Tuesday Poster Sessions, October 30, 2006

Clinical Trials and Therapeutic Developments

1123. HCV RNA Negativity After 12 Weeks of Therapy is the Best Predictor of Sustained Viral Response (SVR) in the Re-Treatment of Previous Interferon-α/Ribavirin Non-Responders (NR): Results from the EPIC3 Program.

T. Poynard; E. Schiff; R. Terg; R. Moreno Otero; S. Flamm; W. Schmidt; T. Berg; F. Goncales; J. Heathcote; M. Diago; T. McGarrity; A. Maieron; J. Reichen; H. Tanno; C. Brandao; J. McHutchison; M. Silva; P. Bedossa; W. Deng; P. Mukhopadhyay; L. Griffel; M. Burroughs; C. Brass; J. K. Albrecht.

Introduction:

The EPIC3 program includes a large, prospective, controlled trial designed to assess the safety and efficacy of re-treatment with peginterferon α-2b (PEG) and ribavirin (RBV) of subjects who have failed previous treatment with any α-interferon plus ribavirin (I/R), including those that had failed PEG/RBV or peginterferon alfa-2a/RBV. We have previously reported a surprisingly high SVR in these patients, especially those with an early viral response.

Aim:

To define early viral response at week 12 as a predictor of SVR in these patients.

Methods:

HCV NRs or those that had relapsed after previous treatment with I/R who have significant fibrosis (Metavir F2-F4) received PEG-Intron 1.5 microgram/kg subcutaneously once weekly plus Rebetol 800-1400 mg/day for up to 48 weeks. All patients had pre-treatment biopsies scored by a single reviewer using METAVIR criteria. Plasma HCV-RNA was determined at weeks 12, 24 and 48 of therapy and FU 12 and 24 using a quantitative Taq-Man assay (SPRI; sensitivity 29 IU/mL). Genotype was determined by sequencing PCR product.

Results:

Of the first 1354 patients treated in the combination therapy trial, 23% achieved SVR. Of those who attained > 2 log decrease in viral load at week 12, 37% achieved SVR: 56% of those who were HCV-RNA (-), but only 6% of those who attained a 2 log decrease in HCV-RNA but remained HCV-RNA positive. Of this latter group, 17% of subjects with very low viral load at TW12 (<100 IU) achieved SVR compared to 5% of those with residual viral load of >100-250IU, and 0 in those with HCV-RNA >750.

Conclusions:

SVR is strongly correlated with a negative HCV-RNA or HCV-RNA near the lower limit of detection at week 12, but is extremely low in those with HCV-RNA>100 IU/ml. These data suggest that undetectable viral load at week 12 (<29 IU/ml) best defines a robust EVR that predicts SVR for previous I/R treatment failures re-treated with PEG-Intron plus WBD ribavirin.

Rate of SVR based on viral load at TW12

HCV-RNA at TW 12 (I.U./mL)	SVR % (n/total)
>750	0 (0/582)
>500-750	4.8 (1/21)
>250-500	5.1 (2/39)
>100-250	5.1 (2/39)
29-100	16.9 (13/77)
Undetectable	56.1 (281/501)

1124. PREDICTORS OF RAPID VIROLOGIC RESPONSE (RVR) IN HCV GENOTYPE 1 CHRONIC INFECTED PTS: RESULTS OF A RANDOMIZED CONTROLLED TRIAL ON INDIVIDUALIZED TREATMENT.

A. Mangia; N. Minerva; V. Carretta; D. Bacca; G. L. Ricci; F. Vinelli; R. Cozzolongo; O. Vuturo; S. Gaetano; F. Spirito; L. Mottola; D. Petruzzellis; A. Andriulli.

Objectives:

To prospectively compare the efficacy of PEG interferons (IFNs) alpha 2a or 2b and Ribavirin (RBV) when given for the standard 48 wks or as individualized treatment, for 24, 48 or 72 wks in accordance with HCVRNA negative by PCR at different time points in naïve pts with HCV genotype 1. To identify predictive factors of both 1) HCVRNA negative test at wk 4 (RVR), and 2) sustained virological response (SVR).

Methods:

A total of 645 naïve pts were enrolled and randomly assigned at 2:1 ratio to a standard 48-wk regimen of PEGIFNs (alternatively alpha 2b, 1.5 mcg/wk or alpha 2a, 180 mcg/wk) plus ribavirin (RBV) 1000-1200 mg/daily on the basis of body weight (n= 215, Group B) or to an individualized treatment based on HCVRNA evaluation at different time points, with the same PEGIFNs and RBV doses (n= 430, Group A). When HCV was firstly not detectable (< 50 UI /ml) at wks 4, 8 or 12, pts in individualized treatment group were treated for 24, 48, 72 wks, respectively. Pts RNA positive at wk 12 were considered non responders. Primary end point was SVR (HCVRNA <50 IU/ml ) 24 wks after the end of treatment.

Results:

Both groups were well matched for baseline characteristics. By wk 8, 54% out of 645 patients were HCVRNA-ve. Overall SVR was 46.2% with the individualized and 44.6% with the standard treatment (p= 0.55). RVR was achieved in 28% of pts (n= 184) in both groups. Of these rapid responders 76.5% in group A and in 84.1% in Group B obtained SVR (p=0.25). RVR was achieved in 29.7% of pts treated with alpha 2b and 27.2% of those treated with alpha 2a. Relapse rate was 18% among pts treated for 24 wks, but 10.5% overall in Group A, and 9.5% in Group B. No differences were found on the rate of relapse between the two IFNs (10.1 vs 10.5%). By univariate analysis, factors associated with RVR were age ≤45 yrs (p=0.01), HCVRNA levels lower than 600.000 IU/ml (p= 0.01) and fibrosis score < 3 (0.008). Factors associated with SVR in the table. The independent predictor of 1)RVR was fibrosis score <3, p=0.024; OR 1.27, 95% CI 1.03-1.57, 2)SVR was RVR, p=0.0001, OR 8.6, 95% CI 5.3-13.9.

Conclusions:

In HCV1 pts, once RVR is obtained, a 24 wks course of treatment is effective as a 48 wks course. Pts with advanced liver damage are less likely to achieve RVR and to be treated for only 24 wks. RVR is the best predictor of SVR. The highest likelihood of SVR is achieved by wk 8.

	NR (N=335)	SVR(N=273)	P value
Age<45 yrs	87	104	0.002
Fibrosis < 3	169	180	0.0001
RVR	38	143	0.0001
Drop out	58	0	0.0001

1125. Peripheral blood gene expression profiles predict sustained virologic response following peginterferon and ribavirin therapy.

C. Huang; C. William; H. Chen; C. D. Howell.

Introduction:

There is a need for biomarkers that when measured either before or during the first month of treatment can accurately predict the outcomes of HCV therapy. Goal: We conducted a study of global gene expression in the peripheral blood mononuclear cells (PBMC) of HCV genotype 1 patients during the first 4 weeks of peginterferon (PEGIFN) plus ribavirin treatment and defined a minimal set of genes for predicting a SVR and no SVR.

Methods:

Treatment-naïve, HCV genotype 1 patients (n = 24) were treated with PEGIFN alfa-2a (180 mcg/wk) plus ribavirin (1000-1200 mg per day) for 48 weeks. PBMC were isolated at baseline (day - 0) before treatment and at day-28 of therapy. PBMC RNA was amplified one time and hybridized to the Affymetrix GeneChip HG-U133 plus 2.0 array representing 39,000 human genes. Significance Analysis of Microarray (SAM) software was used to identify genes expressed differentially between day-0 and day-28 and between SVR (undetected serum HCV RNA > 24 weeks after treatment) and non-SVR patients. Genes were classified by biological process and ranked using DAVID 2.0. Prediction Analysis of Microarray (PAM) software was used to select sets of differentially expressed genes to predict SVR and to determine the misclassification rate.

Results:

Compared to day 0 (pretreatment baseline), the expression of 309 genes was increased significantly and the expression of 668 genes was decreased at day 28 with a false discovery rate of <1.0 %. A large number of interferon-stimulated genes were increased with response to pest, pathogen or parasite (p < 0.0001), response to virus (p < 0.0001), host defense response (p < 0.0001), inflammatory response (p < 0.001), protein kinase cascade (p < 0.001), chemotaxis (p < 0.05), protein modification (p < 0.05), and regulation of NF-kappa B (p < 0.05) being the most significant biological processes. DNA dependent RNA transcription, RNA processing, and protein biosynthesis, modification, and transport (p < 0.001 for each category) were the main processes associated with the decreased genes. The microarray results were confirmed by realtime RT-PCR for 10 select genes. PAM identified differentially expressed gene subsets from 13 to 124 in number that correctly predicted SVR and no-SVR among with a misclassification (i.e. error) rate of <10%.

Conclusions:

PEGIFN alfa-2a and ribavirin treatment is associated with significant alterations in PBMC gene expression during the first 28 days. A change in expression of a limited set of genes at day-28 was able to predict SVR with greater than 90% accuracy.

1126. Hepatitis C virus directly causes insulin resistance independent of the visceral adipose tissue area in non-obese and non-diabetic Japanese patients.

M. Yoneda; K. Fujita; T. Fujisawa; H. Chiba; H. Mawatari; H. Takahashi; A. Goto; H. Kirikoshi; K. Yonemitsu; S. Saito; A. Nakajima.

Introduction:

Insulin Resistance (IR) is associated with obesity, type 2 DM and in particular, the visceral adipose tissue area. However, none of the epidemiological studies conducted until now have analyzed the relationship between HCV infection and the risk of IR independent of the influence of obesity, type 2 DM and heavy alcohol consumption; therefore, the precise relationship between HCV and IR remains unclear. Elucidation of the relationship between HCV and IR is of great clinical relevance, because IR promotes liver fibrosis. In this study, we tested the hypothesis that HCV infection by itself may promote IR, independent of the influence of the visceral adipose tissue area, in non-obese, non-diabetic and non-alcoholic patients with chronic HCV infection.

Material and Methods:

We prospectively evaluated 47 patients with chronic HCV infection who underwent liver biopsy. Patients with obesity (BMI >25), type 2 DM, and a history of alcohol consumption were excluded from this study. IR was estimated by calculation of the modified homeostasis model of insulin resistance (HOMA-IR) index. The abdominal fat distribution in the subjects was determined by computed tomography (CT).

Results:

Fasting blood glucose levels were within normal range in all the patients. The results of univariate analysis revealed a significant correlation between the quantity of HCV RNA and the HOMA-IR. While a significant correlation between the visceral adipose tissue area and the HOMA-IR was observed in the 97 control non-diabetic, non-HCV-infected patients (r= 0.398, p<0.0001. However, to our surprise, no such significant correlation between the visceral adipose tissue area and the HOMA-IR (p= 0.04465) was observed in the patients with HCV infection. Multiple regression analysis with adjustment for age, gender and visceral adipose tissue area revealed a significant correlation between the HCV-RNA titer and the HOMA-IR (p= 0.0446).

Conclusion:

Hepatitis C virus directly causes IR in a dose-dependent manner independently of the visceral adipose tissue area before the onset of diabetes. This is the first report to demonstrate the direct involvement of HCV and IR in patients with chronic HCV infection.

1127. Analysis of HCV NS5B Genetic Variants Following Monotherapy with HCV-796, a Non-Nucleoside Polymerase Inhibitor, in Treatment-Naïve HCV-Infected Patients.

S. Villano; A. Howe; D. Raible; D. Harper; J. Speth; G. Bichier.

Background:

HCV-796, an oral non-nucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase, has demonstrated potent antiviral activity in vitro and in vivo. In a clinical dose-ranging study, HCV-796 was administered twice daily for 14 days and demonstrated dose-related antiviral activity across multiple HCV genotypes, with maximal effects observed at approximately day 4 of treatment. Mean reductions of HCV RNA at day 4 in the highest dose groups were 1.4-1.5 log10 below baseline. In all dose groups, the predominant virologic response pattern demonstrated an initial decline of plasma HCV RNA levels followed by an increase of viral RNA levels that were not explained by changes in plasma concentrations of HCV-796.

Methods:

In a randomized, double-blind, placebo-controlled study, 102 treatment-naïve adult patients with HCV (72% genotype 1) received 50, 100, 250, 500, 1000, or 1500 mg oral doses of HCV-796 or placebo given as monotherapy twice daily (q12h) for 14 days. Samples from baseline, during treatment, and at the end of treatment were selected for analysis from patients with various virologic response patterns (no response, initial decline in HCV RNA levels followed by an increase, and continuous decline). HCV RNA from plasma was isolated, and full length NS5B was amplified using RT-PCR and then sequenced.

Summary/Conclusion:

Sequence data of the NS5B gene are available for 58 patients with HCV genotype 1a.

· HCV-796 demonstrated initial rapid antiviral activity in treatment-naïve patients with HCV infection.

· Subsequent increases of plasma HCV RNA levels during HCV-796 monotherapy appear to be associated with selection of viral variants with reduced susceptibility to the inhibitor.

· The major variant expresses a C316Y substitution in NS5B, and remains susceptible to interferon and ribavirin in vitro.

· C3164/f/s replicons results in 10- to 166 fold reduced susceptibility to inhibition by interferon, ribavirin, and other HCV inhibitors

· Several baseline and on-therapy mutations were identified in patients who did not achieve continued virologic response

· Analyses of additional subjects and timepoints are in progress.

· Validity of these mutation need to be confirmed in phase II studies

1128. Extended Treatment of 72 versus 48 Weeks for Chronic Hepatitis C Patients with Genotype 1 and High Viral Load using Daily Consensus Interferon and Ribavirin.

P. Kaiser; H. Holger; L. Bissinger; L. Bettina; B. Sauter; M. Gregor.

Treatment of naive, genotype 1, high viral load chronic Hepatitis C patients with pegylated interferon and ribavirin (RBV) results in sustained viral response rates of about 30 –35 %. Recently improved response rates have been suggested in treatment trials using an extended treatment duration of 72 weeks. Furthermore, treatment with an bio-optimized interferon, Consensus interferon (CIFN), has shown higher response rates in difficult-to-treat patients such as nonresponders and relapsers.

Methods:

The efficacy of CIFN daily dosing + RBV for 48 versus 72 weeks in genotype 1, high viral load patients was evaluated. 120 patients have been included, average weight of patients was 79 kg. Patients were either treated with CIFN at 9 ug QD for 48 or 72 weeks both in combination with weight-based RBV. All patients had HCV RNA >600 KIU.

Results:

Data show that after the initial 12 weeks a primary response with a 2-log drop of HCV-RNA (EVR) was observed in 89% and 92% of patients in the CIFN QD 48 week and 72 week treatment group. The sustained viral response rates (SVR) were 51 and 68 %, respectively (p<0.05), indicating a significantly higher relapse rate in patients treated with CIFN for 48 weeks compared to 72 weeks. No growth factors were used in this study. Three patients experienced grade III thrombocytopenias, while no grade IV neutropenias or thrombocytopenias were observed. The overall tolerability of the CIFN QD regimen was comparable to PEG IFN standard combination therapy, while the 72 week regimen lead to a higher rate of injection site reactions and a slightly higher drop out rate of 7% versus 4% (p=n.s.).

Conclusions:

Extended CIFN daily dosing combination therapy for 72 weeks shows promising response rates in difficult-to-treat patients with genotype 1 and high viral load when compared to a standard treatment period of 48 weeks. Although a significant proportion of patients also experienced a relapse after cessation of a 72 week treatment period, the overall sustained response rates are nevertheless promising showing a SVR in 68% of patients. It is concluded that extended treatment with CIFN in combination with RBV may be an effective treatment modality for this difficult-to-treat patient group. In addition, a larger prospective study is underway to confirm these findings.

1129. Treatment of Hepatitis C Patients with Child A and B Cirrhosis with Consensus Interferon and Ribavirin in a Low Ascending Dosing Regimen Leads to Significant Viral Elimination Rates.

P. Kaiser; L. Bissinger; H. Hass; B. Lutze; B. Sauter; M. Gregor.

Objective:

Antiviral treatment response in patients with chronic hepatitis C and liver cirrhosis is considerably lower than in non-cirrhotic patients and therapy is complicated by high dropout rates, less tolerablity of side effects and high rates of hematological complications.

Pegylated interferons have shown higher response rates than standard interferons, however, also higher dose-reduction and drop-out rates due to lower tolerability, especially regarding thrombocytopenia, thus resulting in an overall only minor benefit. Consensus interferon (CIFN) is an interferon with a relatively low half-life, but stronger antiviral potency as shown by high efficacy in nonresponders.

Methods:

The efficacy of CIFN together with ribavirin (RBV) was evaluated in 114 patients with chronic hepatitis C and cirrhosis Child A and B. All patients had histologically proven cirrhosis, elevated ALT values and were viremic, with 79% having genotype 1. Child A patients were treated with CIFN 9 ug TIW for 4 weeks, followed by 9 ug QD for another 4 weeks. Continuing treatment consisted of CIFN 9 ug QD with RBV with a stepwise increase from 400 mg by 200 mg increments at 4 week intervals for a total of another 52 weeks. For Child B patients the two lead-in phases with CIFN monotherapy were extended to 6 weeks each, and the starting dose of RBV was 200mg with an otherwise identical therapy as with Child A patients. Based on tolerability the dosing of RBV was increased to a weight-based dosing for all patients.

Results:

At 60 weeks therapy an undetectable HCV-RNA was observed in 76% and 47% of Child A and B patients, respectively, with drop out rates of 13% and 27%. Sustained response rates showed a 64% and 29% response for Child A and B, respectively. Due to side effects CIFN had to be dose reduced in 11% and 31%, mainly due to low platelet counts. As growth factors erythropoetin as well as G-CSF was used. Three patients experienced grade III and one patients a grade IV thrombocytopenia. Overall tolerability of the CIFN QD regimen was comparable to a standard therapy with pegylated IFN and RBV, while CIFN even as QD treatment resulted in a lower rate of thrombocytopenias.

Conclusions:

CIFN as a low ascending and finally daily dosing regimen with subsequent escalating RBV shows significant response rates in Child A and B cirrhotic patients. Therapy is also safe, however, a significant portion of patients was unable to even tolerate lower doses of CIFN or RBV. These data suggest that for a subgroup of cirrhotic patients even in stage Child B a combination therapy of CIFN and RBV may lead to viral eradication.

1130. The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and anti-HCV activity in treatment-naïve HIV/HCV co-infected subjects.

R. Flisiak; A. Horban; J. Kierkus; J. Stanczak; I. Cielnak; G. P. Stanczak; A. Wiercinska-Drapalo; E. Siwak; J. Higersberger; C. Aeschlimann; P. Grosgurin; V. Nicolas; J. Dumont; H. Porchet; R. Crabbé; P. Scalfaro.

Background:

In Poland almost 50% of HIV-1 infected patients are HCV co-infected. Available therapies do not include agents with a dual antiviral activity. DEBIO-025, a cyclophilin inhibitor, showed strong anti-viral activity in in vitro and in vivo studies, both against HIV-1 and HCV. This phase I study aimed to determine the anti-viral effect, the pharmacokinetic profile and the safety of an oral therapy with DEBIO-025.

Methods:

Two centers, double blind, placebo controlled, oral dosing, single arm, phase I study design. Treatment-naïve HIV-1 mono- or HIV/HCV co-infected subjects received 1200 mg of DEBIO-025 or placebo twice daily during 15 days (unbalanced randomization). DEBIO-025 blood and plasma levels were assessed on days 1 and 15. Viral loads were determined with the Abbott Realtime m2000 PCR system (HCV limit of quantification LOQ=10 IU/mL, HIV-1 LOQ= 25 copies/mL) daily from day -1 to 2, at days 4, 8, 10, 15 of treatment and at 1, 2 and 3 weeks after the last dose.

Results:

23 Caucasian subjects (19 DEBIO-025, 4 placebo) completed the study. DEBIO-025 was rapidly absorbed with peak plasma levels reached after 2 hours and a terminal half life of 100 hours. The mean maximal decrease in HIV-1 load was 1.0 log10 (±0.1 SE, p<0.001). A pronounced effect on HCV load was found with a mean maximal decrease of 3.6 log10 (±0.4 SE, p<0.001). All subjects, except one, showed a HCV reduction of >2 log10 with differences depending on genotype (GT; Tab). Three subjects had undetectable HCV plasma levels. Hyperbilirubinaemia was observed in 10 subjects and led to premature treatment discontinuation in 4. No increase of ALT/AST or γ-GT was observed. A platelet decrease was reported on 3 occasions, but was not associated with signs of bleeding. Abnormal bilirubin and platelets returned to baseline after end of treatment.

Safety:

· Hyperbilirubinaemia in 10 subjects

· A total of 4 patients discontinued treatment prematurely for this reason

· Bilirubin levels returned to normal after cessation of treatment

· This was not observed in doses up to 1200mg od for 10 days

· Decreased plates in 2 patients but was not associated with signs of increased bleeding and patients’ platelets returned to normal.

Conclusions:

DEBIO-025 administered for 15 days showed a dual anti-viral effect in HIV-1 and HCV co-infected treatment naïve subjects and appears to be a very promising compound with a new and unique mode of action. Despite good clinical tolerance, the observation of hyperbilirubinaemia and platelet decrease requires further investigation.

1131. High-dose Pravastatin (Prava) 80mg/day is Associated with a Reduction in ALT values among Hypercholesterolemic Patients with Chronic Hepatitis C (CHCV) Infection: Analysis of a Prospective, Randomized , Double-blind, Placeo-controlled Trial.

J. H. Lewis; S. F. Zweig; R. Belder.

Introduction:

The use of HMG-CoA reductase inhibitors (statins) is generally not recommended in pts with chronic liver disease (CLD), although retrospective analyses of statins indicate their safe use in patients’ with elevated ALT (due mostly to NAFLD) and a recent prospective, randomized ,placebo-controlled trial demonstrated the safety and efficacy of pravastatin in hypercholesterolemic subjects with various CLD [Gastroenterology 2006;130(4 suppl 2):A65 abstract #446].

Aim:

We performed a subgroup analysis of subjects with CHCV from our 36-week study of Prava 80mg/day conducted in 320 hypercholesterolemic pts with various well-compensated CLDs (about 25% with CHCV and two-thirds having NAFLD). No statisically signifcant differences were observed between Prava or placebo recipients at any time point in terms of the primary safety endpoint of a doubling of ALT from either a normal or elevated baseline for the cohort as a whole. We did, however, observe a numerically lower number of subjects with ALT events in the Prava group, and sought to correlate this potential beneficial effect with the reduction in lipids that was also seen.

Results:

Changes in mean ALT values were analyzed in 38 and 43 CHCV pts randomized to Prava and placebo respectively and correlated with the percentage change in total cholesterol (TC), LDL, and triglycerides (TGs) over the 36 wks of the trial. Using a 2 sample t-test, we observed a modest reduction in ALT values at nearly all time points over the 36 wk trial among the Prava recipients (ranging up to a 6% decrease from baseline), while ALT values on placebo tended to increase (as much as 33%). At several time points, the comparative difference in the change in ALT approached statistical significance (e.g. p=0.0637). These reductions in ALT on Prava appeared to correlate with the highly statistically significant reductions in lipids seen on Prava compared to placebo (p <0.0001).

Summary:

Pravastatin Efficacy in HCV

· Pravastatin 80 mg daily statistically lowered total cholesterol and LDL-C at week 12 compared with placebo in subjects with chronic hepatitis C

· Mean lipid values at other time points (weeks 4,8,24 and 36) also showed similar statistical significance favoring pravastatin.

Pravastatin Safety in HCV

· ALT events were not statistically different between pravastatin and placebo recipients at any time during the 36 week study in patients underlying compensated chronic hepatitis C.

· However, the incidence of ALT events was lower at all time points compared to placebo in hepatitis C patients (possible treatment effect?).

· No difference in serious AEs or discontinuations due to AEs between the groups.

Conclusions:

This subgroup analysis of our larger prospective, randomized, double-blind, placeo-controlled trial demonstrates the efficacy and safety of high-dose Prava in hypercholesterolemic subjects with CHCV. In addition to the significant reduction of TC, LDL and TGs, there was also a trend toward a significant numerical reduction in ALT values on Prava compared to placebo for the patients with CHCV. While the mechanism for the ALT reduction is uncertain, the results warrant further study relative to the interrelationship between hepatitis C and serum lipids.

1132. Risk Factors for Relapse in Genotype 3 High Viral Load Patients with Hepatitis C In the WIN-R Trial.

R. Brown; I. Jacobson; A. Nezam; B. Freilich; M. Pauly; F. Regenstein; S. Flamm; P. Kwo; S. Becker; L. Griffel; C. Brass.

Aim:

Patients with G2/3 hepatitis C virus (HCV) have high SVR rates to PEG-IFN alfa-2b + RBV and require shorter duration of treatment. G3 patients with a baseline high viral load (HVL) have lower response rates and higher relapse rates than G2 patients (Table), but predictors of relapse are not known. The purpose of this analysis was to determine the predictors of relapse to PEG-IFN alfa-2b + RBV in patients with HCV G3.

Methods:

In the WIN-R trial, which was a multicenter, randomized, open-label, investigator-initiated trial in 225 US sites, treatment-naïve HCV patients with compensated liver disease were randomized to receive PEG-IFN alfa-2b 1.5μg/kg/wk + fixed dosing (FD; 800mg/d) or weight-based dosing (WBD; 800 mg/d, <65kg, 1000mg/d, 65–85kg; 1200mg/d, >85–105kg; 1400mg/d, >105–125kg) of RBV for 24 or 48 wks. HCV RNA was assessed by PCR (Taqman/SPRI, LLQ 29IU/mL) at wks 0, 24, 48 and 72. The primary endpoint was SVR (HCV RNA negative at wk 72) in patients ≥65kg. Multivariate regression analyses were used to analyze predictors of relapse.

Results:

G2/3 patients (n=1829) were enrolled and randomized to WBD (24 wks n=317, 48 wks n=602) or FD (24 wks n=322, 48 weeks n=588). With WBD and 24 wks of therapy, SVR rates were higher and relapse lower with G2 than G3 patients (SVR: 72% vs 63% and relapse: 5% vs 11%). Relapse rates were highest among G3 HVL patients treated for 24 weeks (16%). Univariate analyses revealed G3 (vs G2), viral load (high vs low) and duration of treatment (24 vs 48 weeks) were associated with higher relapse rates in Caucasians. African Americans had a lower relapse rate and no difference between G2 and G3. Multivariate analyses controlling for the above, race, and steatosis revealed only G2 vs G3 as a predictor of relapse. G3 HVL patients had similar relapse rates with WBD/48 wks of therapy than with FD/24 wks therapy.

Summary:

· Overall, G2 patients experienced higher SVR rate3s and lower relapse rates than G3 patients.

· Relapse rates were highest among G3 high viral load patients treated fro 24 weeks.

· Multivariate analysis revealed G3 patients (versus) G2 patients as the only predictor of relapse.

· Similar to G2 patients, when controlling for viral load, G3 patients do no appear to benefit from longer duration of therapy or WBD ribavirin.

Conclusions:

• G3 high viral load is a predictor of relapse.
• G3 patients are more resistant to treatment than G2 patients.
• Higher ribavirin dose may benefit G4 patients
• Further research is required to define the optimal therapy and improve response rates in G3 patients.

	SVR, %	Relapse Rate, %
	WBD vs FD	WBD vs FD
G2 patients	72/68 vs 71/62	6/3 vs 6/66
LVL (24/48 wks)	71/66 vs 73/66	6/5 vs 6/7
HVL (24/48 wks)	69/59 vs 74/58	7/2 vs 8/6
G3 patients	63/54 vs 57/49	10/11 vs 10/13
LVL (24/48 wks)	65/56 vs 61/51	6/9 vs 7/16
HVL (24/48 wks)	70/52 vs 53/55	18/16 vs 14/7

1133. IMPACT OF TARIBAVIRIN AND RIBAVIRIN EXPOSURE ON EFFICACY AND ANEMIA RATES WHEN COMBINED WITH PEGYLATED INTERFERON ALFA-2b IN THE TREATMENT OF CHRONIC HCV.

I. Jacobson ; P. Pockros; Y. Benhamou; R. Esteban-Mur; Y. Lurie; R. Flisiak; N. Afdhal; Y. Kim; Y. Xu; B. Murphy.

Introduction:

A recent Phase 3 trial examining the efficacy and safety of fixed-dose taribavirin when combined with PEG IFN alfa 2b vs weight base dosed ribavirin (RBV) plus PEG IFN alfa 2b revealed that the taribavirin treated pts exhibited a significantly lower anemia rate (5% vs 24%;p<0.001) but failed to meet the non-inferiority criterion when analyzed for efficacy (38% vs 52%). Taribavirin is a liver-targeting pro-drug of RBV and is converted to the active moiety by the enzyme adenosine deaminase. Since the current standard of care in the management of HCV is to weight base drug exposure of RBV, this post-hoc analysis looked at the impact on efficacy and the development of anemia (hemoglobin<10g/dL) of drug exposure based on weight(mg/kg).

Methods:

This Phase 3 study randomized 970 pts in a 2:1 ratio into a fixed dose taribavirin arm vs a weight base dosed RBV arm, stratifying pts on the basis of genotype, baseline viral load, and weight. In this post-hoc ITT population analysis, pts were grouped into quartiles based on mg/kg drug exposure and SVR and corresponding anemia rates were computed based on viral genotype. Pts lost to follow-up were considered treatment failures.

Results:

See table

Conclusions:

o Higher mg/kg exposure of taribavirin resulted in increased efficacy while the anemia rates remained relatively constant.

o Despite having the same drug exposure, pts treated for 24 wk (genotype 2,3) experienced less anemia when compared to the 48 wk treated pts (genotype non-2,3) indicating that the risk of hemoglobin decline can occur throughout the course of therapy, not just within the initial weeks of treatment.

o Dosing taribavirin at levels higher than 18 mg/kg yield response rates similar to the current standard-of-care.

o Future studies should be directed at examining higher drug exposures (mg/kg) of taribavirin to maximize efficacy potential without compromising safety.

TARIBAVIRIN

Dose	N	SVR%	Anemia Rate (%)
Overall
≤13 mg/kg	179	32	4
>13-15 mg/kg	147	31	4
> 15-18 mg/kg	182	38	7
> 18 mg/kg	138	52	7
Genotype 2,3
≤13 mg/kg	51	53	4
>13-15 mg/kg	38	63	3
> 15-18 mg/kg	42	64	0
> 18 mg/kg	43	70	2
Genotype non-2,3
≤13 mg/kg	128	23	4
>13-15 mg/kg	109	20	5
> 15-18 mg/kg	140	30	9
> 18 mg/kg	95	44	8

1134. Final Results of pilot study evaluating safety, viral clearance and antifibrotic efficacy of treatment with Interferon γ1b + an Interferon α + Ribavirin in HCV patients who failed prior Pegylated Interferon + Ribavirin therapy.

V. Balan; J. Braaten; M. Rosati; J. Williams; B. Noble; M. Anderson; J. Hentz; J. Rakela; L. M. Blatt.

Introduction:

~50% of patients with HCV genotype 1 fail therapy with pegylated interferon α2(PEG)+ ribavirin(RBV)and need better therapies.

Aims: To determine

1. safety and tolerability in HCV patients on combination of IFN γ1b+IFNα+RBV

2. percentage who achieve virologic response

3. effect on hepatic fibrosis.

Methods:

30 HCV genotype 1 patients (15 per group) who failed prior PEGα2+RBV therapy were enrolled in this prospective, randomized, open-label, pilot study. Treatment duration-48 wks; Follow-up-24 wks. Patients randomized to receive IFNγ1b + RBV + Interferon Alfacon-1(IFNA) [γRA group] or IFNγ1b + RBV + PEGα2a [γRPEG group] [doses: IFN γ1b(100 mcg TIW); RBV(1000-1400 mg/d); IFNA (15 mcg QD/TIW as tolerated) or PEGα2a 180 mcg/week]. Post treatment liver biopsies assessed in blinded fashion for change in METAVIR and ISHAK Modified Fibrosis Score (MFS).

Results:

Viral efficacy presented as ITT and fibrosis outcome is as observed. Patients: 28(16m; 12f);cirrhotic 12/28 (43%); Mean duration prior therapy-49 weeks. Both 3-drug regimens had acceptable tolerability profile and were comparable in terms of type, incidence and severity of adverse events. 32% had end of treatment response (ETR) and 11% had sustained virologic response (SVR) (Table 1). Fibrosis results using MFS summarized in Tables 2. Significant fibrosis improvement was observed in γRA group in liver biopsy when compared to baseline. Patients with >=1 point decline in MFS according to treatment group: γRPEG 5/12(42%); γRA 6/12(50%). Among patients with advanced fibrosis (MFS >= 5) 4/12(33%) had decline of >= 1 point (γRPEG group 1/6 -17%; γRA group 3/6 - 50%).

Conclusions:

· IFNγ in combination with IFNα based therapy has an acceptable tolerability.

· Overall 32% had an ETR and 11% had SVR.

· IFNγ in combination with IFNα based therapy appears to reduce fibrosis which was significant with IFNγ+IFNA+RBV combination.

This combination therapy may be a novel therapeutic option for failures to PEG + RBV and may be effective in reversing advanced fibrosis. Further larger cohorts studies are warranted.

Table 1. Virologic clearance

	Week 48 HCV RNA-		Week 24 follow-up HCV RNA-
Overall	9/28 (32%)		3/28 (11%)
γRA Group	4/13 (31%)	P=NS	2/13 (15%)	P=NS
γRPEG group	5/15(33%)		1/15 (7%)

Table 2. Fibrosis result using MFS (0-6) in γRA and γRPEG groups¹

Teatment group	Pre-Treatment [Mean (SD) N]	Post-Treatment [Mean (SD) N]	Delta	95% CI	P
γRA	4.25 (1.54)12	3.17 ( 1.75)12	-1.08	-1.87 to -0.30	0.01*^2
γRPEG group	3.92 (1.93)12	3.58(2.15)12	-0.33	-0.90 to 0.23	0.22

¹ Similar results obtained using METAVIR score. Pre and post treatment biopsies available in 24 patients. ²Result also significant with METAVIR

1136. Sustained Virologic Response Rates with albumin interferon alfa-2b in Combination with Ribavirin in Non-responders to Prior Interferon Therapy: Interim Results from a Phase 2 Study.

D. Nelson; V. Rustgi; V. Balan; M. Sulkowski; J. McHutchison; G. L. Davis; L. Lambiase; R. Dickson; R. Yu; L. Novello; W. Freimuth; M. Subramanian.

Background and Aims:

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein consisting of IFNα-2b genetically fused to human albumin. This ongoing randomized Phase 2, study evaluates the efficacy and safety of alb-IFN in chronic HCV patients who were non-responders (NR): failed to achieve EVR12 or clear HCV RNA with previous IFNα based regimens.

Methods:

Subjects were randomized into 3 alb-IFN SC treatment cohorts (900 μg Q2w, 1200 μg Q2w or 1200 μg Q4w) in combination with weight-based ribavirin (RBV) 1000-1200 mg/d. After evaluating safety data, 2 higher dose treatment cohorts of alb-IFN 1500 μg Q2w and 1800 μg Q2w were enrolled. The treatment duration is 48w with 24w follow-up and the primary efficacy end-point is sustained virologic response (SVR). SVR data for the initial 3 cohorts is currently available.

Results:

115 subjects were enrolled. The w24 antiviral response was comparable across the 900-1800 μg cohorts. A subgroup analysis for genotype 1, PEG-IFN+RBV NR revealed the highest response rates in the 1800 μg cohort. Most patients who were RNA negative at w24 remained negative at w48. The overall ETR rate in the 900-1200 μg cohorts was 31% and the SVR rate was 20%. Within the genotype 1 PEG-IFN+RBV NR group, w24 RNA negativity rates ranged from 15% to 27% with the highest rates in the 1500 and 1800 μg cohorts. Hematologic reductions stabilized by week 8 and are well managed with dose reductions. Overall, alb-IFN in combination with RBV was well tolerated and the safety profile in the 1500 μg and 1800 μg cohorts was comparable to the 900-1200 μg cohorts both in type, incidence and severity of AEs. The trough concentrations for alb-IFN showed dose proportional increases, with minimal increase after week 12 in the Q2w cohorts.

SVR for the first three cohorts

The SVR rate overall in the 900-1200 µg cohorts was 21%

Within the genotype 1 PEG-IFN+RVB NR group, SVR rates ranged from 10% to 15.4%.

Conclusions

The combination of alb-IFN with RBV is safe and effective at doses up to 1800 μg Q2w with significant antiviral activity demonstrated in prior IFNα non-responder patients

1137. Comparison of a 24 -week standard combination therapy with PEG-IFN-α2a/Ribavirin with a 12-week monotherapy with PEG-IFN-α2a followed by a 12 week standard combination with Peg-IFN-α2a/Ribavirin in Hepatitis C infected patients with genotype 2 or 3.

B. Kallinowski; K. Stein; W. Böcher; G. Tobias; U. Spengler; R. Link; H. Klinker; T. Bruckner; P. Haiss; P. Buggisch.

Background:

Treatment of HCV genotype (GT)-2 or -3 infected patients (pts) with PegInterferon-α (PEG-IFN) and ribavirin(RBV) for 24 weeks induces sustained virological response rates (SVR) of ~ 80 %. Recent studies demonstrate that a shorter treatment duration, especially in rapid virological responders, does not compromise SVR rates. Due to different ribavirin dosages and different treatment duration used in these trials the role of ribavirin still remains unclear. We therefore conducted a multicentre, prospective, randomised, controlled trial investigating whether a 12 week(wk) PEG-IFN monotherapy followed by a 12 week combination Peg-IFN/RBV treatment is as effective as a 24 week standard combination therapy with Peg-IFN/RBV.

Methods:

226/241 screened pts were randomly assigned 1:1 to group A :Peg-IFN α-2a ( 180 mcg/wk)plus RBV (800 mg/d) for 24 weeks or group B: PEG-IFN α-2a monotherapy (180 mcg/wk) for 12 weeks followed by a 12 week combination therapy PEG-IFN/RBV.End of treatment (EOT) and SVR were assessed by qualitative RT-PCR (<50 IU/ml). This non-inferiority study was based on a one-sided 95%confidence interval with a difference of <15 % in SVR among group A and B with a power of 80 %.

Results:

Rapid virological response (RVR): HCV RNA was undetectable (<50 IU/mL) at week 4 in 84 of 103 patients (82%) in group A and 65 of 95 patients (68%) in group B. According to genotype, 22/25 (88%) GT2 and 62/78 (79%) GT3 patients achieved an RVR in treatment group A, whereas in group B, RVR was lower with a response in 11/17 (65%) GT2 and in 54/78 (69%) GT3 patients.

End of treatment (EOT) response: Irrespective of the treatment arm, EOT rates of 96/103 (93%) and 94/95 (99%) were achieved in group A and B, respectively.

Sustained virological response (SVR): Overall, SVR was achieved in 88/103 patients (85%) in the standard combination group, whereas shortened RBV-treatment induced lower SVR of 73% (69/65). According to genotype, SVR was as high as 92% (23/25, group A), and 59% (10/17, group B) in GT 2 infected patients, whereas, GT 3 patients showed SVR of 83% (65/78) in the standard arm and of 78% (61/78) in the study arm. However considering those patients with RVR, excellent SVR rates of 92% and 89% were achieved, irrespective of treatment arm.

Relapse rates:

Patients treated with standard combination of PEG-IFN alfa-2a/RBV relapsed in an expected range of 8%, whereas the relapse rate increased to 27% in arm B.

SVR according to viral load at baseline: Analysis of SVR indicated in general a higher response in LVL-patients (88%) than in patients with baseline viremia above 400,000 IU/mL (HVL; SVR 69%). In addition LVL and HVL-patients treated in group B achieved lower overall SVR rates than those treated in group A.

Correlation between SVR and liver histology: An overall SVR rate of 82% was achieved in patients with mild steatosis and 73% of patients with steatosis ≥ 20%. SVR rates correlated inversely with grade of liver fibrosis, 84% in patients with F0-F2 fibrosis vs. 64% in patients with F3-F4.

Conclusion:

· There is a trend of higher SVR in the standard 24 week combination arm confirming the results of the Accelerate study presented by Shiffman et al. at the EASL2006. In contrast, concerning our prespecified statistical criteria for non-inferiority, truncated RBV treatment (group B) has been demonstrated to be non-inferior to standard 24 week combination therapy (group A).

· EOT rates were similar in both group (93% vs. 99%) whereas relapse rates were significantly higher in group B (8% vs. 27%), indicating that ribavirin is essential for maintaining SVR.

· As the rapid virological response rates differed between group A and B, initial treatment with ribavirin appears to be critical for rapid virological clearance.

· Finally, clinically significant steatosis and fibrosis were confirmed as negative predictors.

1138. Peginterferon alfa-2b and ribavirin for 14 or 24 weeks in patients with HCV genotype 2 or 3 and rapid virological response. The North-C trial.

O. Dalgard; H. Ring-Larsen; K. Bjøro; H. Verbaan.

Introduction:

Prior treatment trials assessing the effect of shorter than 24 weeks treatment to genotype 2 or 3 patients have yielded conflicting results.

Aim:

The aim of this study is to compare the effect of 14 and 24 weeks combination treatment to patients with genotype 2 or 3 infection and a rapid virological response.

Methods:

This is a multicenter, open labelled randomised controlled non-inferiority trial which including 435 treatment naïve HCV RNA positive patients with genotype 2 or 3 enrolled between March 2004 and September 2005. Patients with rapid virological response (RVR) (defined as <50 IU/ml after 4 weeks of treatment) were randomised to 14 or 24 weeks treatment. Patients without RVR all received 24 weeks of treatment. Patients are treated with pegylated interferon alpha-2b (1.5 μg/kg) s.c. weekly and weightbased ribavirin (800-1400 mg daily) orally daily. Primary endpoint was sustained virological response (SVR) defined as HCV RNA levels <50 IU/ml 24 weeks after end of treatment. The study was powered to demonstrate non-inferiority within 10% between the two groups with RVR.

Results:

In 435 enrolled patients 298 (69%) were HCV RNA negative at week 4 and were randomised to 14 (n=148) or 24 weeks (n=150) treatment. 135 patients without RVR were allocated to 24 weeks treatment. Baseline characteristics (all 435 patients): genotype 2, 22% and genotype 3, 78%. Mean age was 40 years (range: 18-66years) mean weight 79 kg (range 42-160 kg) and male, 63%. RVR was obtained by 72% of genotype 2 patients and 69% of genotype 3 patients (p=0.45). As of early September 2006 all patients will have been followed 24 weeks after end of therapy. Complete SVR rates will be forthcoming.

Conclusion:

This preliminary data shows that in patients with HCV genotype 2 or 3 treated with pegylated interferon alfa-2b and ribavirin 69% obtained RVR and were randomised to 14 or 24 weeks treatment.

1139. Effect of sustained response in the incidence of type 2 diabetes mellitus in chronic hepatitis C.

M. Romero-Gomez; C. M. Fernandez-Rodriguez; R. J. Andrade; R. Barcena; R. Planas; R. Sola; J. A. Pons; I. Carmona; R. Perez; M. Diago.

Aims:

1. To know the influence of impaired fasting glucose (IFG) and/or DM2 in sustained response in patients with chronic hepatitis C treated with peginterferon plus ribavirin.

2. To investigate the incidence of type 2 DM after treatment.

Patients and Methods:

We included 903 patients with chronic hepatitis C treated with interferon plus ribavirin during 24-48 weeks depending on genotype, recruited from 10 Spanish hospitals. We recorded the family history of DM2 (FHDM2), age, gender, weight, height and body mass index, steatosis and fibrosis stage (from F0 to F4). Patients were followed-up until April 2006 (mean 27+/-17 months). The characteristics of the cohort were: 97 patients had baseline DM2 (10.7%) and 62 had IFG (6.8%), 31.2% had family history of DM2, 54.7% were overweight (BMI>25 Kg/m2), 37.5% were women, 71.3% were genotype 1, 40% of them had steatosis and 23.1% showed advanced fibrosis (F3-F4). Mean age was 45+10 years, glycaemia was 93+11 mg/dl, BMI: 26.1+4.7 Kg/m2.

Results:

SVR was lower in patients with IFG and/or DM2 [67/159 (42.1%) vs. 410/736 (55.7%);p=0.002] than in patients with normal glucose metabolism. IFG or DM2 were seen in 32 out of 425 achieving SR (7.5%) and in 54 out of 358 non-SVR (15.1%); log-rank=10.4;p=0.0012. In Cox regression (Backward LR), the independent variables associated with the prediction of the development of IFG or DM2 were the absence of SR [O.R=1,97 (95%CI:1,01-3,86) and age [O.R.=1,06;95%CI:1,02-1,1), whereas family history of DM2, fibrosis, sex and BMI were excluded.

Conclusions:

Sustained response in chronic hepatitis C reduces the risk of development IFG and/or DM2. Moreover, altered glucose metabolism impairs sustained response in chronic hepatitis C.

Acknowledgement: PAI-group CTS-532.

1140. Favorable Pharmacokinetics of albumin interferon alfa-2B in Subjects with Chronic Hepatitis C.

M. Fiscella; V. Balan; D. Nelson; V. Bain; S. Zeuzem; J. McHutchison; W. Freimuth; M. Subramanian; A. Corey.

Background:

Albumin interferon alfa-2b (alb-IFN) is a novel recombinant 85.7 kDa protein comprised of IFNα-2b genetically fused to human serum albumin (HSA) that is being developed for the treatment of chronic HCV infection (CHC). Completed and ongoing trials in IFN naïve and IFN experienced patients with CHC provide insight to the clinical pharmacology of alb-IFN.

Methods:

The data set analyzed includes serum drug concentrations from >600 CHC patients enrolled in 4 clinical studies, in which SC doses of alb-IFN (900 μg to 1800 μg) or pegylated interferon alfa-2a (PEG-IFNα-2a) are being administered for up to 48 weeks. Concentrations of alb-IFN and PEG-IFNα-2a were measured using an IFN capture and IFN detection (IFN-IFN) ELISA. The sensitivity of the assay is <1 ng/mL. Concentration-time data were analyzed by compartmental modeling. The molecular integrity of alb-IFN was determined using an additional ELISA that uses IFN capture and HSA detection (IFN-HSA ELISA), and comparing those results to the data obtained with the IFN-IFN ELISA.

Results:

The PK of alb-IFN and PEG-IFNα-2a PK are consistent with a one compartment model with 1st-order absorption. Exposure is summarized in the table. PK of alb-IFN are linear, and the protein in systemic circulation is intact. Compared with PEG-IFNα-2a, alb-IFN is eliminated more slowly (t1/2, elim of ~3 and ~6 days, respectively). Based on a 6 day t1/2 elim for alb-IFN, more than 95% of steady state would be reached by the time the 3rd Q2w dose is administered. Accumulation for alb-IFN Q2w is similar to that for PEG-IFNα-2a Q1w, despite alb-IFN being dosed less frequently. Minimal accumulation is observed with Q4w dosing. The apparent volume of distribution for alb-IFN (~11 L) is greater than that for PEG-IFNα-2a (~5 L), suggesting alb-IFN may be more extensively distributed. Concentrations of alb-IFN are similar in IFN naïve and experienced patients and do not appear to be affected by age, sex, race, or fibrosis stage.

Conclusions:

o Serum alb-IFN concentration-time profiles are consistent with a one-compartment model with 1^st order absorption.

o Alf-IFN pharmacokinetics are linear.

o Alf-IFN exposure is similar to INF naïve subjects and IFN experienced subjects.

o The t _{½, elim} for alb-IFN is -2 fold greater that that for PEG-IFNa-2a, which supports dosing at 2-4 week intervals. All phase 2 alb-IFN doses provide higher exposure than PEG-IFNa-2a on a molar basis.

o Alb-IFN pharmacokinetics are unaffected by sex, age, and fibrosis score.

o Molecular integrity of the protein in systemic circulation is maintained at day 4 and day 14 post injection

1141. Interim Antiviral and Safety Data with albumin interferon alfa-2b Combined with Ribavirin in a Phase 2b Study Conducted in a Genotype 1, IFN-naïve, Chronic Hepatitis C Population.

J. McHutchison; S. Zeuzem; Y. Benhamou; D. Shouval; V. Bain; S. Pianko; R. Flisiak; M. Grigorescu; V. Rehak; E. Yoshida; K. Kaita; P. Cronin; E. Pulkstenis; M. Subramanian.

Background:

This ongoing phase 2b, active controlled study is evaluating the efficacy and safety of albumin interferon alfa-2b (alb-IFN), a novel recombinant protein consisting of IFNα-2b genetically fused to human albumin, in combination with ribavirin in genotype 1, chronic HCV IFN-naïve patients.

Methods:

458 subjects have been randomized and treated in 4 SC treatment groups: PEG-IFNα-2a (PEG-IFN) (180 μg Q1w (114 pts)) or one of 3 alb-IFN cohorts (900 μg Q2w (118 pts), 1200 μg Q2w (110 pts) or 1200 μg Q4w (116 pts)), all in combination with ribavirin (RBV) 1000-1200 mg/d based on body weight. The primary efficacy end-point is sustained virologic response (SVR). HCV RNA was measured using real-time PCR (Labcorp) (level of quantitation [LOQ]: 43 IU to 69 million IU/mL; level of detection [LOD] is 10 IU/mL). An interim analysis following 12-24w of treatment is presented.

Results:

Subject demographics and early antiviral responses are summarized in the table. Rates of HCV RNA below LOQ at w12 and HCV RNA below LOD at w20-24 were greatest in the 1200Q2w cohort. Robust early antiviral response was observed in heavier subjects (≥75 kg)in the 1200Q2w cohort. Overall, all 4 treatment groups were well tolerated. Hematologic reductions were maximal by w8, and were well managed with dose reductions in all treatment groups. Hematologic reductions were lowest in the alb-IFN 1200Q4w cohort, and comparable across the alb-IFN Q2w and PEG-IFN cohorts. The incidence and severity of adverse events overall and grade 3-4 laboratory values were comparable between treatment groups. The rates of antibody development to interferon was significantly lower in the alb-IFN treatment groups compared with the PEG-IFN treatment group (p<0.0001).

Conclusions:

Maximal early antiviral activity in genotype 1 HCV was observed in the alb-IFN 1200 μg Q2w cohort in the first 12-24 weeks of therapy. These data suggest that alb-IFN may offer longer-term efficacy and safety at least comparable to PEG-IFN with an improved dosing schedule. Sustained response rates are awaited.

1142. Current Status Of Subjects Receiving Peg-Interferon-Alfa-2a (Peg-IFN) And Ribavirin (RBV) After A 14-Day Study Of The Hepatitis C Protease Inhibitor Telaprevir (VX-950), With Peg-IFN.

N. Forestier; C. J. Weegink; S. Purdy; L. McNair; P. L. Jansen; S. Zeuzem; H. W. Reesink.

Introduction/Aim:

Telaprevir (VX-950) is a highly selective peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A protease that is designed to block HCV replication. This 14-day study was designed to explore the viral kinetics and safety during dosing with telaprevir in combination with peginterferon- alfa-2a (Peg-IFN). Results previously reported indicated that telaprevir, with and without Peg-IFN was well-tolerated in this study with no serious adverse events, and the addition of Peg-IFN increased the strong antiviral effects of telaprevir. Here we report patient status during off-study follow-on therapy with Peg-IFN and RBV.

Methods:

The VX04-950-103 clinical study randomized 20 treatment-naïve patients with chronic genotype 1 hepatitis C infection to three dosing arms. At the completion of the of the 14 days study, 19 of 20 patients chose to begin Peg-IFN 2a /ribavirin, starting within 5 days of completing the 14-day dosing period. Clinic visits were conducted at the discreation of the investigators, after completion of the 1-week and 12-week study-mandated follow-up visits.

Nineteen patients have been followed through 24 weeks after the completion of the study dosing. After discussion with the treating physicians, 10 (4 in telaprevir and 6 in the telaprevir/Peg-IFN-2a) patients Peg-IFN-2a/ribavirin treatment at 24 weeks.

The current disposition of the patients is listed below:

	Placebo + Peg IFN2a (n)	Telaprevir (n)	Telaprevir + Peg-FIN-2a (n)	Total (n)
Enrolled	4	8	8	20
Dosed	4	8	8	20
Completed 2 weeks of treatment	4	8	8	20
Off-Study Treatment (peg-IFN-2a/Ribavirin)
Completed 1-week safety follow-up on study	4	8*	8	20
Completed 12-week antiviral therapy	4	7	7	19
Peg-IFN-2a/RBV discontinuation at 24 weeks due to decision by patients	0	4	6	10

*One patient declined Peg-IFN-2a/ribavirin

At last off-study follow up (12 weeks after the last on-study follow-up), all patients who continued with Peg-IFN-2a/RBV, initially randomized in the telaprevir alone and telaprevir/Peg-IFN-2a groups had detectable HCV RNA.

Of the 10 patients who stopped who stopped post-study Peg-IFN-2a/RBV treatment after 24 weeks total treatment:

· 2 of 4 patients who originally received telaprevir alone demonstrated undetectable plasma HCV RNA level at 12 weeks follow-up after stopping Peg-IFN-2a

Safety:

During the post-study Peg-IFN-2a/RBV treatment, safety was assessed as per usual clinical practice. Side effects reported by the treating physicians were considered with the adverse events associated with Peg-IFN-2a/RBV.

Discussion:

· At 24-week off-study follow-up all the patients initially randomized to telaprevir groups and continued with Peg-IFN-2a/RBV, maintained undetectable HCV RNA

· The early (12-week) post-treatment (Peg-IFN-2a/RBV) follow-up viral load data are consistent with models which suggest required duration to achieve SVR rate should be made from these data, given the small sample size and short duration of telaprevir treatment in this 14-day study.

· The more relevant assessment of the long-term safety and efficacy of a telaprevir-based treatment regimen will be the results of presently ongoing Phase 2 studies (PROVE1 and PROVE2).

1143. Effect of an IMPDH inhibitor, merimepodib (MMPD), assessed alone and in combination with ribavirin, on HCV replication: implications regarding ribavirin’s mechanism of action.

C. Hezode; M. Bouvier-Alias; C. Costentin; F. Medkour; E. Franc-Poole; M. Aalyson; J. Alam; D. Dhumeaux; J. Pawlotsky.

Introduction:

Merimepodib (MMPD) is a potent, specific, orally active inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme whose inhibition leads to decreased intracellular concentrations of GTP. Ribavirin (RBV) is a weak inhibitor of IMPDH. Recent pre-clinical results indicated a potential, enhancing, role of IMPDH inhibition in combination with RBV.

Objective:

To compare the in vivo effects of IMPDH inhibition with MMPD to the effects of RBV on HCV replication, and to determine whether IMPDH inhibition enhances the action of RBV over 28 days of treatment.

Methods:

Thirty-two patients infected with HCV genotype 1 (22 males, 10 females, mean age 47 years) were randomized into 4 arms and treated for 28 days: group A, RBV, 1.0-1.2 g/day according to body weight of less or more than 75 kg, respectively; group B, RBV 1.0-1.2 g/day plus MMPD, 50 mg q12h; group C, RBV 1.0-1.2 g/day plus MMPD, 100 mg q12h; group D, MMPD, 100 mg q12h alone. All patients received the standard of care after the end of the study. HCV RNA levels were measured at frequent time points over the 28 days.

Results:

The figure shows the average viral kinetics in the four groups. Five out of 8 patients from group A (RBV alone) experienced a moderate decrease of viral replication during the first days of administration, as already reported. This effect was not modified by the addition of MMPD (50 mg q12h in group B or 100 mg q12h in group C). In contrast, 5 out of 8 patients from group D (MMPD monotherapy) experienced an increase of viral replication of the order of 0.5 log.

Conclusions:

RBV monotherapy produced a modest decrease in HCV-RNA. MMPD monotherapy produced a very different effect on HCV-RNA, indicating RBV’s antiviral activity is not related to IMPDH inhibition. The apparent increase in HCV-RNA with MMPD monotherapy may relate to the ability of IMPDH inhibitors to decrease T-cell activation. The lack of enhanced antiviral effect when MMPD was added to RBV raises the hypothesis that RBV’s mechanism of action is not dependent on incorporation of RBV into the HCV genome.

1144. Eicosapentaenoic acid Maintains Ribavirin Dose in HCV-Infected Patients who treated with the combination therapy of pegylated interferon α plus ribavirin. : A Prospective, Randomized Controlled trial.

S. Takaki; Y. Kawakami; K. Uka; K. Yamashina; N. Mori; S. Tei; A. Hiramatsu; H. Kodama; M. Imamura; H. Aikata; S. Takahashi; K. Chayama.

Background/aim:

One of the major adverse effects of the combination therapy of pegylated interferon (PEG IFN) α plus ribavirin (RBV) on chronic hepatitis C (HCV) is hemolytic anemia. The hemolytic anemia frequently occurs during the first 4-8 weeks. It is thought that Eicosapentaenoic acid (EPA) protect erythrocytes from erythrophagocytic extravascular destruction during the combination therapy, since EPA increase erythrocyte deformability. This study aimed to evaluate the efficacy of EPA against RBV-associated hemolytic anemia during the first 12 weeks on HCV patients treated with combination therapy.

Methods:

This study was a prospective open-label, randomized controlled trial. One hundred patients with HCV genotype 1b,and a high viral load were enrolled in this study. All patients received both PEG-IFNα2b 1.5μg / kg / week subcutaneously and oral RBV adjusted based on body weight for 48 weeks. All patients were randomized to the group of combination therapy with EPA (EPA group n=49), or the group of combination therapy without EPA (Non EPA group n=51). EPA group patients received oral EPA 900mg/day twice daily through the treatment. The dose of RBV was reduced according to Manufactures instructs. The primary end point of this study was reduction of RBV dose during the therapy.

Result:

There were no differences in the distribution of gender, age, body weight, ALT, hemoglobin (Hb), PLT, and viral load between EPA group and Non EPA group. In EPA group, Five of 49 patients withdraw from the study before 12 weeks because of adverse effects but anemia, therefore Forty-four patients were on this protocol at 12 weeks and received continuous treatment. Among the remaining 44 patients, RBV dose reduction were required for 6 patients. While, in Non EPA group, 6 of 51 patients withdraw from the study before 12 weeks because of adverse effects but anemia, therefore Forty-five patients were on this protocol at 12 weeks and received continuous treatment. Among the remaining 45, RBV dose reduction were required for 13 patients. The cumulative RBV reduction rate at 4, 8, and 12 weeks were significantly lower in EPA group than Non EPA group (EPA group 4%,9% and 16% vs Non EPA group 16%, 26%, and 32% ; P<0.05). There were no significant differences in the decline of Hb concentration level from baseline at 4, 8 and 12 weeks between EPA group and Non EPA group.

Conclusion:

EPA could prevent the RBV dose reduction during the first 12 weeks in HCV patients treated with PEG-IFNα plus RBV. Since early viral response with 12 weeks influenced the achievement of SVR, administration of EPA might produce higher SVR on the combination therapy.

1145. Long-term Low Dose Treatment with Pegylated Interferon alpha 2b leads to a significant Reduction in Fibrosis and Inflammatory Score in Chronic Hepatitis C Nonresponder Patients with Fibrosis or Cirrhosis.

P. Kaiser; H. Hass; B. Lutze; B. Sauter; M. Gregor.

Objective:

Treatment with current standard antiviral therapy leaves about 50% of patients without viral clearance with the risk of progression of their liver disease. Recent studies have suggested an antifibrotic effect of low dose interferon treatment.

Methods:

The efficacy of low dose pegylated interferon alfa 2b with 0.5 ug/kg weekly given for 36 months as monotherapy was evaluated based on histological examination and liver function in 142 patients with chronic HCV, nonresponse to antiviral combination therapy and significant fibrosis / cirrhosis (Ishak staging 3-6) and compared to an observational control group (n=64). Histology was evaluated at baseline, at 18 months of treatment and 6 months after end of treatment.

Results:

At 18 months therapy an increase in fibrosis score from 3.86 to 4.09 and at 6 months post observation to 4.86 was detectable in the control group (n=57). In the treatment group a decrease from 3.91 at baseline to 2.42 at 18 months and 2.13 at 6 months post therapy was noted (n=119). The necroinflammatory score showed constant levels with 7.32 at baseline, 7.84 at month 18 and 7.48 at 6 months post observation in the control group. In the treatment group the score decreased from 8.24 at baseline to 5.77 at month 18 and then relapsed again to 7.38 post therapy. 59% of patients in the treatment group showed an HCV viral load decline of > 1 log, and 8% had a negative PCR, which however was not maintained for any patient upon cessation of therapy. The drop out rate was 4% and the dose reduction rate was 12%. 17 SAEs were observed, of which 15 were complications of cirrhosis (6 hydropic decompensations, 3 variceal bleeds and 3 HCC development). There was no significant diffence of theses complications betweens treatment and observational groups.

Conclusions:

Low dose therapy with pegylated interferon alfa 2b in patients with HCV and advanced fibrosis or cirrhosis shows a significant and persistent decrease in fibrosis in comparison to a control group. In contrast the also observed significant decrease in the necroinflammatory score is only temporary as long as treatment lasts. As treatment was well tolerated even for patients with cirrhosis, this treatment could evolve as a salvage therapy for patients with advanced liver disease with HCV where standard antiviral therapy has failed.

1146. Rapid Virologic Response (RVR) Is Enhanced by Higher Drug Exposure Among Patients Receiving Taribavirin in Combination With Pegylated Interferon alfa-2b for the Treatment of HCV Infection.

M. L. Shiffman; M. Rodriguez-Torres; S. Gordon; M. Palmer; P. Pockros; C. Trepo; Y. Kim; B. Murphy.

Background:

Previous studies have demonstrated that the later during treatment with peginterferon (PEGIFN) and ribavirin (RBV) a patient with chronic HCV becomes HCV RNA undetectable, the higher is the likelihood of relapse and the lower the SVR rate. In a recent Phase 3 study, the combination of taribavirin (TBV) plus PEGIFN alpha-2b or was found to have a lower SVR compared to weight base dosed RBV and PEGIFN alfa 2b (38% and 52%, respectively). To try and understand why TBV was associated with a lower SVR a post-hoc analysis of the ITT population was performed to examine the impact of treatment on viral kinetics and other demographic features such as patient age, body weight and total drug exposure.

Methods:

This Phase 3 study randomized 970 patients in a 2:1 ratio into a fixed dose taribavirin arm versus a weight base dosed RBV arm, stratifying patients on the basis of genotype, baseline viral load, and weight. Viral load was assessed throughout the study using the NGI SuperQuant Assay with a lower limit sensitivity of 39 IU/ml. Variables assessed included percent of patients younger than 45yo as well as average drug exposure expressed in mg/kg based on response activity at treatment weeks 4, 12, 24, and week 24 follow-up.

Results: See table.

Conclusions:

Patients achieving rapid virologic response (RVR) had similar an SVR approaching 90%, when treated with either TBV or RBV. In contrast, patients who had a slower virologic response, particularly those who failed to drop HCV RNA by 2 logs within the first 4 weeks of treatment, had a marked increase in SVR when treated with TBV when compared to RBV (63% vs 36% if HCV RNA undetectable at week 12 and 23% vs 12% if HCV RNA undetectable at week 24, respectively). The improvement in SVR in patients who fail to clear HCV RNA early during treatment is likely secondary to the improved tolerability of TBV over RBV.

	TBV				RBV
wk 4/ wk 12/ wk 24 response	N	% <45 yo	mean mg/kg	SVR %	N	% <45 yo	mean mg/kg	SVR %
neg /neg /neg	144	71%	16.4	87%	103	58%	14.8	88%
≥2 log ↓ / neg / neg	146	49%	16.1	57%	73	32%	14.7	78%
<2 log ↓ /neg / neg	24	50%	15.6	63%	14	36%	13.7	36%
≥2 log ↓ / ≥2 log ↓ / neg	27	30%	15.6	26%	10	40%	12.6	20%
<2 log ↓ / ≥2 log ↓ / neg	35	37%	15.8	23%	25	56%	14.7	12%

1147. An Open Label, Comparative, Multicenter Study of Peginterferon Alfa-2a plus Ribavirin in the Treatment of Patients with Chronic Hepatitis C/Hepatitis B Co-Infection versus those with Monoinfected Chronic Hepatitis C: An Interim Report.

C. Liu; P. Chen; J. Kao; M. Lai; C. Chen; C. Liu; M. Yu; C. Dai; Z. Lin; W. Chuang; S. Lu; J. Wang; T. Hu; C. Hung; C. Lee; W. Su; S. Wu; C. Lin; L. Liao; H. Kuo; H. Tung; Y. Chao; S. Tung; S. Yang; D. Chen.

Introduction:

Pilot studies using standard interferon in combination with ribavirin for 6 months to treat patients with dual chronic hepatitis C and B infection have shown that a sustained hepatitis C virus (HCV) clearance rate could be achieved to an extent comparable to that observed in HCV monoinfected patients. We have therefore conducted a multicenter clinical trial using peginterferon-based combination therapy in Taiwan.

Patients and Methods:

Eligible patients with active HCV (serum ALT level >=1.5X ULN and HCV RNA >=100,000 copies/mL), with (n=161) or without (n=160) co-existence of hepatitis B surface antigen, were consecutively enrolled. Patients infected with HCV genotype 1 received 48 weeks of combination therapy with peginterferon alfa-2a 180 mcg weekly plus daily 1000-1200 mg ribavirin. Patients with HCV genotype non-1 received 24 weeks of combination therapy with peginterferon alfa-2a 180 mcg weekly plus daily 800 mg ribavirin. The primary efficacy endpoint was sustained HCV RNA clearance at 24 weeks post-treatment.

Results:

Patients were recruited and enrolled between June 2004 and end of February 2006. By the end of March 2006, 21 (6.5%) patients were withdrawn prematurely from the study. The causes of withdrawal were skin lesions (n=8), non-compliance (n=7), constitutional symptoms (n=3), and dyspnea or cough (n=3). A total of 162 patients have completed treatment and follow-up, with the remainder still undergoing therapy. Interim results by intention-to-treat analysis are shown (Table 1).

Conclusions:

Combination therapy using peginterferon alfa-2a with ribavirin appears safe for patients dually infected with HCV and HBV. Interim results look promising and will be presented and discussed.

Table 1: HCV RNA clearance at the end of treatment (EOT) and at 24 weeks post-treatment (SVR)

	Dual Hepatitis B and C		HCV monoinfection
HCV genotype	1	Non-1	1	Non-1
Pts Enrolled (n)	97	64	110	50
Pts withdrawn (n/%)	8 (8.2)	3 (4.7)	8 (7.3)	2 (4.0)
Pts Completing trmt/follow-up	19 (19.6)	33 (51.6)	66 (60.0)	44 (88.0)
HCV EOT response*	17/27 (63.0)	31/36 (86.1)	64/74 (86.5)	43/46 (93.5)
HCV SVR*	15/27 (55.6)	30/36 (83.3)	54/74 (73.0)	38/46 (82.6)

*Pt numbers (%) completing study course including withdrawals analyzed; withdrawn cases without HCV RNA testing at 24 weeks post treatment counted as treatment failure

1148. Prospective Comparison of Two Commercial Non-invasive Fibrosis Serum Marker Panels (FibroSure and FibroSpect II) Before and During Therapy with albumin interferon alfa-2b in A Chronic HCV Genotype 1 Population.

K. Patel; K. Kaita; E. Yoshida; S. Zeuzem; Y. Benhamou; M. Torbenson; E. Pulkstenis; M. Subramanian; J. Mchutchison.

Background:

Noninvasive methods that distinguish between mild and severe stages of fibrosis and follow histologic changes during antiviral therapy could provide an alternative to liver biopsy for many chronin HCV (CHC) patients.

Methods:

Comparisons between the two commercially available HCV fibrosis serum marker panels (HCV FibroSure (Labcorp, Burlington, NC) and FibroSpect II (Prometheus Laboratories, San Diego, CA) have not been performed previously. These two panels were independently evaluated in serum samples obtained pre-treatment and during the study (w12, w24, w48 on treatment and w12 follow up), as part of an ongoing Phase 2b, active controlled study of alb-IFN in genotype 1 CHC, IFN-naïve patients. Pre-treatment liver biopsy specimens were graded for METAVIR fibrosis by a central pathologist.

Results:

Pre-treatment serum marker panel tests were evaluated from 92 CHC patients (n=92 assessed via FibroSpect II, n=84 assessed via FibroSure), with a prevalence of F2-F4=24% (22/92), and mean biopsy length of 17.6 ± 8.0 mm. Both panels indicated a high sensitivity (FibroSure=1.00; FibroSpect II=0.95) in detecting stage F2-F4, although with a lower but comparable specificity (FibroSure=0.61; FibroSpect II=0.65) and a good AUROC (0.89 for both). 12/36 F0 and 14/30 F1 patients were classified as false positive F2-F4 by FibroSure, and 9/37 F0 and 16/33 F1 by FibroSpect II. In the subset of patients with liver biopsies >15 mm, the specificity improved to 0.66 and 0.71 for FibroSure and FibroSpect II respectively. For the detection of advanced (F3-F4) fibrosis with FibroSure, sensitivity was 0.91 and specificity was 0.77 (AUROC=0.92). Among 83 samples evaluated with both tests, classification (F0-F1 vs. F2-F4) agreement was high in that 80% (66/83) were classified the same under either test (kappa=0.59).

Conclusions:

· Both commercially available marker panels demonstrate comparable and accurate performance characteristics for differentiating CHC patients with moderate-to-severe stage disease only.

· Both panels demonstrate good sensitivity for stage F2-4, indicating potential utility in excluding patients with significant fibrosis in CHC.

· Ongoing studies will determine their performance characteristics during antiviral therapy.

Fibrosis	F0-F1*	F2-F4*	Sensitivity (95% C.I.)	Specificity (95%)	AUROC**±SE	P value***
FibroSure			1.00 (0.81, 1.00)	0.61 (0.48, 0.72)	0.89±0.04	0.8123
F0-F1	40	0
F2-F4	26	18
FibroSpect			0.95 (0.77, 1.00)	0.64 (0.52, 0.75)	0.89±0.03
F0-F1	45	1
F2-F4	25	21

* Liver Biopsy ** Area Under empirical ROC Curve *** P value for comparison between FibroSure and FibroSpect II with respect to AUROC

1149. Combined immunomodulatory activities of the C-Class TLR9 agonist, CPG 10101, IFN-α and ribavirin on IFN-dependent and regulatory gene expression in human immune cells.

J. Vollmer; M. Jurk; K. Völp; N. Ahluwalia; S. M. Efler; T. Wader; A. Janosch; S. Tluk; H. L. Davis ; A. Krieg.

Purpose:

Toll-like receptors (TLRs) selectively recognize pathogen-expressed molecular patterns in principal absent in vertebrates and stimulate strong innate and adaptive immune responses. C-Class TLR9 agonists, such as the investigational TLR9 agonist CPG 10101, stimulate B and NK cell activation, and strong IFN-α production from plasmacytoid dendritic cells (pDC). CPG 10101 has demonstrated antiviral activity in human clinical trials in chronic hepatitis C virus (HCV) infections. Ribavirin, a synthetic guanosine analogue, is used for the treatment of chronic HCV in combination with recombinant pegylated-IFN-α. The mechanism by which ribavirin increases the antiviral activity of IFN-α is not well understood, but hypotheses include acting directly as a viral inhibitor, an RNA mutagen, or a Th1 immune modulator. Although some guanosine analogues were described to be ligands for TLRs, our previous studies demonstrated that ribavirin neither exerts immunomodulatory activities alone nor induces substantial TLR7/8/9-mediated signaling. Recently, we described IFN-α contributing to the strong TLR9-mediated Th1-like chemokine production in vitro from human immune cells, and we and others have reported that TLR9-mediated IL-10 secretion may have counter-regulatory immune-suppressive effects.

Methods:

Human peripheral blood mononuclear cells (PBMC) from healthy blood donors were cultured in vitro with increasing concentrations of CPG 10101 in the presence or absence of either ribavirin or IFN-α. Cytokine and chemokine production were measured by ELISA.

Results:

Ribavirin alone had no significant effects on cytokine production by human PBMC. However, we observed a dose-dependent suppressive effect of ribavirin on CPG 10101 (investigational TLR9 agonist)-induced IL-10 production at non-cytotoxic concentrations that did not influence CPG 10101-mediated IFN-α production. By blocking the CPG 10101-induced IL-10 production, but not the IFN-α secretion, ribavirin might enhance the Th1 effects of TLR9 activation. Furthermore, IFN-α priming of human PBMC was found to increase their responsiveness to TLR9 activation. Co-stimulation with CPG 10101 and IFN-α enhanced the PBMC production of IFN-α compared to that induced by CpG 10101 alone; pretreatment of the PBMC with exogenous IFN-α resulted in an even greater immunomodulatory effect upon subsequent stimulation with TLR9 agonists.

Conclusion:

The synergistic effect of IFN-α and CpG TLR9 agonist, as well as the suppression of IL-10 by ribavirin strongly suggests the potential of a greater activity of the combination of CPG 10101 and ribavirin with or without IFN-α in HCV immunotherapy.