered and HOMA-IR remained in the model. In a subgroup of 117 patients with estimated duration of infection, multiple linear regression analysis showed that HOMA-IR was independently associated with an increased rate of fibrosis progression (P=0.03).

HCV infected subjects had a greater degree of insulin resistance than healthy volunteers matched by gender, body mass index and waist/hip ratio.

The degree of insulin resistance is related to severity of hepatic inflammation and viral genotype 3 patients have lower insulin resistance compared to other genotypes.

Insulin resistance is associated with more rapid fibrosis progression in chronic hepatitis C.


  • This study provides the direct evidence for a genotype-specific association between chronic hepatitis C and insulin resistance, which in turn increases the risk of hepatic fibrosis.

  • Strategies to improve insulin sensitivity should be explored as they may compliment anti-viral therapy in the management of chronic hepatitis C infection, particularly in mitigating against fibrotic progression in non-responders to interferon based anti-viral therapies.

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Steve Livingston, Alaska Native Tribal Health Consortium, Anchorage, AK; Heike Deubner, University of Washington, Department of Pathology, Seattle, WA; Brian McMahon, Alaska Native Tribal Health Consortium; Arctic Investigations Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AK; Dana Bruden, Thomas Hennessy, Arctic Investigations Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AK; Dan Sullivan, David Gretch, University of Washington, School of Medicine, Seattle, WA; Chriss Homan, Josephine Simonetti, Henry Cagle, James Williams, Alaska Native Tribal Health Consortium, Anchorage, AK.

Steatosis has been reported to occur in up to 50% of liver biopsies in patients with chronic hepatitis C virus (HCV) infection.Risk factors for steatosis include alcohol abuse and those found in nonalcoholic steatohepatitis: obesity, increasing age, insulin resistance and hypertriglyceridemia. Studies have shown an association between genotype 3 and hepatic steatosis in chronic HCV infection, and others have found an association between steatosis and fibrosis stage. Previously published studies have been based primarily on cohorts of clinic referral patients and often have not analyzed for confounding variables. We herein report a population-based study of hepatic steatosis in hepatitis C.

In a study of 924 Alaska Natives/American Indians with chronic HCV infection, 185 patients underwent at least one percutaneous liver biopsy as part of evaluation for treatment. All patients had a positive HCV RNA by PCR and were negative for HBsAg and HIV. All biopsy slides were reviewed by a pathologist blinded to patient identity, demographic, clinical and biological data. Histologic activity was scored using the Knodell system and fibrosis using the Ishak system. Steatosis was graded as 0, 1 (<30%), 2 (30-65%), and 3 (>65%). Patients were analyzed for a) gender, age, estimated length of infection and BMI at the time of biopsy, b) genotype, current ethanol use, HCV RNA within 1 year of biopsy, c) ALT within 30 days of biopsy, and d) histologic activity and fibrosis found on biopsy, using univariable and multivariable analysis.

Steatosis was found in 79/185(43%) of liver biopsies; 62 (33%) had grade 1; 13 (7%) grade 2, and 4 (2%) grade 3. Genotype distribution was as follows: 114 genotype 1 (62%), 44 genotype 2 (24%), and 27 genotype 3 (14%). Steatosis was found in 39% (44/114) of genotype 1, 48% (21/44) of genotype 2, and 52% (14/27) of genotype 3 patients (p = 0.34). Grade 2 or 3 was found in 6% (7/114) of genotype 1, 11% (5/44) of genotype 2, and 19% (5/27) of genotype 3 patients (p = 0.09). There was no significant association found between steatosis and gender (p = 0.93); age at biopsy date (p = 0.09); ALT (p = 0.58); histologic activity (p = 0.27), viral load (p = 0.27) and estimated length of infection (p = 0.22). There was a significant association of steatosis with BMI (< 0.01), fibrosis score (p < 0.01) and current ethanol use (p = 0.03). BMI > 30 occurred in 52% (42/81) of genotype 1, 39% (11/28) of genotype 2, and 27% (6/22) of genotype 3 patients (p = 0.10). After controlling for BMI, there was no significant relationship found between steatosis and genotype. For BMI < 30, 23% (9/39) of genotype 1, 47% (8/17) of genotype 2, and 50%(8/16) of genotype 3 patients had steatosis (p = 0.08). For BMI > 30, 60% (25/42) of genotype 1, 55% (6/11) of genotype 2, and 67% (4/6) of genotype 3 patients had steatosis (p = 1.00). Multivariable analysis was performed on 5 variables (p < 0.25 in univariable analysis) and genotype. These included age (categories < 30, 30-40, 40-50, 50+), BMI (< 30, 30+), current ethanol use (yes, no), Ishak fibrosis score (0-1, > 2), and estimated length of infection (< 10, 11-15, 16-25, 25+ years). A significant association with steatosis was found in 3 variables: Ishak fibrosis score > 2 (OR 4.2, 95% CI 1.5-11.6, p = 0.005), BMI > 30 (OR 3.7, 95% CI 1.6-8.8, p = 0.003), and current ethanol use (OR 2.5, 95% CI 1.0-5.8, p = 0.04) after adjustment for HCV infection length, which itself was not statistically significant (p = 0.82).

Contrary to a number of previously reported studies, this population-based study did not find an association between steatosis and genotype, including genotype 3 in chronic HCV infection after multivariable analysis. This may be due to the sample size. We did find that Ishak fibrosis score, BMI and current ethanol use were associated with steatosis after adjustment for HCV infection length, but age and histologic activity were not associated.

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Lawrence D. Serfaty Sr., Laetitia Fartoux, Jérome Guéchot, Armelle Poujol-Robert, Raoul Poupon, ap-hp, hopital Saint-Antoine, Paris, France.

Insulin resistance (IR) is a frequent feature in chronic hepatitis C while risk factors of steatosis are body mass index in patients infected with genotype 1 and viral load in those infected with genotype 3. In patients with chronic hepatitis C, we adressed the following issues:

1) Is IR the cause or consequence of steatosis and fibrosis ?
2) What are the risk factors of IR ;
3) Des IR play a role (and to what extent) in the occurrence of steatosis ?
4) Is IR involved in the progression of fibrosis ? Therefore, this study was designed to assess relationships between IR, steatosis and fibrosis according to HCV genotypes in non diabetic patients.

152 non-diabetic patients with biopsy proven non-cirrhotic chronic hepatitis C had fasting serum glycemia and insulinemia measurements. IR was evaluated by using HOMA model assessment. 4 groups of patients were defined according to HCV genotypes (1 or 3) and degree of steatosis (absent or mild vs moderate to severe).

The 4 groups were similar in terms of age, sex ratio, BMI and disease duration. Prevalence of IR (HOMA higher than1.64) was significantly higher in genotype 1 patients with steatosis than that of other patients (77% vs 27, 23 and 21% respectively, p=0.0001). IR was significantly associated with extensive fibrosis in genotype 1 patients (p=0.008) but not in genotype 3 patients. Among genotype 1 patients, independent parameters associated with IR were age (p=0.002) and steatosis (p=0.03) but not fibrosis. Independent risk factors for steatosis in genotype 1 and genotype 3 patients were IR (p=0.04) and viral load (p=0.02) respectively. Steatosis was associated with significantly higher fibrosis score whatever the genotype (p=0.01). Among genotype 1 patients, the median progression rate of fibrosis was significantly higher in those having steatosis and IR together than in other patients (0.1 vs 0.05, p=0.02).

In non-diabetic patients with non-cirrhotic chronic hepatitis C:
1) steatosis and fibrosis are associated with IR in genotype 1 patients but not in genotype 3 patients,
2) among genotype 1 patients, IR mainly depends on age but not fibrosis
3) IR is a major risk factor of steatosis in genotype 1 patients,
4) the combination of steatosis and insulin resistance is a risk factor of fibrosis progression. These results suggest that IR is not the consequence but rather the cause of steatosis and fibrosis progression.

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Jorge Rakela, Marek Radkowski, Tomasz Laskus, Jeffrey Wilkinson, Debra Adair, Mayo Clinic, Scottsdale, AZ; Marek Nowicki, Andrea Kovacs, University Southern California, Los Angeles, CA.

Mother-child transmission of HCV is relatively common in the setting of HIV-coinfection but the mechanism of infection is unclear. I has been reported that perinatal transmission of HIV involves macrophage-tropic HIV-1 variants and furthermore, HCV RNA has been found in macrophages and lymphocytes from HCV/HIV coinfected patients. The current study was undertaken to determine the role of extrahepatic HCV replication in mother-to-infant transmission.

As part of a perinatal HIV transmission study at the Maternal Child and Adolescent HIV Management and Research Center (MCA: LAC/USC, Los Angeles) we assessed mechanisms of HCV transmission among HIV+ women co-infected with HCV. HCV RNA was determined in serum and peripheral blood mononuclear cells (PBMC) from 50 co-infected women and 53 of their newborns by RT-PCR. Presence of viral negative strand was determined by strand-specific Tth-based assay. To determine origin of HCV strains, amplified sequences were compared by single strand conformational polymorphism (SSCP).

Among the 45 HIV/HCV co-infected pregnant women 15 (33%) had detectable HCV RNA in PBMCs and 13 (29%) transmitted to their neonates. Seven of 15 PBMC-HCV RNA positive mothers (47%) and 6 out of 30 (20%) PBMC-HCV RNA negative mothers had perinatal HCV transmission (p= .08, Fisher's exact test). However, in the first month of life, in 4 of these 13 newborns, HCV RNA was only detected in PBMCs and not plasma. In 2 neonates, the SSCP band patterns of PBMC-derived viral sequences were different from maternal sequences in serum or PBMC; however, they were identical to HCV RNA negative strand amplified from mothers' PBMC. The latter strongly suggests that the infection was transmitted through maternal infected PBMCs. Another infant harbored different HCV strains in serum and PBMC; both strains were present in the mother's serum. Only 7 of 13 HCV-RNA positive children developed HCV antibody at one year. HIV infection was found in 2 out of 13 HCV RNA-positive and in 6 out the 35 HCV RNA-negative infants (NS).

We have found that 1) HCV strains infecting neonates may be derived from strains residing in maternal PBMCs. 2) HIV+ pregnant women who were HCV RNA positive in PBMCs were more likely to transmit HCV to their infants. These data suggest that one mechanism for perinatal transmission of HCV is maternal-fetal transfusion of HCV-infected PBMCs late in pregnancy or during labor and delivery. Additionally, HCV infected neonates may have a limited ability to develop HCV antibodies in the first year of life and thus there may be an underestimation of the prevalence of HCV infection by anti-HCV determination among children born to HCV RNA positive mothers.

Supported by NIH grants DA13760 and R01 A152065.

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