Tuesday Poster Sessions, November 6, 2007

 

Topic: Experimental Therapies – R1626

 

1298. A high barrier to resistance may contribute to the robust antiviral effect demonstrated by R1626 in HCV genotype 1-infected treatment-naive patients

S. Le Pogam; A. Seshaadri; A. Kosaka; S. Hu; H. Kang; J. Symons; K. Klumpp; N. Cammack; I. Najera 

 

Introduction:

R1626, a prodrug of R1479, is a potent inhibitor of HCV replication that has shown maximum mean (median) HCV RNA reductions of up to 3.7 (4.1) log10 following 2 weeks of monotherapy study), and 5.2 log10 following 4 weeks in combination with peginterferon alfa-2a (PEG-IFNα-2a) ± ribavirin (RBV) (phase 2A) in patients infected with HCV genotype 1. In vitro studies have identified NS5B polymerase amino acid substitutions, S96T or S96T/N142T, that result in 4-5-fold reduced sensitivity to R1479 as determined in the replicon assay. These mutations also resulted in a ~95% reduction in replication capacity compared to the wild type replicon.

 

Aim:

To study resistance development in vivo, phenotypic and genotypic analyses were performed on multiple serum samples.

 

Patients

·        Serum samples from patients involved in two multicenter, randomized clinical studies designed to evaluate the safety, pharmacokinetics and antiviral activity of R1626 in treatment-naďve patients chronically infected with HCV genotype (GT) 1 were used to evaluate the in vivo resistance selection:

o       Study 1 was a placebo-controlled, multiple ascending dose, Phase 1b study with 47 patients who received oral R1626 at doses of 500 mg, 1500 mg, 3000 mg or 4500 mg or placebo twice daily (bid) for 14 days with 14 days of follow-up

o       Study 2 was a Phase 2a study that investigated R1626 in combination with PEGASYS and COPEGUS. 103 patients were randomized to: R1626 (1500 mg bid) plus PEGASYS (Dual Low); R1626 (3000 mg bid) plus PEGASYS (Dual High); R1626 (1500 mg bid) plus PEGASYS and COPEGUS (Triple Low); or PEGASYS plus COPEGUS (standard of care) for 4 weeks

 

Viral resistance evaluation

o       The viral load profiles of all participants were assessed for a viral rebound phenotype defined as:

o       A ≥ 0.5 log10 IU/mL increase of viral load from nadir during treatment with R1626, where nadir is defined as a ≥ 0.5 log10 IU/mL decrease from baseline (lowest point)

o       Selection of patient samples for resistance monitoring

o       Samples from patients who experienced a viral load reduction ≥ 0.5 log10 IU/mL followed by a viral load rebound were taken before treatment (baseline) and at the time point after the viral load rebound was observed, which corresponded to the end of treatment point for most patients. For 2 patients, the rebound occurred earlier and the end of treatment time point was also included in the study

o       Measurement of sensitivity to R1479 in the HCV NS5B phenotypic assay

o       HCV RNA was extracted from patients’ serum and the NS5B coding region was amplified and cloned into replicon vectors (GT 1a samples in GT 1a H77 replicon and GT 1b samples in GT 1b Con1 replicon). Ninety-six clones of each sample were pooled to represent the viral genetic diversity present in the patients

o       In vitro transcribed replicon RNA containing the NS5B region from the clinical isolates was transfected into cured-Huh7 cells

o       R1479 (or medium as a control) was added 24 hours post-transfection in 3-fold dilutions at a final DMSO concentration of 1%

§        Firefly luciferase reporter signal was read 72 hours after addition of compounds and the IC50 values were assessed as the compound concentration at which a 50% reduction in the levels of firefly luciferase reporter was observed as compared to control samples in the absence of compound

o       Sequencing of NS5B coding region

o       The entire NS5B polymerase coding region was sequenced

o       Detailed analysis of the NS5B viral quasispecies was performed by sequencing of the 96 molecular clones included in the pool to represent the viral genetic diversity

 

Results

R1626 showed a time- and dose-dependent HCV RNA reduction in monotherapy and combination therapy

o       Study 1: Time- and dose-dependent reductions in HCV RNA levels were achieved with mean HCV RNA reductions of up to 3.7 log10 IU/mL following 2 weeks of monotherapy

o       Study 2: Time- and dose-dependent reductions in HCV RNA levels were achieved with mean reductions of 5.2 log10 IU/mL in patients treated with Triple Low, 4.5 log10 IU/mL in patients treated with Dual High, 3.6 log10 IU/mL in patients treated with Dual Low and 2.4 log10 IU/mL in patients treated with SOC after 4 weeks

 

R1626 resistance evaluation

o       Among all 150 participants from all dose groups in both studies, 11 patients experienced a viral load rebound as follows:

o       3 patients from the 500 mg bid dose group in the monotherapy study

o       8 patients from the combination therapy study:

§        3 in the R1626 1500 mg bid plus PEGASYS group

§        4 in the R1626 3000 mg bid plus PEGASYS group

§        1 in the PEGASYS plus COPEGUS (standard of care) group

o       Among all participants from all dose groups in both studies, 3 patients did not respond to the treatment in the 500 mg bid dose group of the monotherapy study

 

No reduction in sensitivity to R1479 after up to 28 day treatment

o       Phenotypic characterization of the clinical isolates from patients receiving R1626 monotherapy that experienced a viral load rebound showed no change in susceptibility to R1479, with a 0.7–1.4-fold shift in IC50 at Day 14 compared to baseline; these values are well within the 2.6-fold variability of the assay compared to baseline sample and compared to reference controls (HCV GT 1a H77 and GT 1b Con1 reference strains, data not shown)

o       Phenotypic characterization of the clinical isolates from patients receiving R1626 combination therapy study showed no change in susceptibility at any of the time points compared to their respective baseline or to the reference controls

o       Phenotypic characterization of the clinical isolates from patients receiving R1626 monotherapy that did not respond to the treatment showed no change in susceptibility to R1479

o       The patients who had viral rebound in the monotherapy study had low levels of R1479 in plasma as shown by the pharmacokinetic data presented in Table 1. Cmin values were lower (0.42 to 1.33 μg/mL) than the overall Cmin range (0.86 to 5.98 μg/mL)

o       All patients who showed viral rebound on combination therapy had discontinued therapy or had dose reductions. 

 

No known R1479 resistance mutations nor other common substitutions in any of the patients that showed a viral load rebound during treatment or a non response to R1626

o       In the monotherapy study, NS5B sequence comparisons between baseline and day 14 time points revealed no pre-existing amino acid substitutions (S96T or S96T/N142T) known to be responsible for in vitro resistance to R1479 nor common amino acid changes across the three patients that showed a viral load rebound before the end of treatment

o       Likewise, NS5B sequence comparison between baseline and treated time points from the combination therapy study revealed no known R1479 resistance mutations nor any other common amino acid substitutions selected upon treatment. Detailed analysis of the quasispecies of all rebound samples (~1000 NS5B molecular clones) did not show any known R1479 resistance mutations at baseline or during treatment at low level (sensitivity of 1%)

o       In the patients that did not respond to R1626 monotherapy, no known R1479 resistance mutations nor other common substitutions were found. Detailed analysis of the NS5B viral quasispecies of the baseline sample showed no pre-existing amino acid substitution responsible for resistance to R1479

 

No pre-existing amino acid substitutions were observed at baseline that could be a predictor of treatment outcome (response or failure)

 

Conclusions

o       R1626 exhibited a strong HCV antiviral effect in monotherapy and combination therapy.

o       The absence of evidence for phenotypic and genotypic changes in patients with viral rebound demonstrates a lack of selection of viral resistance to R1626 after up to 4 weeks of treatment

o       The viral load rebound observed in a few patients treated with R1626 was likely due to inadequate drug levels (all were from the lowest dose arm of the monotherapy study or following drug dose reduction or discontinuation in patients in the combination study)

o       Despite the inadequate plasma levels of R1479 in the studied patients (that could represent an opportunity for the selection of drug resistant variants), there was no selection of viral resistance to R1626, neither at a population level nor at low level in the quasispecies, as evaluated through the extensive study of molecular clones

o       Sequence analysis revealed a lack of pre-existing amino acid substitutions at baseline that could be a predictor of treatment outcome (response or failure)

o       Given that in vitro studies have shown the poor replication capacity of S96T and S96T/N142T R1479-resistant replicons,2 the lack of selection of viral resistance after up to 4 weeks of treatment may indicate that R1626 exhibits a high genetic barrier to selection of viral resistance

o       R1626, appears to be a promising agent for treatment of patients chronically infected with HCV genotype 1

 


Topic: Diagnostic Tools

 

1299. What is the impact of higher sensitivity assay on response-guided therapy in hepatitis C virus (HCV)? Comparative analysis between TaqMan™ and Amplicor™ tests from two large randomized international trials of PEGASYS® plus COPEGUS®

C. Sarrazin; M. L. Shiffman; S. J. Hadziyannis; A. Lin; G. Colucci; H. Ishida; S. Zeuzem 

 

Background:

HCV treatment is rapidly evolving from a fixed duration of peginterferon alfa-2a (40KD) plus ribavirin (RBV) (48wks for genotype [G] 1; 24wks for G2/3) to response-guided therapy (RGT), adjusting duration according to on-treatment virologic response at wk4 and wk12; rapid virologic response (RVR) and complete early virologic response (cEVR), respectively. RGT originally used sensitive PCR assays (e.g. COBAS Amplicor HCV, v2.0; detection limit 50 IU/mL). It is unclear how the more sensitive TaqMan assay (COBAS AmpliPrep/COBAS TaqMan HCV Test: detection limit 15 IU/mL) will influence RGT. We therefore reanalysed serum samples (stored at –70°C) from two large international studies, ACCELERATE (G2/3) and NV15942 (G1,2&3), and compared clinical outcomes when using Amplicor or TaqMan.

 

Methods:

In ACCELERATE, TaqMan data were available from patients who had sufficient sample volume at baseline (BL; n=122) and wk4 (n=663). In NV15942, TaqMan data were available from patients who had BL, wk4, wk12, end of treatment (EOT) and end of follow-up samples (n=629). RVR rates and sustained virologic response (SVR) rates in patients with RVR were compared by Amplicor or TaqMan (HCV RNA <15 IU/mL [undetectable or below the limit of detection] or Undetectable [true negative]) in G2/3 (ACCELERATE) and G1 (NV15942) patients treated with peginterferon alfa-2a (40KD) plus RBV standard dose. cEVR (HCV RNA-negative at wk12) and relapse rates were compared by these two tests in G1 and G2/3 patients in NV15942. BL viral loads were compared by Amplicor Monitor v2.0 and TaqMan in G2/3 patients in ACCELERATE.

 

Results:

RVR and SVR rates were similar when RVR was defined as <50 IU/mL or <15 IU/mL regardless of genotype (Table). RVR rates were slightly lower when defined as HCV RNA undetectable by TaqMan. cEVR rates were similar when cEVR was defined as <50 IU/mL or <15 IU/mL. Relapse rates were lowest when TaqMan undetectable cut-off was utilized to determine EOT response. BL viral loads were well correlated between the two tests.

 

Conclusions:

A detection limit of <15 IU/mL by TaqMan serves as a reasonable definition of RVR and cEVR, along with <50 IU/mL, for RGT, regardless of genotype. The significance of HCV RNA “undetectable” by TaqMan should be investigated in prospective trials.

 

Definition of response:

Amplicor <50

TaqMan <15

TaqMan UD*

RVR  

SVR(pts with RVR):16wks Tx  

SVR(pts with RVR):24wks Tx

G2/3,n=663

50%  

82%  

91%

49%  

83%  

91%

37%  

83%  

91%

RVR

SVR(pts with RVR):24wks Tx

SVR(pts with RVR):48wks Tx

G1,n=164

32%  

 

91%  

 

100%

32%  

 

90%  

 

94%

24%  

 

89%  

 

91%

cEVR§

G1,n=169  

G2/3,n=135

77%  

97%

76%  

98%

68%  

96%

Relapse rate

G1:48wks Tx,n=109  

G2/3:24wks Tx,n=77

 

18%  

 

9%

 

15%  

 

8%

 

14%  

 

5%

RBV standard dose: 1000/1200mg/d for G1, 800mg/d for G2/3; *UD: Undetectable; §cEVR: –ve at wk12.

 


Topic: HIV/HCV Coinfection - Pegasys

 

1300. Patients coinfected with HCV and HIV who achieve an RVR (HCV RNA <50 IU/mL at week 4) or cEVR (HCV RNA <50 IU/mL at week 12) have similar rates of SVR to monoinfected patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®)

M. Rodriguez-Torres; F. Torriani; J. Rockstroh; J. Depamphilis; G. Carosi; D. T. Dieterich 

 

Background:

Patients coinfected with HIV-HCV represent a challenging population to treat. In the APRICOT study coinfected patients treated with 180 µg/wk peginterferon alfa-2a (40KD) and 800 mg/d ribavirin achieved an SVR rate of 40% (29% genotype [G] 1; 62% G2/3). These rates compare poorly to those in monoinfected patients. In monoinfected patients serum samples collected at wks 4 and 12 are increasingly being used to guide therapy decisions (response-guided therapy). There are limited data in coinfected patients on whether early treatment responses are also useful to predict rates of SVR and how rates of SVR in early responders compare between monoinfected and coinfected patients.

 

Methods:

Patients included in this analysis were all patients from the APRICOT study randomised to 180 µg/wk peginterferon alfa-2a (40KD) and 800 mg/d ribavirin with G1, 2 or 3 HCV. Rates of SVR were determined as a function of response to therapy at wk 4 and 12. RVR was defined as undetectable HCV RNA (<50 IU/mL) at wk 4; complete EVR (cEVR) was defined as non-RVR but undetectable HCV RNA (<50 IU/mL) at wk 12; partial EVR (pEVR) was defined as non-RVR but ≥2 log reduction from baseline in HCV RNA but remaining detectable HCV RNA (>50 IU/mL) at wk 12; SVR was defined as undetectable HCV RNA (<50 IU/mL) 24 wks after the end of therapy.

 

Results:

Data from 271 patients were included (Table). Rates of SVR for G1 and G2/3 were greatest in patients achieving an RVR (G1 = 81.8%; G2/3 94.3%), followed by cEVR (G1 = 63.2%; G2/3 69.7%) and then pEVR. Patients not achieving an RVR or cEVR/pEVR had minimal chance of achieving an SVR. Considering only patients with pEVR, rates of achieving SVR were influenced by several baseline and treatment factors indicating that response in this category of patients is heterogeneous.

 

Conclusions:

Coinfected patients who achieve an RVR have a similarly high chance as monoinfected patients of achieving an SVR irrespective of genotype. Patients that achieve cEVR also have similarly high rates of SVR as in monoinfected patients. As in monoinfected patients RVR is the strongest predictor for SVR, but in addition achieving a cEVR is also highly predictive of achieving an SVR.

 

Early response category

SVR rate n/N (%)

Genotype 1 (n=176)

Genotype 2/3 (n=95)

RVR

18/22 (81.8)

33/35 (94.3)

cEVR

24/38 (63.2)

23/33 (69.7)

pEVR

8/46 (17.4)

2/11 (18.2)

No RVR/EVR

1/70 (1.4)

1/16 (6.3)

 


Topic: Current Treatment - Pegasys

 

1301. Response-guided therapy in a prospective trial of peginterferon alfa-2a (40KD)/ribavirin treatment in patients with genotypes 1 or 4

P. Ferenci; H. Laferl; T. Scherzer; H. Brunner; A. Maieron; M. Gschwantler; R. E. Stauber; R. Hubmann; K. Staufer; C. Datz; M. Bischof; H. Hofer; K. Löschenberger ; P. E. Steindl-Munda 

 

Background:

The rate and extent of virological response to therapy in patients infected with HCV genotypes (G) 1 or 4 is highly variable. Retrospective analyses show that patients treated with peginterferon alfa-2a (40KD) plus ribavirin (RBV) who achieve an RVR (HCV RNA <50 IU/mL at wk 4) may achieve an SVR after only 24 wks, while patients with a slower response may benefit from prolonged therapy. This prospective study investigated response-guided therapy of Peg-IFN alfa-2a (40KD) plus RBV in G1 and 4 patients based on RNA level at wk 4 & 12. We aimed to evaluate whether patients with RVR, EVR (HCV RNA <600 IU/mL or ≥2-log drop) and non-responders (NR) can be differentiated at baseline (BL). We will present the final data for the 24 wk treatment arm (Arm D).

 

Methods:

Treatment-naive G1 and 4 chronic hepatitis C patients were treated with Peg-IFN alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day prior to allocation to one of four arms based on RNA tests at wk 4 & 12. At wk 4, patients with an RVR were assigned to a further 20 wks of therapy (Arm D). All other patients continued to receive treatment until wk 12 when RNA was retested. Patients with an EVR were randomized to a total of 48 (Arm A) or 72 wks (Arm B) of treatment. Wk 12 NRs were offered to continue treatment for a total of 72 wks (Arm C). Treatment was stopped if RNA remained detectable at wk 24.

 

Results:

Of the 580 patients screened 510 patients (G1=443; G4=67) received treatment and were evaluable. Of these 121/443 (27.3%) G1 patients and 29/67 (43.3%) G4 patients had an RVR and were allocated to Arm D. RVR was associated with younger age, lower body weight, lower BL viral load, and G4. By multiple logistic regression analysis viral load (high vs. low OR: 0.26 [95% CI:0.16–0.41]) and genotype (1 vs. 4: OR: 0.29 [95% CI:0.16–0.56]), body weight and ALT but not fibrosis were significantly associated with not achieving an RVR. The outcome of patients with RVR is shown in the table.

 

Conclusion:

More patients with G4 than with G1 achieved an RVR. Both G1 and G4 patients with RVR achieved high rates of SVR with 24 wks of treatment. These rates are similar to rates of SVR in G1 patients achieving an RVR with 48 wks of therapy. We confirm that a substantial proportion of patients with G4 and G1 benefit from shortening therapy to 24 wks. Here we show that RVR is predictive of SVR in G4 patients and that G4 patients with an RVR have an even greater chance of achieving an SVR compared to G1 patients.

Genotype

Pts with RVR n/N (%)

Per protocol SVR rate in pts with an RVR (%)

Per protocol relapse rate in pts with an RVR (%)

1

121/443 (27.3%)

90/103 (87.4%)

13/103 (12.6%)

4

29/67 (43.3%)

25/26 (96.2%)

1/26 (3.8%)

 


Topic: Experimental Therapies - HCV-796

 

1302. Phase 1 evaluation of antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in combination with different pegylated interferons in treatment-naive patients with chronic HCV

S. Villano; D. Raible; D. Harper; P. Chandra; L. Bazisotto; G. Bichier 

 

Background:

HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated clinical antiviral activity across multiple HCV genotypes when administered as monotherapy or in combination with pegylated interferon alfa-2b (PEG2b). We further evaluated HCV-796 when administered with pegylated interferon alfa-2a (PEG2a).

 

Methods:

Evaluations were performed within a randomized, double-blind, Phase 1 study in adult patients with chronic HCV infection who were naďve to treatment. In one group, patients were randomized to receive oral HCV-796 or placebo Q12h for 14 days, and all were to receive PEG2b (1.5 mcg/kg) on day -1 (one day before start of HCV-796/placebo) and day 7. In another group, the design was the same except the PEG therapy was PEG 2a (180 mcg) on day -1 and day 7. In each group 12-16 patients were to receive the active HCV-796 (500 mg Q12h) with one of the PEG therapies.

 

Results:

The mean baseline HCV RNA level was 6.4-6.5 log10 in each group and 71% of patients were infected with HCV genotype 1. For both PEG therapies, combination with HCV-796 reduced plasma HCV RNA levels to a greater extent than either PEG alone. At day 14, the mean reduction in HCV RNA for HCV-796+PEG2b was 3.4 log10 vs. 1.6 log10 for PEG2b alone. The mean reduction for HCV-796+PEG2a was 3.7 log10 vs. 1.1 log10 for PEG2a alone. For both groups, activity differed by HCV genotype. Mean HCV RNA reductions at day 14 for genotype 1 was 2.9 log10 for HCV-796+PEG2b and 3.2 log10 for HCV-796+PEG2a. For genotype non-1 the respective reductions were 4.4 vs. 4.7 log10. Combination of HCV-796 with either PEG therapy was generally well tolerated. Common adverse events in all groups were those typically associated with interferons, including headache, chills, and myalgia.

 

Conclusions:

The combination of HCV-796 with either PEG2b or PEG2a provides similar antiviral activity across multiple HCV genotypes over 14 days of therapy. Results support clinical studies of more long-term administration of HCV-796 with either PEG therapy.

 


Topic: Current Treatment - Pegasys

 

1303. Peginterferon ALFA-2A and Ribavirin for 12 or 24 Weeks in Patients With HCV Genotype 2/3: The Nordynamic Trial

M. Lagging; C. Pedersen; M. Rauning Buhl; M. Färkkilä; N. Langeland; K. Mřrch; J. Westin; Ĺ. Alsiö; G. Norkrans 

 

Background and Aims:

Prior trials investigating the efficacy of treatment for less than 24 weeks in HCV genotype 2/3 infected patients have yielded discordant results. The aim of this study was to compare the efficacy of 12 or 24 weeks of combination therapy, as well as to identify patients achieving SVR using liver biopsy evaluation, IP-10 levels-interferon concentrations, ribavirin concentrations, and HCV RNA measurement using Roche COBAS TaqMan at baseline, day 3, day 7, day 8, week 4, and week 8.

 

Methods:

Three hundred and eighty-two genotype 2/3 infected patients at 31 centers in Denmark, Finland, Norway, and Sweden were randomized at baseline to 12 or 24 weeks of treatment with peginterferon α-2a 180 μg/week plus ribavirin 800 mg/day from February 2004 to November 2005.

 

Results:

Twelve weeks of combination therapy was inferior to 24 weeks for patients infected with genotype 2 (SVR rates 56% vs. 82%, p=0.007) and genotype 3 (58% vs. 78%, p=0.001). Likewise, 12 weeks of treatment was inferior for patients with non-significant fibrosis (p=0.024) and bridging fibrosis (p=0.0033), and a similar trend was noted for patients with cirrhosis (p=0.078). Multivariate analysis demonstrated that age as well as HCV-RNA levels on day 7 and 29 were independent predictors of SVR following 12 weeks of therapy. For patients <40 years, no significant difference was noted between 12 and 24 weeks of therapy regardless of HCV-RNA level day 29. Similarly, for patients ≥40 years, no significant difference was noted between the treatment arms if both HCV-RNA day 7 was below 1,000 IU/mL and HCV-RNA was undetectable day 29. If both of these two criteria were unmet for patients ≥40 years, 24 weeks of therapy was superior (p<0.0001).

 

Conclusion:

Our findings indicate that 12 weeks of combination therapy may be acceptable for subgroups of, but not for all patients infected with HCV genotypes 2 or 3.


Topic: Experimental Therapies - GI-5005

 

1304. HCV-Specific Cellular Immunity, RNA Reductions, and Normalization of ALT in Chronic HCV Subjects after Treatment with GI-5005, a Yeast-Based Immunotherapy Targeting NS3 and Core: A Randomized, Double-blind, Placebo Controlled Phase 1b Study

E. R. Schiff; G. T. Everson; N. Tsai; N. H. Bzowej; R. G. Gish; J. G. McHutchison; I. M. Jacobson; M. J. Tong; D. M. Jensen; G. M. Lauer; S. Cruickshank; J. Ferraro; A. Haller; R. Duke; T. Rodell; D. Apelian 

 

PURPOSE:

Evaluation of the efficacy, immunogenicity, and safety of GI-5005 in subjects with chronic HCV infection.

 

METHODS:

GI-5005 is a whole heat-inactivated S. cerevisiae immunotherapy expressing HCV NS3 and Core. Subjects with chronic HCV infection who were interferon (IFN) partial responders, relapsers, or treatment naďve were eligible. Five weekly subcutaneous (SC) doses of GI-5005 monotherapy over 29 days were followed by two monthly SC GI-5005 doses and 9 months of post-treatment follow-up. Dose groups of 0.05, 0.5, 2.5, 10, 20, and 40YU (1 YU = 10,000,000 yeast cells) were randomized 3:1 treated:placebo.

 

Discussion:

Safety:

o       GI-5005 was well tolerated, with no dose limiting toxicities (DLTs) through 40YU.

 

Efficacy:

o       Viral load reductions from -0.75 to 1.4 log 10 were observed only in GI-5005 treated patients 6/54 (11%).

o       GI-5005 dose response for ALT normalization reaching 50% in the 40 YU group.  No ALT normalization has been observed in the placebo group.

o       HCV specific cellular immune response only observed in GI-5005 treated subjects (9/39, 23%) using stringent criteria for amplitude and breadth of immune response.  The strongest ELIspot responses (>250 activiated cells per million lymphocytes) were detected only in the highest GI-5005 doses tested (10YU, 20YU, and 40YU).

 

These results indicated that a short course of GI-5005 monotherapy is capable of generating an HCV specific immune response that is associated with viral load reductions of up to 1.4 log10, and ALT normalizations in up to half of the high dose patients.  A Phase 2 trial comparing GI-5005 plus pegylated interferon/ribavirin vs. pegylated interferon/ribavirin alone is being initiated at 50 centers in the US, EU, and India.  Long-term GI5005 salvage will also be provided in this trial to patients who fail to achieve an early virological response (EVR) or do not tolerate treatment in the pegylated interferon/ribavirin arm.

 


Topic: Current Treatment - Pegasys

 

1305. Association of Pre-Treatment and On-Treatment Factors with Rapid Virologic Response in HCV Genotype 1 Infected Patients Treated with PegIFNα-2a/RBV

M. Rodriguez-Torres; M. Sulkowski; R. T. Chung; F. Hamzeh; D. M. Jensen 

 

Introduction

Rapid virologic response (RVR), defined as undetectable serum HCV RNA after 4 weeks of treatment, is associated with likelihood of sustained virologic response. This retrospective analysis assessed the effect of baseline and demographic factors and drug dose/modification during the first 4 weeks of treatment on RVR.

 

Methods

Patients in 5 clinical trials who were infected with HCV genotype 1 and randomized to 180 μg/wk pegIFNα-2a/1000-1200 mg/d RBV were included. Baseline factors utilized for multiple logistic regression analyses included age (≤40 vs >40 years), gender, race/ethnicity (non-Latino white vs other), BMI (≤27 vs >27 kg/m2), baseline ALT quotient (≤3 vs >3X ULN), baseline serum HCV RNA (≤400,000 vs >400,000 IU/mL) and cirrhotic classification (cirrhotic vs non-cirrhotic). On-treatment factors included average daily exposure to RBV (≤13 vs >13 mg/kg/day) and pegIFNα-2a dose reductions (yes vs no). Any factor with p≤.2 was considered significant.

 

Results

Of 1550 treated patients, 234 (15.1%) attained RVR and 1316 (84.9%) did not; 1 (0.4%) and 16 (1.2%), respectively, withdrew for safety reasons, and 0 and 17 (1.3%), respectively, for non-safety reasons. Of these 1550 patients, 1050 (67.7%) were non-Latino whites, 295 (19.0%) were Latino whites, 154 (9.9%) were black, and 51 (3.3%) were Other; 1031 (66.5%) were men; 1112 (71.7%) were >40 years old; 797 (51.4%) had BMI >27 kg/m2; 1184 (76.4%) had ALT quotient >3X ULN; 1346 (86.8%) had serum HCV RNA >400,000 U/mL; and 239 (16.4%) were cirrhotic. Multiple logistic regression analysis showed that white non-Latino race (OR 1.48; 95% CI 1.04-2.12, p=.031), age ≤ 40 years (OR 1.63; 95% CI 1.27-2.26, p=.0035), baseline ALT quotient >3X ULN (OR 1.96; 95% CI 1.40-2.76, p=.0001), baseline serum HCV RNA ≤400,000 IU/mL (OR 8.67; 95% CI 6.13-12.37, p<.0001), non-cirrhotic status at baseline (OR 1.63; 95% CI 1.01-2.64, p=.0444), male sex (OR 1.37; 95% CI 0.98-1.91, p=.0687) and BMI ≤27 kg/m2 (OR 1.37; 95% CI 0.99-1.91, p=.0545) were predictive of RVR. After adjusting for significant risk factors, multiple logistic regression analysis showed that average daily RBV >13 mg/kg/day (OR 2.15; 95% CI 1.41-3.27, p=.0004) was a significant predictor of RVR, whereas pegIFNα-2a dose reduction was not.

 

Conclusion

RVR in patients infected with HCV genotype 1 was associated with younger age, white race, higher ALT quotient, lower serum HCV RNA, absence of cirrhosis, male sex and lower BMI, and with greater exposure to RBV over the initial 4 weeks. Patients exposed to ≤13 mg/kg/day RBV over the first 4 weeks were less likely to achieve RVR.

 


Topic: Current Treatment – Consensus Interferon

 

1306. Treatment of Peginterferon/Ribavirin Nonresponders with daily Dosing of Consensus Interferon and Ribavirin - Preliminary Results of the German Consensus Interferon Multicenter Study

S. Kaiser; W. Boecher; J. F. Schlaak; B. Lutze; B. Sauter; L. Bissinger; C. Werner; H. Hass; M. Gregor 

 

Objective:

Current standard treatment with pegylated interferon (PEG IFN) and ribavirin (RBV) in genotype 1 patients shows sustained response rates of 31 – 47%, thus leaving more than half of the patients with a relapse or nonresponse to . Recently improved response rates have been observed in pilot trials using consensus interferon (CIFN) in combination therapy in PEG IFN / RBV nonresponders.

 

Methods:

The efficacy of CIFN daily dosing therapy followed by CIFN / RBV in PEG IFN combination treatment nonresponders was evaluated. 400 patients have been included, with 92% having genotype 1. Average weight of patients was 79.3 kg. Patients were either treated with CIFN at 9 ug QD for 16 weeks or with CIFN 27 ug QD for 4 weeks, followed by 12 weeks of CIFN 18 ug QD. Thereafter, treatment was continued in all treatment groups with CIFN at 9 ug QD with weight-based RBV for 32 - 56 weeks, depending when a patient became first PCR negative, ensuring a treatment period for 48 weeks with a negative PCR.

 

Results:

Preliminary data show that after the initial 12 weeks of CIFN monotherapy, a primary response with undetectable serum HCV-RNA was observed in 37 % of patients with a prior nonresponse to PEG IFN a2b and in 48% in prior PEG IFN a2a nonresponders (n=189). At the end of treatment, a negative PCR was observed in 34% in PEG IFN a2b nonresponders, and in 48% of PEG IFN a2a nonresponders. The sustained viral response rates (SVR) were 16% and 23% for PEG IFN a2b and PEG a2a nonresponders, respectively (n=143).

 

When response rates were calculated according to the treatment arm used, the SVR for PEG IFN a2b nonresponders were 13% in the CIFN 9 ug arm and 19% in the CIFN high dose arm. For PEG IFN a2a nonresponders the SVR were 19% and 27% for the CIFN 9 ug dose and high dose arms, respectively. The overall tolerability of the CIFN 9 ug regimen was comparable to a standard therapy with pegylated IFN and RBV, while the CIFN 27/18/9 ug regimen was less tolerable during the high dose induction period. However, drop out rates were not different between the two dosing regimen.

 

Conclusions:

CIFN daily dosing / induction therapy together with subsequent RBV combination therapy thus shows promising response rates in previous PEG IFN combination therapy non-responders. Especially PEG IFN a2a nonresponders appear to have a benefit from CIFN QD retreatment. It is concluded that CIFN may be an effective treatment modality for this difficult-to-treat patient group.

 


Topic: Experimental Therapies - PF-03491390

 

1307. PF-03491390 inhibits liver fibrosis in patients with chronic hepatitis C virus infection via suppression of pro-apoptotic caspase-activation.

G. Burgess; P. Colman; E. Engmann; H. Bantel; P. N. Soni 

 

Background:

In patients with chronic HCV infection, the pancaspase inhibitor, PF-03491390 may minimise hepatocellular (HCC) damage, as reflected by reductions in elevated ALT and AST levels. As caspase activation plays a pivotal role in inflammatory and fibrotic liver injury in HCV-infection, we investigated caspase activation and a range of inflammatory and fibrotic serum biomarkers during therapy with this agent.

 

Methods:

204 patients (63% male, 51 yo average age)  with chronic HCV infection and liver fibrosis were randomized to receive placebo or PF-03491390 5 mg, 25 mg, or 50 mg orally twice daily for 12 weeks in a placebo-controlled, double-blind, parallel-group study. If ALT and AST levels remained elevated at Week 10, the dose of study drug was doubled to Week 12. Changes in serum markers of inflammation, fibrosis and apoptosis are reported.

 

Results:

At Week 12, compared with placebo, PF-03491390 therapy was associated with decreases in serum levels of transforming growth factor (TGF) β1, α-2 macroglobulin, caspase-mediated cytokeratin-18 fragments (M30-Antigen), active caspases 3/7 and α-fetoprotein. PF-03491390 therapy was also associated with increases in serum levels of haptoglobulin and Fas ligand, at Week 12, compared with placebo. PF-03491390 therapy had no apparent impact on serum levels of the other measured biomarkers (Table 1).

 

Safety

·        In total, three (1.5%) subjects withdrew from the study due to treatmentemergent adverse events.

o       two subjects in the placebo treatment group;

o       one with a severe elevated liver function test

o       one with dyspnea, upper abdominal pain, asthenia and palpitations (all severe).

o       one subject in the PF-03491390, 5 mg treatment group;

o       with moderate exacerbation of a migraine.

 

·        During the study, 139 (68%) subjects reported a total of 443 adverse events.

·        The most frequently reported treatment emergent events were headache (24 [12%] subjects) and fatigue (22 [11%] subjects), with the majority of adverse events being of mild or moderate severity.

 

HCV viral load

·        No changes in HCV RNA viral load were observed.

 

Conclusions:

·        PF-03491390 effectively reduced aminotransferase levels in patients with chronic hepatitis C. These reductions were evident as early as Day 7 and were sustained for the full 12-week duration of treatment. ALT/AST normalization rates were low, however, necessitating increases in the dose of study medication in most patients.

·        Levels of caspases 3/7 and M30 antibody decreased during 10 weeks’ treatment with PF-03491390. The decreases in caspases 3/7 were partially dose dependent, but no dose dependency was observed for the M30 antibody response. These observations suggest that PF-03491390 may inhibit liver fibrosis via suppression of pro-apoptotic caspase activation.

·        The observed decreases in serum levels of caspases 3/7 and M30 antibody are consistent with those that would be expected if PF-03491390 inhibited the apoptosis of activated hepatic stellate cells, suggesting that the drug has the potential to limit hepatic fibrosis.

·        Although the lack of clear dose dependency observed for the M30 antibody response might not be expected if PF-03491390 inhibited the apoptosis of activated hepatic stellate cells, it could indicate the existence of a steep dose response that reached maximal at the lowest dose tested in this study. It could also indicate that the initial levels of CK-18 neo-epitope were lower than expected for this population of patients with chronic liver disease.

·        Levels of the other markers of inflammation and fibrosis measured in this study showed little or no change during 12 weeks’ treatment with PF-03491390. These observations probably reflect low initial levels of these markers and the relatively short duration of the study rather than a de facto absence of effect of PF-03491390 on liver inflammation and fibrosis.

·        Larger and longer-term studies, with a histology endpoint, are required to explore further the impact of PF-03491390 treatment on serum markers of inflammation, fibrosis and apoptosis, and their potential implications in clinical practice

Table 1: Median absolute change of serum markers of inflammation, fibrosis and apoptosis from baseline at Week 12

Serum marker

Placebo

PF-03491390

 

 

5 mg bid

25 mg bid

50 mg bid

Fibrosis

N=47-50

N=49–53

N=48–50

N=44-57

 

M30-Antigen (U/L)

-17.0

-114.5

-93.0

-105.0

 

Active caspases 3/7 (RLU)

 

-46.0

 

-292.0

 

-285.0

 

-464.0

 

TGFβ1 (ng/ml)

6.2%

-14.4%

-2.9%

-7.3%

 

α-2 macroglobulin (mg/dl)

 

0.5%

 

-0.9%

 

-0.1%

 

-2.5%

 

Haptoglobin (mg/dl)

-0.6%

8.4%  

5.6%

8.0%

 

Apolipoprotein A1 (mg/dl)

 

0.3%

 

-2.1%

 

0.3%

 

-2.2%

Inflammation

N=48–51

N=49–55

N=46–50

N=43–48

 

Tumor necrosis factor-α (pg/ml)

 

0%

 

5.3%

 

0%

 

0%

 

C-reactive protein (mg/dl)

 

-7.9%

 

-4.4%

 

-3.6%

 

-13.0%

 

α-fetoprotein (ng/ml)

0%

-12.2%

-17.0%

-11.1%

 

Interleukin-6 (pg/ml)

0%

16.2%

-12.4%

-13.6%

 

Interleukin-8 (pg/ml)

-3.0%

0%

-6.5%

-7.9%

 

Fas ligand (pg/ml)

-0.4%

2.9%

4.2%

3.2%

Mechanism of Action

N=25

N=28

N=29

N=20

 

Interleukin-1β (pg/ml)

0%

0%

0%

0%

 


Topic: Current Treatment - Pegasys

 

1308. Differentiation of early virologic response (EVR) into RVR, complete EVR (cEVR) and partial EVR (pEVR) allows for a more precise prediction of SVR in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®)

P. Marcellin; D. M. Jensen; S. J. Hadziyannis; P. Ferenci 

 

Background:

Early on-treatment responses in HCV RNA at wks 4 & 12 post initiation of therapy are increasingly being used to predict those pts likely to achieve an SVR. Pts achieving an RVR (HCV RNA <50 IU/mL at wk 4 and maintained at wk 12) have a high rate of SVR irrespective of genotype. The standard definition of an early virologic response (EVR) had been defined as pts at wk 12 achieving either an undetectable HCV RNA (<50 IU/mL) or a ≥2 log drop in HCV RNA but still detectable. However, rates of SVR in pts achieving an EVR by this definition are heterogeneous. By further subdividing pts achieving early responses into RVR, complete EVR (cEVR or non-RVR but HCV RNA <50 IU/mL at wk 12) and partial EVR (pEVR or non-RVR but HCV RNA ≥2 log drop in HCV RNA at wk 12 but still detectable) it may be possible to improve the prediction of pts likely to achieve an SVR and may allow for tailoring of treatment duration. Here we performed a retrospective analysis of 2 large, multinational phase III studies of genotype 1 pts treated with peginterferon alfa-2a (40KD) in combination with ribavirin (RBV) (Fried et al. NEJM 2002 & Hadziyannis et al. Ann Intern Med 2004).

 

Methods:

569 pts treated for 48 wks with 180 µg/wk peginterferon alfa-2a (40KD) and 1000/1200 mg/d RBV were included in the present analysis (ITT). Early responses were divided into 4 mutually exclusive categories as defined above: RVR, cEVR, pEVR and non-EVR (<2 log drop at wk 12). Rates of SVR were then calculated for each category.

 

Results:

16% (90/569) pts were classified as achieving an RVR, 42% (240/569) pts a cEVR, 22% (128/569) pts a pEVR and 20% (111/569) non-EVR. Rates of achieving an SVR in these groups were 87% (78/90) for RVR, 68% (162/240) cEVR, 27% (34/128) pEVR and 5% (5/111) for non-EVR pts.

 

Conclusions:

Pts achieving an RVR have high rates of SVR and may benefit from shortened treatment duration (24 wks; also see Jensen et al. Hepatol 2006). Pts with a cEVR also have high rates of SVR but should be encouraged to remain on therapy for the standard duration of therapy (48 wks). Pts with a pEVR have lower rates of SVR with the standard 48 wks of therapy and may benefit from intensified treatment (72 wks; also see Sánchez-Tapias et al. Gastroenterol 2006) and pts that are non-EVR at wk 12 have a low chance of achieving an SVR and consideration should be given to change treatment strategy. Early on-treatment virologic responses in HCV RNA are highly predictive of achieving an SVR and subdividing early responses into RVR, cEVR and pEVR allows for a more precise prediction of achieving an SVR.

 


Topic: Current Treatment - Pegasys

 

1309. Final Results of Patients 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

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

 

Purpose:

Telaprevir (TVR, 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 TVR in combination with peginterferon-alfa-2a (Peg-IFN). Here we report the final results of patient status after stopping follow-on standard therapy with Peg-IFN and ribavirin (RBV).

 

Methods:

The VX04-950-103 clinical study randomized twenty treatment-naďve patients with chronic genotype 1 hepatitis C infection to three dosing arms. Eight patients received TVR (750 mg as tablets q8h) with Peg-IFN on Days 1 and 8, and eight patients received TVR alone. Four patients received Peg-IFN alone on Days 1 and 8. At the completion of the 14-day study, off-study therapy with Peg-IFN and RBV was offered to all patients. Nineteen of 20 patients began therapy within 5 days of completing the 14-day dosing period. The patient who refused post-study Peg-IFN/RBV was in the TVR-alone group.

 

Results:

At week 12 of therapy, all 8 patients in the TVR/Peg-IFN group and 5 of 7 patients in the TVR alone group had undetectable HCV RNA. At week 24, all 15 patients who received TVR had undetectable HCV RNA(<10 IU/mL). Ten patients (6/8 TVR/Peg-IFN and 4/7 TVR alone) chose to stop Peg-IFN/RBV treatment at week 24 and 5 patients chose to continue Peg-IFN/RBV for a total of 48 weeks. All groups were followed for the subsequent 24 weeks. In patients who had received TVR-based therapy for 14 days before starting off-study Peg-IFN/RBV therapy, 7/10 patients treated for a total of 24 weeks and 2/5 patients treated for a total of 48 weeks achieved a sustained viral response (SVR) One patient, treated for 48 weeks, was lost to follow-up. From the group who received Peg-IFN alone before 48 weeks of Peg-IFN/RBV therapy, 1/4 patients achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy. Sequence analysis of the 5 patients who relapsed after TVR-based therapy is in progress.

 

Conclusions:

SVR was achieved in 9 of 15 patients treated for 14 days with TVR or TVR/Peg IFN followed by Peg-IFN/RBV therapy for a total of 24 or 48 weeks. These results suggest that TVR-based regimens may increase SVR rates compared to current therapies. Large Phase 2 clinical studies of TVR-based regimens are now ongoing to evaluate this hypothesis and the possibility of shortening the duration of therapy.

 


Topic: Current Treatment – Pegasys

 

1310. Retreatment of HCV Genotype 1 Relapse Patients to Peginterferon/Ribavirin Therapy with an extended Treatment Regimen of 72 weeks with Consensus Interferon/Ribavirin versus Peginterferon alpha/Ribavirin

S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C. Werner; H. Hass; M. Gregor 

 

Objective:

Treatment with pegylated interferon and RBV for 48 weeks in naive chronic Hepatitis C patients results in relapse rates of about 20 –30 %. Recently improved response rates have been observed in treatment-naďve patients with a slow viral response as well as in retreatment trials using an extended treatment duration of 72 weeks. However, the optimal retreatment regimen and treatment time remains unclear at present.

 

Methods:

The efficacy of CIFN daily dosing + RBV versus PEG IFN a2a + RBV for 72 weeks in patients with a prior relapse to 48 weeks of treatment with PEG IFN + RBV was evaluated. 120 patients with genotype 1. Average weight of patients was 79 kg. Patients were either treated with CIFN at 9 ug QD for 72 weeks or with PEG IFN a2a at 180 ug QW for 72 weeks, both in combination with weight-based RBV.

 

Results:

Data show that after the initial 12 weeks a primary response with undetectable serum HCV-RNA was observed in 85 % of patients in the CIFN QD group and in 81 % in the PEG IFN 180 ug group (diff. = n.s.). At the end of treatment at week 72, a negative PCR was observed in 86 % in the CIFN group, and in 78% of the PEG IFN 180 ug group (diff. = n.s.). The sustained viral response rates (SVR) were 69% for the CIFN arm and 42 % for the PEG IFN a2a arm, respectively (diff. p<0.05), indicating a significantly higher relapse rate in patients being retreated with PEG IFN a2a.

 

No growth factors were used in this study. 5 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 the PEG IFN a2a therapy, while the CIFN QD regimen lead to a higher rate of injection site reactions and a slightly higher drop out rate of 19% versus 11% for the PEG IFN a2a group. In contrast, hematologic grade III alterations were higher in the PEG IFN a2a group.

 

Conclusions:

Both extended CIFN daily dosing combination therapy and PEG IFN a2a combination therapy for 72 weeks show promising response and SVR rates in previous relapse patients to standard PEG IFN / RBV therapy, while relapse rates are significantly lower in the CIFN retreated patents leading finally to higher SVR rates. Although a significant proportion of patients experienced a second relapse in both treatment regimens after cessation of therapy, the overall sustained response rates are nevertheless promising showing a SVR in up to 70% of patients. It is concluded that extended treatment especially with CIFN in combination with RBV may be an effective treatment modality for this difficult-to-treat patient group.

 


Topic: Current Treatment - Peg-intron

 

1311. 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

S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C. Werner; H. Hass; M. Gregor 

 

Objective:

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.

 

Aim:

To evaluate the efficacy and safety of low-dose PEG-IFN ALFA-2B (PEGINTRON) as maintenance therapy in patients with chronic hepatitis C and advanced fibrosis or cirrhosis.

 

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 182 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=83). Histology was evaluated at baseline, at 18 months of treatment and 6 months after end of treatment.

 

Results:

182 patients receiving treatment were enrolled in the study, and 167 patients were included in the analysis—Although all patients have completed therapy, 15 patients have not undergone a second liver biopsy.  An additional 83 untreated patients were enrolled to serve as an observation cohort. 

Patient characteristics were balanced in the two groups except there were more genotype 4 patients in the PEG-INF group compared to the group of patients who did not receive treatment (3.8% vs. 12.0% respecitively).

The mean fibrosis scores improved during treatment and were maintained 24 weeks after cessation of treatment in patients receiving PEG-IFN alfa-2b 0.5 μg/kg/wk.  In contrast, fibrosis scores slowly increased in untreated patients (indicating a progressive  histology) during the 36-month observational period and throughout follow-up.

 

HCV RNA Levels, Dropout Rates, and Discontinuation Rates:

·        Overall, 61% of treated patients experienced a >1 log10 decrease in HCV RNA from baseline during treatment

o       In 10 (6%) of 167 patients, HCV RNA was undetectable at the end of treatment      

o       All patients who received PEG-IFN alfa-2b 0.5 μg/kg/wk experienced relapse after withdrawal of treatment

·        Among treated patients, dropout and dose-reduction rates were 3% and 13%, respectively

o       The drop out rate was 3% and the dose reduction rate was 13%

Safety

Mean changes in laboratory parameters among patients receiving PEG-IFN alfa-2b 0.5 μg/kg/wk:

Mean Decrease During Tx        Lowest Recorded Value During Tx

White blood cell count, cells/μL 1630                                                     1390

Hemoglobin, g/dL                                  0.8                                                        8.4

Platelets, cells/μL                                  45,563                                                   24,000

Alanine aminotransferase, U/L               19                                                         NA

  • 22 Serious adverse events were reported among patients receiving PEG-IFN alfa-2b 0.5 μg/kg/wk, of which 17 were attributed to complications of cirrhosis (Table 3)
    • There was no significant difference in the complication rates between treated and untreated patients (data not shown)
    • At the end of the study, more patients in the untreated group (n = 3) required transplants than patients in the treated group (n = 1)

 

 

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.

 


Topic: Experimental Therapies - General

 

1313. Effect of Infliximab on the Efficacy of Peginterferon alfa-2b (PEG-2b) Plus Ribavirin (RBV) Therapy in Treatment-Naive Patients With Hepatitis C Genotype 1 and High Tumor Necrosis Factor α (TNF-α) Levels

C. Cooper; S. Shafran; S. Greenbloom; R. Enns; J. Farley; M. Neuman; N. Abadir 

 

Background:

High levels of TNFα may contribute to the pathogenesis of hepatitis C virus (HCV) infection. This study evaluated the safety of infliximab in HCV-infected patients and assessed the effect of infliximab induction therapy on early virologic response and sustained virologic response (SVR). This interim analysis reports viral kinetics during the first 12 weeks of treatment.

 

Methods:

This was a randomized, prospective, open-label trial conducted at 8 academic and community sites in Canada. Treatment-naive patients with HCV G1 infection and high serum TNFα values (>300pg/mL) were randomly assigned to receive either a single pretreatment induction infusion of infliximab (5mg/kg) 7 days before antiviral therapy (Arm A) or no pretreatment (Arm B). All patients received PEG-2b (1.5μg/kg/wk) plus weight-based RBV (800–1400mg/d) for up to 48 weeks. Rapid virologic response (RVR) was defined as undetectable HCV RNA at week 4 (<50IU/mL HCV RNA; Amplicor HCV Monitor Test v2).

 

Results:

This analysis is based on the first 29 randomly assigned patients (16 Arm A, 13 Arm B) who received 12 weeks' of PEG-2b + RBV; 70% of participants were male. Infliximab was well tolerated, without excessive side effects. More infliximab recipients had advanced (F3) fibrosis (38% vs 15%). At initiation of PEG-2b + RBV, lower mean serum TNFα levels were observed in patients in Arm A than in Arm B (P=.013). In Arm A, 7/16 (43.8%) patients attained RVR, compared with 4/13 (30.8%) patients in Arm B. By week 8, significantly more patients (11/16, 69%) in Arm A had undetectable HCV RNA than in Arm B (6/13, 46%; P=.024). The number of patients who attained undetectable HCV RNA at week 12 was similar between study arms (11/16 patients in Arm A [69%] vs 11/13 patients [85%] in Arm B; P=.183), suggesting that the effect of infliximab may not be sustained past week 8.

 

Conclusion:

The anti-TNFα effect of infliximab on HCV may provide viral decline during the first 8 weeks of HCV therapy. It is unknown whether infliximab treatment before combination PEG-2b + RBV therapy will translate into greater SVR rates.

 

HCV RNA Log 10

F1-F2 Patients

Arm A

Arm B

Visit, wk

Mean

SD

Mean

SD

1(–3)

5.9

0.78

6.09

0.33

2(–1)

5.82

0.68

6.08

0.43

3(0)

5.65

0.82

5.57

1.05

4(2)

3.62

2.28

4.02

1.89

5(4)

1.84

2.78

3.07

2.36

6(6)

1.77

2.68

2.31

2.13

7(8)

1.26

2.51

1.75

1.94

8(12)

1.23

2.44

0.52

1.66

 


Topic: Current Treatment - General

 

1314. Treatment of Alcoholic HCV Patients with Acetaminophen 4 g/Day for 5 Days Does Not Affect Hepatic Tests Compared to Placebo

J. L. Green; K. Heard; G. M. Bogdan; B. Brands; R. C. Dart 

 

Introduction:

Retrospective accounts question the safety of maximum labeled daily dose of APAP in alcoholics and in patients with hepatitis C.

 

Methods:

As part of a larger trial of APAP use in alcoholic patients, we evaluated the effect of APAP on hepatic tests in alcoholic patients who also had hepatitis C virus (HCV) antibody. This was a randomized, double-blind, placebo-controlled trial of recently abstinent alcoholics.

 

Results:

Patients were randomized 1:1 to APAP (1g every 4 hr for 4 doses x 5 days) or placebo. Exclusion criteria included a baseline serum APAP > 20 mcg/ml, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 200 IU/L, or international normalized ratio (INR) > 1.5. Laboratory measures were obtained at baseline and days 2, 4, 6, and 7. Of 141 patients (73 APAP group, 68 placebo group), 50 subjects were positive for HCV antibody (24 APAP, 26 placebo). Demographics, nutritional status and baseline measures were similar between groups (p>0.05). Baseline ALT was significantly higher in the HCV reactive group (59 ± 38 IU/L) than in the HCV non-reactive group (42 ± 32 IU/L, p>0.05). The ALT in HCV reactive patients was significantly higher throughout the study than HCV non-reactive patients (p<0.05), regardless of treatment group assignment. Of the HCV reactive subjects, the ALT increased during the trial in both groups. However, the ALT was not different between APAP and control groups. The peak ALT mean of HCV reactive subjects was on Day 7 (70 ± 55.7 IU/L in APAP group, 48.4 ± 40.4 in placebo group). Maximum reported ALT was 216 IU/L in APAP group and 246 IU/L in placebo group. Total bilirubin decreased significantly after Day 2, regardless of treatment group assignment. The INR was unaffected in either group.

 

Conclusion:

Short term treatment of alcoholic subjects with hepatitis C at the maximum labelled daily dose of acetaminophen (4 g/day) does not impact ALT.

 


Topic: Current Treatment - PegIntron

 

1315. Favorable quality of life (QoL) with albinterferon alfa-2b plus ribavirin in genotype 1, IFN-naďve, chronic hepatitis C (CHC) patients

S. Pianko; E. M. Yoshida; S. Zeuzem; Y. Benhamou; V. G. Bain; E. Pulkstenis; J. G. McHutchison; G. M. Subramanian 

 

Background/Aim

This Phase 2b, active controlled study evaluated the efficacy and safety of albinterferon alfa-2b (alb-IFN)in IFN-naďve, CHC patients. The effects of alb-IFN on subject quality of life (QoL) and disability days were compared with those of PEG-IFNa-2a (PEG-IFN).

 

Methods

458 patients were randomized and treated in 4 groups: PEG-IFN 180mcg Q1w or one of 3 alb-IFN arms (900mcg Q2w, 1200mcg Q2w or 1200mcg Q4w). The primary efficacy end-point was SVR. SF-36v.2 and the Hospital Anxiety and Depression Scale (HADS) were used to assess subject QoL and anxiety/depression. Subject disability days were evaluated by a number of missed work days or days with impaired activity. Missing data for patient reported outcomes were handled using LOCF (last observation carried forward).

 

Results

Based on ITT analysis, SVR rates were comparable (p=NS) across treatment groups. SVR in the 900Q2 was 58.5% and for PEG-IFN was 57.9%. Overall, QoL was similar or favorable for all albIFN arms compared to PEG-IFN at all timepoints assessed. At w12 and w24 on treatment, the 900Q2w cohort performed better in all 10 SF-36 domains relative to PEG-IFN. Statistically significant and clinically meaningful differences were observed in mental health (figure), bodily pain, vitality, and social functioning domains. Changes in mental health correlated strongly (r=0.7) with changes in HADS and by w12 post-treatment had recovered to baseline in 67% of 900Q2w subjects and 57% of PEG-IFN subjects. Subjects receiving alb-IFN 900Q2 experienced significantly fewer days of missed work: at w12 and 24, ~5% of 900Q2w subjects missed at least 7 days of work the previous month compared to ~20% for PEG-IFN.

 

Conclusions

The alb-IFN 900mcg Q2w dose was associated with the most favorable QoL and fewest missed work days while maintaining efficacy at least comparable to PEG-IFN.

 


Topic: Current Treatment - Pegasys

 

1316. High chance of cure in HCV genotype 1 patients with a low viral load achieving an RVR treated for 24 wks with peginterferon alfa-2a (PEGASYS®) plus ribavirin (COPEGUS®): Prospective, randomized, controlled study comparing 24 and 48 weeks of treatment

M. Yu; C. Dai; J. Huang; L. Lee; M. Hsieh; C. Chiu; N. Hou; Z. Lin; S. Chen; M. Hsieh; L. Wang; W. Chang; W. Chuang 

 

Background:

Recommended treatment for patients with HCV genotype 1 (G1) infection is Peg-IFN plus ribavirin (RBV) for 48 wks and 24 wks for HCV G2/3. A rapid virological response (RVR; <50 IU/mL HCV RNA at wk 4) is a strong predictor of sustained virological response (SVR; <50 IU/mL HCV RNA 24 wks after untreated follow-up). SVR rates of >80% with a shorter treatment duration of 12-16 wks peginterferon alfa-2a (40KD) plus RBV in HCV G2/3 pts with an RVR have questioned whether shorter treatment duration can yield high SVR rates for G1 patients with an RVR. Therefore, we determined the efficacy of 24 wks therapy to standard 48 wks treatment in HCV G1 patients with an RVR.

 

Methods:

In a controlled, multicenter, open-label study in Taiwan, 200 treatment-naive G1 patients were randomized (1:1) to 24 wks or 48 wks peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/d, with a follow-up period of 24 wks. The primary endpoint was an SVR.

 

Results:

Baseline (BL) characteristics were similar in the 24 and 48 wk arms. At BL, respectively for the 24 and 48 wk arms, male patients accounted for 57/58% of all patients, with a mean age of 49.7/49.1 years, a mean weight of 65.5/67.5 kg and with 25/19% having a BL diagnosis of advanced hepatic fibrosis (F3/4). BL log HCV RNA (IU/mL) was 5.43 (24 wk) and 5.66 (48 wk). Overall, the 48 wk arm had a significantly lower relapse rate and a higher SVR rate than the 24 wk arm (ITT). Patients with an RVR had a significantly higher SVR rate than patients without an RVR in both treatment arms. For patients with a lower BL viral load (LVL, <400,000 IU/mL) and an RVR at wk 4, the rates of relapse and SVR in the 24 wk arm was comparable to those in the 48 wk arm. MLR analysis in all patients showed that an RVR was the strongest independent factor associated with an SVR, followed by treatment duration, adherence and BL viral load. The 48 wk arm had a significantly higher rate of discontinuation than the 24 wk arm.

 

Conclusion:

In this study, high SVR rates (>96%) were seen with both 24 and 48 wks of peginterferon alfa-2a (40KD) plus RBV 1000/1200 mg/d in HCV G1 patients with a LVL and an RVR. BL viral load and an RVR at wk 4 could provide decision-making information for a shorter treatment duration for HCV G1 patients.

 

Efficacy, n (%)

24wks (n=100)

48wks (n=100)

p-value

RVR

45 (45.0)

42 (42.0)

0.669

End of treatment response

93 (93.0)

90 (90.0)

0.447

Relapse, n/N (%)

 

 

 

Overall  

Pts with LVL and RVR  

Pts with RVR  

Pts without RVR

34/93 (36.6)  

1/28 (3.6)  

5/45 (11.1)  

29/48 (60.4)

11/90 (12.2)  

0/24 (0)  

0/42 (0)  

11/48 (22.9)

<0.0001  

1  

0.056  

<0.0001

SVR, n/N (%)

 

 

 

Overall  

Pts with LVL and RVR  

Pts with RVR  

Pts without RVR

59 (59.0)  

27/28 (96.4)  

40/45 (88.9)  

19/55 (34.5)

79 (79.0)  

24/24 (100)  

42/42 (100)  

37/58 (63.8)

0.002  

1  

0.056  

0.002

 


Topic: Current Treatment – Consensus Interferon

 

1317. 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

S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C. Werner; H. Hass; 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 a lower tolerability. 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 120 patients with chronic hepatitis C and cirrhosis Child A and B (average Child score 7.9, maximum MELD score 20) . 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 57% and 27% response for Child A and B, respectively. Due to side effects CIFN had to be dose reduced in 17% and 34%, mainly due to low platelet counts. As growth factors erythropoetin as well as G-CSF was used. 11 patients experienced grade III and 7 patients 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.

 


Topic: Experimental Therapies - TMC435350

 

1318. Results Of A Phase I Placebo-Controlled Trial In Healthy Volunteers To Examine The Safety, Tolerability And Pharmacokinetics Of The HCV Protease Inhibitor TMC435350 After Single And Repeated Dosing

R. Verloes; K. Abou Farha; A. van Vliet; G. van 't Klooster; F. Aharchi; K. Marien; H. de Kock; K. Simmen 

 

Background:

This trial studied the safety, tolerability and plasma pharmacokinetics (PK) of a novel HCV NS3/4A protease inhibitor, TMC435350, after single oral dosing and, in a second step, after 5 days of oral dosing in HCV-negative volunteers.

 

Methods:

The single ascending dose (SAD) part was studied under fed conditions using two panels of 9 males or females followed by an investigation on the effects of fasting. In the multiple ascending dose (MAD) part, 4 panels of 9 volunteers were included. Each panel was designed to have 6 subjects receiving TMC435350 solution and 3 subjects receiving placebo. Safety monitoring included physical examination, vital signs, laboratory parameters (haematology, biochemistry, urinalysis), extensive cardiovascular safety (ECGs, and additional biomarkers and echocardiography during the MAD phase), and adverse events. In the SAD study a full PK profile was evaluated up to 72 h post-dose. In the MAD study, a full PK profile was studied on Days 1 and 5, with samples taken up to 72 h post-dose.

 

Results:

In the SAD study, oral doses up to 600 mg were well tolerated without attaining any dose-limiting toxicity. The plasma exposure increased in a more than dose proportional fashion. A single dose of 200 mg studied under fasted conditions was well tolerated and yielded comparable exposure to the fed condition. TMC435350 displayed good plasma exposure, with a Tmax of 4-6 hours, which together with a half-life of ~12 hours, supports once daily dosing (qd) in the MAD phase.

 

In that phase, a starting dose of 100 mg was given qd for 5 days. Subsequent doses were 200 mg qd, 200 mg bid and 400 mg qd. All doses of TMC435350 or placebo were well tolerated. There were no grade 3 or 4 adverse events and no clinically relevant changes from baseline on laboratory parameters, vital signs, ECG recordings and echocardiographic evaluations. Minor effects observed were mainly gastrointestinal tract related. Mild, short-lasting erythema was also noted after sun exposure in a few subjects receiving the 200 mg bid dose or placebo. The plasma levels of TMC435350 detected 24 hours after the Day 5 dosing were substantially in excess of the replicon EC50 value for all doses.

 

Conclusions:

·        In this phase I study, TMC435350 was safe and well-tolerated when given to HCV-negative healthy volunteers at single oral doses up to 600 mg, and at 5 days of oral doses up to 400 mg once-daily.

·        The pharmacokinetic profile of TMC435350 supports once-daily dosing.

·        This is no food effect.

·        The plasma levels of TMC435350 24 hours after day 5 dosing are substantially in excess of the replicon EC50 value for both 100 and 200 mg qd doses.

·        Minor (grade 1 only) adverse events:

o       Mainly gastrointestinal tract related.

o       Transient photosensitive reaction in some subjects (mild, short-lasting erythema).

·        TMC435350 will be further investigate following once-daily administration in HCV patients.

Mean PK parameters after single doses of TMC435350.

Dose

50 mg

100 mg

200 mg

300 mg

450 mg

600 mg

tmax, h

5

5

6

6

6

6

Cmax, ng/mL

.29

.58

2.96

5.09

10.46

13.55

AUC24h, ng.h/mL

 

3.35

 

6.28

 

30.05

 

46.38

 

125.0

 

166.70

 


Topic: Current Treatment - Consensus Interferon

 

1319. Analysis of Relapse Rates in Pegylated Interferon and Ribavirin Non-Responders Treated With Daily Consensus Interferon and Ribavirin

T. Hassanein; R. H. Ghalib; N. N. Zein; K. D. Rothstein; S. N. Joshi; P. Kwo; J. Hammond 

 

Background:

Relapse rates in HCV treatment-naďve patients treated with pegIFN/RBV occurs in over 30% of patients. A recent controlled trial of pegIFN/RBV non-responders retreated with a subsequent course of pegIFN/RBV showed a relapse rate of more than 80% and a sustained response in only 3% of patients. While several factors associated with relapse after therapy of naďve patients with pegIFN/RBV have been identified (genotype 1, high viral load, advanced histology, and non-adherence to treatment regimen), predictors of relapse after re-treatment of pegIFN/RBV nonresponders with consensus interferon (CIFN) and RBV remain unknown. Therefore, viral and host factors associated with relapse following 48 weeks of therapy with CIFN/RBV in patients who failed previous pegIFN/RBV treatment were analyzed.

 

Methods:

The DIRECT clinical trial is Phase 3, multi-center, and open-label US-based study. 27 genotype 1 patients who had an end-of-treatment response and received daily CIFN (15μg/d) and RBV (1.0-1.2 g/d) were identified for this retrospective analysis. 54% of these patients had a high baseline viral load (VL; ≥850,000 IU/mL), 41% had advanced liver disease/cirrhosis, 44% had evidence of steatosis, and a mean weight of 89kg. 59% of patients had a <2log10 drop in VL during their previous course of pegIFN/RBV therapy. Relapse was defined as VL negative at end of treatment and virus detectable at anytime within the 24-week follow-up period. No adjunctive growth factors were used. Patients had a negative VL if virus was undetectable by both bDNA and TMA assays.

 

Results:

The relapse rate in the 27 patients was 59%. The relapse rate in patients with steatosis was 83% compared to 38% in patients who did not have steatosis. Patients that achieved viral negativity by week 12 had the lowest relapse rate (33%), followed by patients that were negative by week 24 (45%). All patients that became viral negative after week 24 relapsed. There was no apparent difference in relapse rates between patients that had a null response (<2log10 drop in VL) versus a partial response (>2log10drop in VL but detectable HCV RNA) to previous pegIFN/RBV therapy (63% vs. 57%, respectively).

 

Conclusions:

Previous pegIFN/RBV non-responders treated with daily CIFN/RBV that achieved viral negativity earlier in the course of treatment were less likely to relapse. The presence of steatosis also appeared to worsen the relapse rates. Previous response to pegIFN/RBV did not appear to have an impact on relapse with retreatment with daily CIFN 15µg/d and RBV. To reduce relapse rates in this population, additional studies evaluating longer duration of CIFN and higher doses of RBV are warranted.

 


Topic: Current Treatment - General

1320. The Effect of Complete and Partial Response at Week 12 on Sustained Virologic Response: Results from Controlled Trials in Naďve HCV Genotype 1 Patients Treated With Pegylated Interferon and Ribavirin

M. L. Shiffman; H. Mansbach; J. Hammond; M. O'Neill 

 

Background:

Early virologic response (EVR) has been defined as a >2log10 decline in HCV RNA from baseline or undetectable HCV RNA at treatment week 12. However, within the context of EVR are patients who are HCV RNA undetectable at treatment week 12 (complete responders) and a second group that remains HCV RNA positive at week 12 (partial responders). Previous studies have suggested that this latter group has a significantly lower chance of achieving a sustained virologic response (SVR). We, therefore, analyzed a large database of HCV patients who received either pegIFN alfa-2a or -2b along with ribavirin (RBV) and determined the impact of EVR, complete, and partial response on SVR.

 

Methods:

A retrospective review of the active control arms (pegIFN/RBV) of two global phase 3, multi-center, randomized, parallel group, double-blinded studies in treatment-naďve patients was performed. This analysis pooled 392 genotype 1 patients, 204 of whom were treated with pegIFN alfa-2b (1.5mg/kg/wk) and 188 treated with pegIFN alfa-2a (180µg/wk). Both studies used standard weight-based doses of RBV (1.0-1.2 g/day). Week 12 response was categorized as HCV RNA negative (complete responder), >2log10 decline but HCV RNA positive (partial responder), and <2log10 decline in HCV RNA (null responder). Each category of response was evaluated with respect to its ability to achieve SVR. HCV RNA was assessed using the NGI SuperQuant assay (sensitivity to 39 IU/mL).

 

Results:

The patient population was 82% Caucasian; mean body weight 81kg; 71% high viral load (>2 million copies), and 34% with advanced fibrosis or cirrhosis (F3-4). At week 12, 56% of patients were complete responders (HCV RNA undetectable), 29% partial responders, and 15% null responders. 335 patients (85%) achieved an EVR and 54% of these patients went on to achieve an SVR. 220 of the EVR patients (66%) were complete responders, and 115 patients (34%) were partial responders. 162 (74%) of complete responders went on to achieve SVR. In contrast, SVR was achieved by only 18 (16%) of partial responders. Only 1 of 57 (2%) null responders achieved an SVR.

 

Conclusions:

Approximately 56% of genotype 1 treatment-naďve patients treated with pegIFN/RBV became HCV RNA undetectable at week 12, and 74% of these patients achieved SVR. In contrast, only 16% of patients with partial response at week 12 achieved SVR. A study to determine if SVR can be increased in partial responders (those with EVR but HCV RNA positive at week 12) by switching to a more aggressive IFN regimen at week 12 is, therefore, warranted.

 


Topic: Current Treatment - General

 

1321. Comparison of standard vs extended pegylated interferon plus ribavirin treatment according to the time of HCV RNA negative in patients with genotype 1 and high viral load.

T. Ide; T. Arinaga; I. Miyajima; K. Ogata; R. Kuwahara; Y. Koga; K. Kuhara; R. Kumashiro; M. Sata 

 

Background and aims:

Standard duration of pegylated interferon and ribavirin therapy for HCV genotype 1 and high viral load is 48 weeks in Japan. Prior trials investigating the efficacy of longer treatment duration than 48 weeks for HCV genotype 1 demonstrated high sustained virologic response (SVR) rates. Many studies extended the duration of therapy from 48 weeks to 72 weeks. However, in some patients, 72 weeks therapy might be excessive and we should set up the optimal duration of therapy. On the other hand, in patients whose HCV RNA became negative at 4 weeks, SVR can be obtained in almost 100%. These patients maintained HCV RNA negative for 44 weeks. Therefore, we designed extended the therapy which was set up to be HCV RNA negative for 44 weeks and conducted a prospective, randomized, controlled trial investigating whether this extended treatment have higher SVR rate than standard 48 weeks treatment.

 

Methods:

83 genotype 1b and high viral load (>100 KIU/ml, Roche amplicore) patients were randomized at baseline for standard (n=41) or extended (n=42) treatment group. Standard group patients received 48 weeks of treatment. Duration of extended treatment was determined by the time of HCV RNA negative to be HCV RNA negative for 44 weeks (ex. If HCV RNA became negative at week 16, total treatment duration was 60 weeks.). If HCV RNA is positive at week 24, the patient was dropped out of the trial.

 

Results:

Two patients in standard group were lost to follow-up. 9 in standard group and 8 in extended group were dropped out because of HCV RNA positive at 24 weeks. 6 in each group discontinued treatment because of the side effects and other reasons. SVR rates were 56.0% (14/25) in standard group versus 81.1% (23/28). Especially, in patients who obtained HCV RNA negative at from week 12 to week 24, SVR rate was significantly higher in extended group (standard vs extended: 35.3% vs 78.9%, P<0.05).

 

Conclusion:

Extension of treatment with pegylated interferon plus ribavirin therapy significantly increased the SVR rate in patients with HCV RNA undetectable at 12-24 of treatment.

 


Topic: Current Treatment - PegIntron

 

1322. Tolerability of Low-Dose Peginterferon alfa-2b in Hepatitis C Patients with Cirrhosis: Results from the CoPilot Trial

M. B. Shah; R. S. Brown; T. Barski; B. Freilich; R. A. Levine; N. H. Afdhal 

 

Introduction:  

Quality of life (QOL) is critical for the utilization of long term maintenance therapies. The aims of this study were to evaluate baseline QOL in patients with advanced fibrosis and to evaluate changes with Peginterferon alfa-2b (PEG-IFN) vs. Colchicine (COLC).

 

Rationale:   

Given side effects of standard doses of PEG-IFN, it is unclear whether lower-dose maintenance therapy would improve or impair QOL.

 

Methods:

475 patients with advanced Hepatitis C refractory to conventional treatment with Interferon and/or Ribavirin were randomized to receive 0.5μg/kg PEG-IFN alfa 2b weekly vs. COLC 0.6mg PO BID. QOL was assessed by administering the Medical Outcome Trust’s SF-36© survey annually throughout the study. Responses were scored using the norm-based scoring approach, where 50 is the mean for the general population and 10 is the standard deviation.

 

Results:  

Mental Component Summary (MCS) scores and Physical Component Summary (PCS) scores were calculated for each of the two groups at baseline, 48-weeks, and 96-weeks. Mean values are reported in Table 1. All demographics including age, gender, duration of disease, histology, viral load, biochemical tests, and Child Pugh classification were comparable between the 2 groups. Mean MCS and PCS scores were not significantly different between the study groups at baseline. QOL was relatively stable in the groups with no statistically significant change between baseline and week 96. Mixed procedure analysis revealed a statistically significant effect of treatment assignment only on MCS score (p = 0.02) at week 48 in the COLC group, and values returned to baseline by week 96. The actual difference in score was a modest 4-point reduction in MCS. There was no significant effect of treatment assignment on PCS over time (p = 0.16) in either group.

 

Conclusion:

Surprisingly, cirrhotic patients were not more than 1 SD below the normal population in either MCS or PCS at baseline. Treatment with low-dose PEG-IFN did not adversely affect QOL over a 2-year period in patients staying on therapy, suggesting that it can be tolerated as a maintenance therapy.

Mean MCS and PCS Scores

Randomization

Week

N

MCS Score (Mean ± SE)

PCS Score (Mean ± SE)

Colchicine

0

161

46.4 ± 0.9

42.6 ± 0.8

48

88

42.6 ± 1.3*

40.4 ± 1.2

96

69

46.2 ± 1.2

43.9 ± 1.2

PEG-IFN

0

177

44.4 ± 0.9

42.1 ± 0.8

48

106

45.3 ± 1.1

41.6 ± 1.1

96

76

43.7 ± 1.2

41.0 ± 1.3

 


Topic: Current Treatment – Consensus Interferon

 

1323. Daily consensus interferon versus peg-interferon alfa2b with weight based or 800 mg ribavirin in treatment-naive patients with chronic hepatitis C genotypes 2 or 3

F. Rahman; M. Schuchmann; H. F. Löhr; R. Link; P. Buggisch; M. Fuchs; S. Kaiser; C. Antoni; T. Witthöft; J. Schlaak; P. R. Galle; W. Bocher 

 

Introduction:

Consensus interferon (CIFN) is a synthetic type 1 interferon with enhanced in vitro activity compared to conventional IFN-alfa (IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial (PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is compared to PegInterferon (PegIFN) alfa2b plus ribavirin in genotype 2 and 3 patients.

 

Methods:

262 patients with chronic HCV infection and genotype 2 or 3 were randomly assigned to treatment with peg-IFNa2b (1,5 mcg/kg body weight once weekly, group A) or 9 mcg qd CIFN (group B) for 24 weeks. 194 patients received weight based ribavirin doses, however due to a later protocol amendment, 68 patients received a fixed ribavirin dose of 800 mg qd. Follow up was 24 weeks.

 

Results:

There were no significant differences in patient baseline characteristics between both treatment groups concerning age, gender, genotype and viral load. No significant differences were detected between both treatments at end of therapy (EoT) and for sustained virological response (SVR) rates in the intent to treat (ITT) and the per protocol (PP) analysis (ITT: 82% vs. 75% at EoT and 67% vs. 65% SVR; PP: 95% vs. 95% at EoT and 84 vs. 90% SVR). However, the CIFN group displayed a significantly lower relapse rate than group A (3% vs. 9%, p = 0,042) resulting in a slightly higher SVR rate in group B in the PP analysis. Furthermore, no difference in the treatment outcome was found between weight based or fixed ribavirin dose regimens. Treatment was well tolerated in both treatment groups, despite more dose modifications for leucopenia in group B (9% vs. 3%, p = 0,015) without an increased discontinuation rate.

 

Conclusions:

In treatment-naive patients with chronic hepatitis C and genotype 2 or 3, daily treatment with CIFN combined with ribavirin has similar antiviral efficacy and safety profile as weight adjusted PegIFNa2b.

 


Topic: Current Treatment – Consensus Interferon

 

1324. Daily consensus interferon versus peg-interferon alfa2b with weight based ribavirin in treatment-naive patients with chronic hepatitis C genotype 1

F. Rahman; M. Schuchmann; H. F. Löhr; R. Link; P. Buggisch; M. Fuchs; S. Kaiser; C. Antoni; T. Witthöft; J. Schlaak; P. R. Galle; W. Bocher 

 

Introduction:

Consensus interferon (CIFN) is a synthetic type 1 interferon with enhanced in vitro activity compared to conventional IFN-alfa (IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial (PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is compared to PegInterferon (PegIFN) alfa2b plus ribavirin.

 

Methods:

310 patients with chronic HCV genotype 1 infection were randomly assigned to 48 weeks of treatment with: PegIFNa2b induction regimen (group A: 2 weeks IFNa2b 10 -> 5 MU qd, followed by 36 weeks peg-IFNa2b 1,5 mcg/kg x week plus ribavirin); PegIFNa2b standard regimen (group B: 48 weeks Peg-IFNa2b plus ribavirin); CIFN induction regimen (group C: 12 weeks CIFN 27 -> 18 mcg qd, followed by 36 weeks CIFN 9 mcg qd plus ribavirin); or CIFN standard regimen (group D: 48 weeks CIFN 9 mcg qd plus ribavirin). Follow up was 24 weeks.

 

Results:

There were no significant differences in patient baseline characteristics between treatment groups concerning age, gender and viral load. In the intent to treat (ITT) analysis, group D displayed reduced sustained virological response rates (SVR), although due to limited statistical power this was not statistically significant (A: 39%, B: 40%, C: 37%, D: 29%). Drop out rates were 13-19% in the qd treatment regimens A, C and D. In the per protocol analysis (PP), both PegIFN groups had lower end of treatment responses compared to the CIFN groups (A: 58%, B: 58%, C: 84%, D: 70%). However, due to higher relapse rates in the CIFN groups, no significant differences were found in the SVR. All four regimens were similarly well tolerated with 3-9% adverse events (AE) -related treatment discontinuations. However, group C displayed a higher rate of dose reductions due to AE, mainly during the induction phase.

 

Conclusions:

Thus, in treatment-naive patients with chronic hepatitis C and serotype 1 infection, daily CIFN could not increase SVR rates over those of PegIFN alfa2b due to higher relapse rates. Moreover, neither IFN alfa2b nor CIFN induction therapy increased cure rates in these patients compared to the standard regimen.

 


Topic: Diagnostic Tools

 

1325. Correlation between liver biopsy and FibroSURETM during screening for a Phase II study to assess the antifibrotic activity of Farglitizar in chronic hepatitis C infection

K. Patel; J. G. McHutchison; Z. D. Goodman; D. Theodore; A. Webster; M. Schultz; B. Stancil; M. Gartland; S. Gardner 

 

Background:

Non-invasive biomarkers have been proposed as an alternative to liver biopsy for initial staging and assessing changes in fibrosis with therapy in chronic hepatitis C (CHC) patients. Our aims were to assess the utility of the FibroSURE panel in staging fibrosis during screening for enrollment into a multicenter phase II, placebo-controlled, antifibrotic study of a PPARγ agonist (Farglitizar) in CHC infection.

 

Methods:

482 adult CHC non-responder patients with compensated liver disease had a screening biopsy, and FibroSURE (FS) assay obtained through a central laboratory. Liver biopsy assessment for Ishak staging was performed independently by a single central histopathologist; subjects with Ishak stages 2-4 were subsequently randomized into the study. Screening data were analyzed to determine the accuracy of FS for predicting Ishak fibrosis stage.

 

Results:

CHC patients were mostly Caucasians (363/482;75%), male (297/482; 62%) and with a mean age 52 ±6.7 yrs. Mean biopsy length was 22.6 ±11.4 mm. Overall Spearman correlation for Ishak stage and FS, r=0.38 (CI,0.31 – 0.47;p<0.0001); weighted Kappa = 0.15 (CI, 0.11 – 0.19; p<0.0001). FS demonstrated good sensitivity but relatively poor performance for the detection of moderate-to-severe stage (F3-F6) disease (AUC=0.69). For FS detection of cirrhosis (F5-F6), AUC=0.73, r=0.25 (95% CI, 0.16 – 0.34). For FS index scores 0.32-0.58 that predicted stage F2-F3 disease, biopsy indicated F0-F1=53/134 (40%), F2-F3=72/134 (54%), and F4-F6 = 9/134 (7%).

 

Conclusions:

Non-invasive serum biomarkers such as FibroSURE demonstrate good performance for exclusion of significant disease. However, their utility in differentiating moderate stage disease is relatively poor, and this may limit their ability to accurately follow changes in fibrosis stage with treatment. This will be further evaluated based on follow-up biopsies at the end-of-treatment in this study.

Performance characteristics of FibroSURE for detection of moderate and advanced disease

Ishak Fibrosis stage

Prevalence

FS Index Score

Sensitivity

Specificity

PPV

NPV

AUC(SE)

F3-F6

40%

≥0.32  

(n=386)

0.90

0.27

0.45

0.80

0.69(0.02)

F4-F6

15%

≥0.59  

(n=252)

0.80

0.53

0.23

0.93

0.70(0.03)

F5-F6

8%

≥0.73  

(n=151)

0.70

0.72

0.19

0.96

0.73(0.03)

AUC, Area under ROC curve

 


Topic:Treatment - General

 

1326. A 52 week multi-centre, randomized, double-blind placebo-controlled trial evaluating the efficacy and safety of glycyrrhizin in patients with chronic hepatitis C not responding to IFNα or PEG-IFN plus ribavirin therapy

M. P. Manns; I. G. Bakulin; N. P. Blokhina; N. I. Khomutjanskaja; H. Wedemeyer; T. Roskams; H. P. Dienes; M. Hasebe; J. V. Platon; F. Baschiera 

 

Background:  

A significant number of patients with chronic hepatitis C genotype 1 fail to respond to the standard therapy of PEG-IFN-α plus RBV, or cannot be treated for various reasons. There are no options for non-responders to previous standard therapies. Glycyrrhizin (GL) is used in Japan for more than 20 years to treat such cases (SNMC, Minophagen). Studies in non-Asian patients are missing.

 

Objectives:  

Confirm efficacy (based on ALT and histology) and safety of GL in non-responders to combination therapy.

 

Methods:

The trial consists of 2 phases (12 plus 40 weeks). Phase 1 is a randomized, double-blind, placebo-controlled, parallel group comparison of i.v. injections of GL (200 mg glycyrrhizic acid), administered intravenously 5x/ and 3x/ week, or 5x/ week placebo, for 12 weeks. The following phase 2 is a randomized, open comparison of GL 200 mg administered iv 5x/ versus 3x/ week, for 40 weeks (no placebo for ethical reasons). Adaptive design plan and 2 primary efficacy endpoints: 1 - proportion of patients with ≥ 50% ALT reduction after 12 weeks, and 2 - proportion of patients (>60%) with improved necroinflammation score after 52 weeks. Inclusion criteria: pos. HCV-RNA, non-response or relapse to IFNα or PEG-IFN plus ribavirin, abnormal ALT, liver biopsy at entry or performed within 6 months. In this study were enrolled 374 patients from 2002 to 2004, (5x/week GL, 3x/week GL, and placebo with N= 123, 127, and 129, respectively.), carrying genotype type 1 in 73 % of cases. Baselines (mean, SD): ALT 77 ±49 IU/L, necroinflammation score 7.6 ± 2.5, fibrosis score 3.1 (±1.8).

 

Results:

The rate of ALT reduction ≥ 50% after 12 weeks was significantly higher with 5x/week GL (30%, p = 0.000003) and 3x/week GL (32%, p = 0.000001) compared to placebo (6%). Significant ALT (mean; 95% CI) decrease under active treatment (-33 % -40 to -25) and (-27 %; -33 to -21) respectively, but not under placebo (1 %; -8 to +10).

 

The rate of patients with an improvement in HAI necroinflammation score after 52 weeks of treatment was 34.6% in the 5x/week GL (n=53 patients, p = 1.000) and 32.2% in the 3x/week GL group (n=48 patients, p=1.0).  Thus, the second formal primary endpoint (>60% of patients with improved necroinflammation) could not be reached.  Considering cases with no further deterioration as success, rates increased to 63% and 61% respectively.

 

Fibrosis score (architectural changes, fibrosis and cirrhosis):  Improvement or no further deterioration in 67% of patients.  Improvement was higher with 5x/week GL compared to 3x/week GL (37% vs. 29%). 

 

There were no remarkable changes in HCV viral load during the double-blind and open phase and no remarkable differences between treatment groups. 

 

Quality of life including health change assessments showed slight improvements in all treatment groups during both treatment phases.  Improvements appeared to be more pronounced in patients receiving GL than receiving placebo (double-blind phase) and more pronounced in patients receiving 5x/week GL than those receiving 3x/week GL. 

 

Conclusion:

The study results show a statistically significant (compared to placebo) reduction of elevated ALT-levels by GL, which was maintained during the entire study duration.  Treatment with 5x/week GL appeared to be slightly more effective than 3x/week GL (mean ALT reduction -33% vs.-27%, NS).  The results of the liver biopsies showed positive effects of GL on necroinflammation and fibrosis if ‘no worsening’ is considered a positive effect-which should be, since chronic hepatitis C in general is a progressive disease.

 


Topic: Current Treatment - Pegasys

 

1327. Comparison of peginterferon alfa-2a and ribavirin for 12 or 24 weeks in patients with HCV genotype 2 or 3: the CLEO trial

F. Mecenate; G. Barbaro; A. Pellicelli; A. Barlattani; E. Mazzoni; M. Bonaventura; M. Romano; L. Nosotti; P. Arcuri; A. Picardi; G. Barbarini; F. Soccorsi 

 

Background:

In chronic hepatitis C (CHC) patients with genotype 2 or 3, 24 weeks treatment with peg-interferon and ribavirin induces a sustained virological response (SVR) in about 80% of the cases. Recent trials have shown that a similar response rate may be obtained with a shorter treatment period (12 or 16 weeks), especially in patients with rapid virologic response (RVR).

 

Aim:

Primary endpoint of the study was to assess whether 12 week treatment with peg-interferon and ribavirin is as efficacious as 24 week treatment in inducing a SVR in CHC patients with genotype 2 or 3. Secondary endpoint was the rate of relapsers among groups.

 

Methods:

We performed a multicenter, prospective, randomized trial on 180 histologically confirmed CHC patients with genotype 2 or 3 enrolled in 11 italian centers. All patients were treated with peg-interferon alpha2a (180 mcg/week) and ribavirine (800-1200mg/day). After 4 weeks of treatment, the patients with HCV-RNA <600 UI/ml (RVR) were randomized either to 12 weeks (Group A1; n=60) or to 24 weeks (Group A2; n=60) of combination therapy in a 1:1 ratio. The patients without RVR continued standard 24 weeks combination therapy (Group B n=60). In all groups of patients HCV-RNA was checked 12 and 24 weeks after the end of therapy.

 

Results:

At the end of the study period SVR was observed in 84% of patients of Group A1, in 74% of patients of Group A2 and in 54% of patients of Group B (P<0.05 vs Groups A1 and A2). Relapsers rate at the end of the study period was 3% in Group A1, 2% in Group A2 and 6% in Group B. Logistic regression analysis showed that baseline HCV-RNA< 1 million/UI/ml (OR: 3.5; P<0.001), a baseline histological inflammation score <7 (OR:2.5; P<0.001), a fibrosis score <2 (OR: 3.3; P<0.001) and a RVR <4 week (OR: 3.5; P<0.001) were the strongest covariates predictive of SVR.

 

Conclusions:

In CHC patients with genotype 2 or 3, 12 week combination therapy is as efficacious as 24 week therapy. A RVR is an independent covariate predictive of SVR along with low baseline HCV levels and a low baseline histological inflammation and fibrosis score without significant differences in the rate of relapsers.

 


Topic: Current Treatment - Pegasys

 

1329. Viral Kinetics Of HCV Genotype 4 During Pegylated Interferon Alpha 2a –Ribavirin Therapy

M. F. Derbala; N. Z. El Dweik; S. R. Al Kaabi; A. D. Al Marri; A. Bener; F. Shebl; A. M. Amer; M. T. Butt; R. Yakoob; M. Al Mohanadi; M. Al Khinji 

 

Background:

Kinetics of Hepatitis C virus (HCV) during pegylated Interferon (PEG-IFN) and early monitoring of viral decline were recently described to predict treatment outcomes and in turn reduce the course of treatment, adverse effects and cost. There is limited information on the viral dynamics of HCV-4.

 

Aim:

To follow the HCV-RNA kinetics during Peg-IFN-α2a and Ribavirin therapy and the best time for predicting SVR in genotype 4 patients.

Methods: Serum HCV-RNA levels before initial dosing, 24h later then at weeks 1, 4, 12, 24, 48 and 72 were assessed in 84 HCV genotype 4 patients treated weekly by PEG-IFN alpha2a 180microgram and daily Ribavirin(1000-1200mg).

 

Results:

At the end of treatment, out of the 84 treated patients, 19 (22.6%) were non-responders while 65 (77%) showed end of treatment response (ETR). However 9 patients relapsed (9.5%), thus the sustained viral response (SVR) was observed in 57 patients (67.9%). Younger patients were more likely to attain SVR, where the odds of SVR increased by a factor of 0.94 for each year increase in age (95% CI 0.90, 0.99, p=0.019). Although a significant negative correlation between stage of fibrosis and rate of viral decline at week 1 &4 (p <0.005 & 0.001, respectively) was seen, neither fibrosis stage (X2 =3.4882, p>0.1) nor grade of inflammation (X2= 0.0057, p >0.1) significantly predicted response to treatment. Non-responders had no or only a limited decline at week 1 and week 4, whereas sustained virological responders had a significant decline both at week 1 and week 4.Area under (ROC) curve revealed that week 12 is better than any other time point in predicting SVR (AUC 0.97; 95% CI 0.94, 1.01), (sensitivity 98.3%; 95% CI 90.7, 99.9), (specificity 88.5%; 95% CI 71.0, 96.0), positive predictive value (PPV) of 94.9% and negative predictive value (NPV) of 95.8%. A drop of more than 1.17 log viral load at week 1 and viral clearance or decline >3log at week 4 were considered as the earliest predictors of SVR.

 

Conclusion:

In genotype 4 patients, while failure to achieve an EVR at week 12 predicts non-response, and RVR at week1 & week 4 98% guaranteed SVR. These findings further re-enforce the value of week 12 in the course of IFN treatment. Genotype 4 patients who show significant viral clearance (>1.17 log viral load) by the first week of treatment and viral clearance >3log by week 4 are expected to show SVR and would therefore be assigned to a shorter drug regimen lasting for 24 weeks. Those unfortunate cases who do not achieve viral clearance by week 1 or week 4 should not be deprived from treatment but rather given more time till week 12 before being classified as non-responders.

 


Topic: Disease Progression

 

1330. Effects of chronic HCV infection on health-related quality of life and fatigue: the role of liver fibrosis progression

G. Teuber; A. Schaefer; J. Rimpel; K. Paul; C. Keicher; M. Scheurlen; S. Zeuzem; M. R. Kraus 

 

Background and Aims:

Health-related quality of life (HRQoL) is significantly impaired in patients with chronic hepatitis C. However, only few studies have been published investigating the relationship between the stage of liver disease and quality of life and revealed conflicting results. Therefore, we investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV) infection in relation to the degree of fibrosis while controlling for the influence of relevant demographic and medical variables.

 

Patients and Methods:

HRQoL and fatigue were assessed in a cross-sectional multi-center study including a total of 215 consecutive outpatients (92 women and 123 men, mean age 46.7) with chronic HCV infection using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the German version of the Fatigue Impact Scale (FIS-D). Applying multiple linear regression analyses, the contribution to the variability of these psychometric scores was evaluated for the degree of fibrosis (Ishak Score) as well as viremia, gender, age, mode of transmission, genotype, and ALT.

 

Results:

Concerning HRQoL, there was a strong negative association between the degree of liver fibrosis and the physical SF-36 summary score (p=0.016), mainly due to the subscale “general health” (p=0.046). No such relationship was found with respect to the mental domain of SF-36. These effects were independent of the covariate age, also significantly predicting physical HRQoL (p=0.001). Similarly, the absolute FIS score – including the subscale “physical functioning” (p=0.011) – was significantly increased in patients with advanced fibrosis (p=0.043), indicating a higher burden of fatigue symptoms. A further noticeable finding was the more pronounced impairment of the mental SF-36 summary score (p=0.007) and fatigue (p=0.017) in females. However, the psychometric scores of HRQoL and fatigue were found to be unrelated to viremia, mode of transmission, genotype and ALT levels.

 

Conclusions:

The present study suggests a significant association of the physical aspects of both HRQoL (SF-36) and fatigue (FIS-D) with the extent of fibrosis in patients with chronic hepatitis C while viral factors such as viremia and genotype exert no significant effect. Female HCV patients were particularly affected by impaired mental components of HRQoL and fatigue, possibly indicating gender-specific aspects of coping. Our findings stress the need for considering fibrosis stage for the identification and management of HCV patients at risk for reduced physical HRQoL.

 


Topic: Experimental Therapies - Thymosin

 

1331. Retreatment of treatment experienced HCV patients with pegylated interferon alfa-2a and thymosin alpha-1: Pooled analysis of two randomized controlled trials

K. E. Sherman; S. C. Gordon; R. Iftikar; M. Rodriguez-Torres; V. K. Rustgi; A. M. Di Bisceglie 

 

Background:  

Management of HCV-infected treatment non-responders remains a significant clinical challenge. Early pilot studies suggested that an immunomodulatory peptide, thymosin alpha-1 (TA-1) may play a role in enhanced viral clearance, histologic improvement and sustained viral response (SVR). We performed two parallel randomized controlled trials to evaluate efficacy of TA-1 in this difficult to treat population.

 

Methods:

Both trials had similar designs. Patients were randomized to receive either pegylated interferon alfa 2a 180 mcg (PEG) SQ qweek + TA-1 for 48 weeks, or PEG with placebo TA-1 for 48 weeks. One trial (803) permitted subjects with mild fibrosis through bridging fibrosis (Metavir F1-3) while the other (804) enrolled subjects with more advanced baseline fibrosis (F3 or F4). Each trial planned enrollment of at least 500 subjects with a 1:1 randomization between TA-1 and placebo TA-1. Baseline and post-treatment liver biopsies were obtained.

 

Results:

Cumulative enrollment in the two trials was 1061 subjects. Nearly all were genotype 1 (93.5%), and 83% had previously failed treatment with interferon alfa + ribavirin and 17% with interferon alfa alone. HCV RNA viral load at baseline was similar between the two trials and averaged log 6.2 copies/ml. 71% of subjects were male and their mean age was approximately 50 years. By intention-to-treat analysis (ITT), viral clearance at week 48 occurred in 74/533 (13.9%) of subjects treated with PEG + TA-1 vs. 76/528 (14.4%) in the control arm. SVR was observed in 13 subjects (2.4%)in the active treatment arm and 9 subjects (1.7%) in the placebo arm (not significant). The proportion of patients demonstrating an improvement of Knodell Histologic Activity Score (HAI) by 2 or more points was similar in treatment and control groups. Decreases in circulating CD4 lymphocytes were lower among subjects with more advanced fibrosis who received TA-1 vs those receiving placebo. Treatment emergent toxicities were similar between treatment groups.

 

Conclusion:

·        Among treatment experienced subjects with HCV infection, retreatment with PEG + TA-1 resulted in a similar sustained virologic response when compared to use of PEG monotherapy, and is not effective in the management of prior non-responders.

·        Studies utilizing PEG, TA-1 and ribavirin are in progress.

 


Topic: Current Treatment – Consensus Interferon

 

1332. U.S. multicenter pilot study of daily consensus interferon (infergen) plus ribavirin for “difficult-to-treat” HCV genotype 1 patients: tolerance and on-therapy virologic response.

S. B. Ho; B. Aqel; E. Dieperink; L. Tetrick; Y. Falck-Ytter; C. A. de Comarmond; C. I. Smith; D. McKee; A. A. Mihas; W. Boyd; C. C. Kulig; M. Pedrosa; E. J. Bini 

 

Introduction:

Patients in the U.S. with HCV genotype 1 respond poorly to treatment with pegylated interferon alfa and ribavirin (RBV). Consensus interferon (CIFN; infergen, interferon alfacon1) demonstrates enhanced activity in vitro compared with other alfa interferons. Genotype 1 patients may benefit from an interferon with increased activity, more favorable viral kinetics from daily dosing, and a longer duration of therapy.

 

Purpose:

To determine the efficacy and safety of daily CIFN+RBV for initial treatment of patients with HCV genotype 1 and other “difficult-to-treat” characteristics.

 

Methods:

Patients with HCV genotype 1 were prospectively enrolled in 7 Veterans Affairs (VA) and 2 private medical centers. Patients were randomized to treatment with daily CIFN (15 mcg/d sq) and RBV (1-1.2 gm/d PO) given for (A) 52 weeks, vs (B) 52 to 72 weeks (from time of initial virologic response + 48 wks). Treatment is discontinued if HCV RNA is detectable at wk 24.

 

Results:

64 patients initiated treatment (92% male, 33% African American, 78% VA, 67% high viral load, 59% stage III-IV fibrosis, mean body weight 92.5+2.1 kg). ITT analysis of 64 patients with virologic data through 24 wks indicated that 43 (67%) achieved undetectable viral levels; overall 21 (33%) demonstrated a rapid virologic response (RVR) at 4 wks, 16 (25%) were early virologic responders between 8-12 wks, and 6 (9%) were late virologic responders between 12-24 wks. During treatment 27 (42%) patients required CIFN dose reduction and 18 (28%) required RBV dose reduction. Five patients were discontinued at 24 weeks due to virologic non-response. Overall early discontinuation of treatment before 24 wks occurred in 22/64 (34%) patients (9 due to intolerance; 10 due to noncompliance; 1 due to chest pain; and 2 due to cellulitis). This is comparable with the 32% discontinuation rate reported in a large VA cohort treated with interferon alfa-2b+RBV (J Viral Hep 2006;13:242). Final ETR and SVR data are pending.

 

Conclusions:

Patients with hepatitis C genotype 1 and “difficult-to-treat” characteristics treated with daily CIFN+RBV demonstrated a high RVR rate, with 33% virus-negative at 4 wks and 67% virus negative by 24 wks. This compares favorably with RVR rates of 19-22% for genotype 1 patients treated with pegylated interferon alfa-2a and ribavirin (Gastroenterology 2006;130:1086 and 131:451). Although adherence and tolerability are limitations, these data indicate that daily CIFN+RBV for initial treatment of U.S. genotype 1 patients have promise primarily via an enhanced RVR rate. (Supported by Valeant Pharmaceuticals; Veterans Affairs Research Service)

 


Topic: HIV/HCV Coinfection - Pegasys

 

1333. Outcomes in HIV-HCV Co-infected Genotype 1 Patients Treated with Peginterferon alfa-2a (40KD) plus Ribavirin (RBV) 1000/1200 mg/d: Predictions Based on a Generalized Additive Model (GAM)

F. Torriani; M. Rodriguez-Torres; J. Rockstroh; E. Snoeck; K. Jorga; D. T. Dieterich 

 

Background:

It is now well established that HCV genotype 1 (G1) mono-infected patients benefit from starting RBV at a dose of 1000/1200 mg/d instead of the lower 800 mg/d dose used in earlier studies. In the APRICOT trial, HIV-HCV co-infected patients were treated with peginterferon alfa-2a (40KD) plus RBV 800 mg/d for 48 weeks. The 800 mg/d dose of RBV was selected to minimize hematologic toxicity and the potential for drug–drug interactions with nucleoside reverse transcriptase inhibitors. In APRICOT, the rate of SVR was 40% overall and 29% in G1 patients. We modeled the probability of SVR and anemia in co-infected G1 patients and predicted the outcomes for treatment with RBV 1000/1200 mg/d.

 

Methods:

Binary data from 176 G1 patients in APRICOT were incorporated into an existing generalized additive model (GAM) established with data from 817 mono-infected G1 patients enrolled in two phase III clinical trials. The effect of prognostic factors on SVR and anemia (Hgb <10 g/dL) were analyzed and simulations run with the updated GAM to predict SVR and the incidence of anemia in co-infected G1 patients treated with peginterferon alfa-2a (40KD) plus RBV 1000/1200 mg/d. Uncertainty was quantified by ‘bootstrapping’.

 

Results:

After incorporating data from APRICOT, significant predictors of SVR retained in the model included baseline (BL) viral load, RBV dose (mg/kg), age, BL ALT quotient, histological diagnosis (cirrhosis vs no cirrhosis) and HIV status (yes vs no). BL factors predictive of anemia included BL Hgb level, RBV dose (mg/kg), age, sex, HIV status, BL ALT quotient and BL viral load. Use of RBV 1000/1200 mg/d in co-infected G1 patients is predicted to increase the SVR rate by 8% (from 29% to 37%) and the incidence of anemia from 14% to 23% (Table).

 

Conclusions:

Our simulations suggest that increasing RBV dose to 1000/1200 mg/d, would improve SVR rates in patients co-infected with HIV and HCV G1. However, higher doses of RBV would also be associated with a higher incidence of anemia. Therefore, Hgb levels should be monitored closely and the RBV doses should be decreased in small decrements to preserve chances for higher end of treatment responses and to prevent relapses.

Predicted outcomes after 48wks treatment with PegIFN alfa-2a/RBV in G1

RBV dose (mg/d)

800

1000 (<75kg) or 1200 (≥75kg)

Predicted median SVR (%, 95% CI)

 

 

HCV mono-infection

41 (36-45)

49 (45-53)

HIV-HCV co-infection

29 (23-35)

37 (29-45)

Predicted median incidence of anemia (%, 95% CI)

 

 

HCV mono-infection

7 (5-9)

13 (11-15)

HIV-HCV co-infection

14 (11-17)

23 (18-30)

Anemia=Hgb <10 g/dL; SVR=undetectable HCV RNA (<50 IU/mL) at wk72

 


Topic: Experimental Therapies - R7025

 

1377. A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Escalating Single Doses of R7025, a Novel Pegylated Interferon α Compared to Placebo and Peginterferon α 2a (40KD) (PEGASYS®) in Healthy Volunteers

B. Brennan; R. Robson; I. Rodriguez; J. Symons; J. Huang; M. Chan; S. Blotner; N. Jennings; B. Rawal; M. Brunda; G. Hooper; A. Rakhit 

 

Background:

Pegylated interferon (PEG-IFN) in combination with ribavirin is the standard of care for patients with chronic hepatitis C (CHC). However, treatment is not yet optimal in patients infected with HCV genotype 1 with sustained viral response rates of ~50%. R7025 is a novel human pegylated IFNα molecule generated using DNA Shuffling (Maxygen, Inc.) technology that exhibits ~50-fold higher antiviral activity compared to PEG-IFNα-2a, but only 2- to 10 fold greater antiproliferative activity in vitro. R7025 contains the identical branched chain 40KD PEG molecule used in the synthesis of PEG-IFNα-2a. The primary objective of this study was to evaluate the safety, tolerability, PK and PD activity of single ascending doses of R7025 in healthy volunteers.

 

Methods:

In each cohort, subjects were randomized to receive a single dose administered subcutaneously in the abdomen according to the following scheme: 8:R7025, 2:placebo, 2:180 μg PEG IFNα-2a. Subjects were evaluated frequently for safety, tolerability, PK and PD assessments. The following dose levels were evaluated 1, 5, 20, 40, 80 and 120 µg.

 

Results:

12 subjects were enrolled and completed the study:

·        8 received R7025

·        2 received placebo

·        2 received pegylated interferon alfa-2a 180 ug (positive control)

 

The PD markers, serum neopterin and 2’,5’-oligoadenylate synthetase (2,5 OAS) levels were increased in subjects who received a 20- 120 µg dose of R7025. Doses of 40 µg and higher produced a similar level of PD induction as a 180 μg dose of PEG IFNα-2a. Serum exposure (Cmax and AUC) of R7025 increased with dose and was sustained over 168 hrs, supporting a minimum of once weekly dosing. Doses up to 80 µg were well tolerated with most adverse events rated (AEs) as mild or moderate. No serious AEs have been reported. In the 120 µg group, 4/8 R7025 treated subjects experienced severe flu-like symptoms, which were adequately controlled with analgesics and fully reversible. Most subjects who received 20-120 µg of R7025/placebo exhibited a reversible decrease in neutrophils but only grade 1/2 changes in neutrophils were observed.

 

Conclusions:

·        R7015 doses ≥ 20 ug produced similar levels of PD marker induction to 180 ug dose of pegylated interferon alfa-2a

·        Most adverse events were mild and consistent with those absorbed after administration of other IFNa’s

·        At a dose  120 ug transient severe flu-like symptoms were observed.

·        Changes in haematological parameters observed across all doses were mild and reversible. 

 


Topic: Treatment – Herbal Treatment

 

1383. Botanical Medicines for Hepatitis C

S. J. Polyak; J. Wagoner; O. Kane; M. Austin; D. Lee; C. Morishima 

 

Background:

A striking feature of hepatitis C virus (HCV) infection is its propensity to establish a chronic disease state. Because state-of-the art antiviral treatments are costly, have serious side-effect profiles, and moderate probabilities for durable cures, many patients opt for complementary and alternative medicine (CAM)-based approaches to improve liver health. However, mechanisms of action studies are lacking to support the use of CAMs for management of chronic hepatitis C.

 

Methods:

In the current study, we examined two widely used botanicals, silymarin and sho-saiko-to (SST), for antiviral and immunomodulatory actions.

 

Results:

Silymarin inhibited expression of TNF-α in anti-CD3 stimulated human PBMC and NF-κB dependent transcription in human hepatoma Huh7 cells. Moreover, both silymarin and SST dose-dependently inhibited infection of Huh7 and Huh7.5.1 cells by JFH-1 virus. Both compounds also displayed prophylactic and therapeutic effects against JFH-1 infection, and when combined with IFN-α, inhibited HCV replication more than IFN-α alone. Antiviral effects induced by Silymarin involved Jak-Stat dependent and independent signaling, while SST enhanced ISRE transcription via p38 MAP kinase activation. HPLC fractionation of the herbal preparations permitted identification of the components eliciting antiviral actions.

 

Conclusions:

The data demonstrate that standardized silymarin and SST have antiviral action against in vitro HCV infection, and that silymarin has immunomodulatory and anti-inflammatory actions. Therefore, CAM-based approaches may assist in the management patients with chronic hepatitis C.

 


Topic:Treatment - General

 

1384. SVRScore: a Novel and Highly Predictive Score for SVR Prediction in Chronic Hepatitis C Genotype 1 Infected Patients

P. Halfon; G. Pénaranda; M. Bourličre; A. Tran; D. Botta-Fridlund; I. Portal; C. Renou; M. Picon; C. Wartelle; J. Arpurt; M. Antoni; M. Guisset; C. Gueyffier; P. Delasalle; D. Ouzan 

 

Background:

Previous studies demonstrated that viral load (VL) is an important predictor for treatment outcome in patients with chronic hepatitis C virus (CHC). We looked at pre-treatment (BL) VL, and week 4 VL (W4) to assess a predictive score achieving probability of sustained virological response (SVR) in CHC genotype 1 patients: the SVRScore.

 

Patients-Methods:

113 CHC genotype 1 patients were included in the study among which 86 patients achieved complete 48 weeks treatment (54 had an SVR). Patients were treated with PEG-IFN alpha2b+RBV. Serum HCV RNA was measured using COBAS TaqMan HCV Test (TaqMan HCV; Roche Molecular Systems Inc., Branchburg, N.J.). Binary logistic regression analysis was assessed with BL VL and W4 VL as predictors of SVR, to obtain the SVRScore.

 

Results:

In univariate analysis BL VL and W4 VL were both associated with SVR (p<.0001 and p<.01 respectively). In multivariate analysis, BL VL and W4 VL were both independent predictors of SVR (respective odds ratio 0.29 (95% CI 0.09-0.95), and 0.39 (0.24-0.63). From the binary logistic regression, we calculated the SVRScore combining BL VL and W4 VL (cf. formula below).

 

Area under the ROC curve for SVR prediction was of 0.89 and positive predictive value of SVR was 86% (44/51).

 

Conclusions:

·        We developed the SVRScore, a new, simple, and highly predictive score for SVR prediction in CHC genotype 1 infected patients.

·        With high predictive values the SVRScore remain useful for the treatment management of CHC infected patients.

·        In the near future an analysis will be conducted to validate the SVRScore on an independent cohort.

 

 


Topic: Experimental Therapies - GS-9190

 

1385. GS-9190, a novel substituted imidazopyridine analogue, is a potent inhibitor of hepatitis C virus replication in vitro and remains active against known drug resistant mutants.

I. Vliegen; J. Paeshuyse; E. Marbery; B. Peng; I. Shih; L. S. Lehman; H. Dutartre; B. Selisko; B. Canard; S. Bondy; W. Tse; H. Reiser; E. De Clercq; W. A. Lee; G. Puerstinger; W. Zhong; J. Neyts 

 

Background and Aims:

Following lead optimization of a novel series of substituted imidazopyridines, GS-9190 was identified as a promising drug candidate based on its potent inhibition of in vitro HCV RNA replication and excellent selectivity index. The aim of this study was to characterize the biological activity of GS-9190 against HCV replicons of different genotypes and against various drug resistant mutants. GS-9190 was also studied in combination with known anti-HCV agents.

 

Methods:

The antiviral activity of GS-9190 was evaluated in HCV genotypes 1b, 1a and 2a replicon cells, in the JFH1 (genotype 2a) infectious system, and against several related and unrelated viruses. Cytotoxicity of GS-9190 was determined in a panel of cell lines. A transient replication assay using Lunet cells (Huh-7) was used to characterize susceptibility of known drug resistant mutants to GS-9190. Combinations of GS-9190 with other HCV agents were evaluated in the genotype 1b (Con-1) replicon cells.

 

Results:

GS-9190 is a potent inhibitor of HCV genotype 1b and genotype 1a replicon replication (EC50 = 0.6 and 2.5 nM, respectively). The 50% cytostatic concentration of GS-9190 in various cell lines is > 50µM, illustrating a high degree of selectivity (SI > 20,000). GS-9190 has lower potency against a genotype 2a replicon or against the JFH1 infectious virus (EC50 ~ 1 µM) and is inactive against a number of related and unrelated viruses. Replicons resistant to various HCV protease and polymerase inhibitors remained fully susceptible to GS-9190. The combination of GS-9190 with either IFN-α or several HCV protease and polymerase inhibitors resulted in an additive antiviral activity. The combination of GS-9190 with a protease inhibitor was more efficient in clearing hepatoma cells from their replicon than either agent alone. Following long-term culture with increasing concentrations of GS-9190, resistant replicons were selected. Transfection of naďve Lunet cells with total RNA isolated from the GS-9190res replicon cells transferred drug resistance, indicating that resistance is associated with the viral genome. In biochemical assays, GS-9190 is inactive against HCV NS3 serine protease, NS3 RNA helicase, and NS5B polymerase (either in initiation or elongation assays).

 


Topic: Experimental Therapies - ITM-191

 

1386. Genotype Coverage of the HCV NS3/4A Protease Inhibitor ITMN-191 (R7227): Biochemical Data Reveals Potent Inhibition and Slow Dissociation with Genotype 1-6 Proteases

P. Rajagopalan; S. Stevens; A. Stoycheva; B. Brandhuber; H. Zhang; M. Gale; L. M. Blatt; S. Seiwert; K. Kossen 

 

Background:

Combination therapy for chronic hepatitis C with pegylated interferon alfa and ribavirin (SoC) results in a Sustained Virologic Response (SVR) rate of approximately 50%. Direct antiviral agents may improve the rate of SVR when used in combination with SoC or in novel regimens. A desired characteristic of potential therapeutics is the ability to function against multiple HCV genotypes. ITMN-191 is a potent HCV NS3/4A protease inhibitor in clinical development. Previous studies demonstrate that ITMN-191 binds genotype 1b NS3/4A in a two-step mechanism, inhibits with picomolar potency, and that the enzyme-inhibitor complex is stable for hours. The biochemical potencies and inhibition kinetics of ITMN-191 against proteases from multiple HCV genotypes are defined here.

 

Methods:

Coding sequences for genotype 1a, 1b, 2b, 3a, 4, 5, and 6 variants of NS3 were cloned and used to express full-length proteins in baculovirus infected cells. A continuous fluorometric assay for NS3/4A protease activity was used under conditions that maximize sensitivity and protease stability. ITMN-191 dissociation was studied by examining recovery of protease activity following dilution of the pre-formed NS3/4A-ITMN-191 complex. Results were interpreted in light of structural data obtained via X-ray crystallography, homology modeling, and inhibitor docking.

 

Results:

A kinetic characterization of genotype 1-6 proteases suggests that ITMN-191 binds the majority of these proteins through a two step mechanism similar to that previously proposed for a replicon-derived protease sequence. In this mechanism, ITMN-191 forms an initial complex with NS3/4A that subsequently isomerizes to a more stable species from which ITMN-191 dissociates slowly. IC50 values for genotype 1a, 1b, 4, 5 and 6 proteases are similar to the 0.8nM potency previously obtained with a replicon-derived protease when assays are conducted with minimal preincubation of enzyme and inhibitor. Under these conditions, the genotype 2b and 3a proteases show 3 and 19 fold reduced sensitivity to ITMN-191, respectively. In assays that monitor the recovery of activity following dilution of a preformed enzyme-inhibitor complex, all tested proteases show evidence for slow dissociation of ITMN-191 with the exception of genotype 3a. Structural and computational analyses of ITMN-191 binding implicate key sequence differences between the 3a isolate and other genotypes.

 

Conclusions:

ITMN-191 is a highly potent, slowly dissociating inhibitor of the HCV NS3/4A protease. The strong inhibition of genotype 1-6 proteases supports the use of ITMN-191 to treat multiple genotypes of HCV.

 


Topic: Experimental Therapies - General

 

1387. A Hepatitis C T-Cell Vaccine Candidate Covering HCV Genotype Complexity and HLA Type Diversity

A. Van der Aa; V. Goossens; K. Allosery; G. Verheyden; S. Southwood; C. Dahlberg; D. McKinney; M. Newman; H. M. Diepolder; G. Maertens; M. Buyse 

 

Background:

Viral clearance of HCV has been shown to be associated with multi-specific, strong CD8+ T-cell (CTL) responses together with strong CD4+ T-cell (HTL) responses. A candidate therapeutic polyepitope T-cell vaccine able to induce such potent specific T-cell responses could ultimately lead to viral clearance. Also, by taking human HLA as well as HCV genotype diversity into account, such a vaccine should be applicable to the majority of infections.

 

Methods:

HCV-derived CTL and HTL epitopes for a wide range of HLA class-I and HLA-DRB1 alleles were identified applying different algorithms on the full HCV genome. Further selection was made based on in vitro HLA binding affinity of the peptides, immunogenicity in HLA transgenic mice, and recall reactivity of CD8+ and CD4+ T-cells in an IFNγ-ELISPOT assay using HCV patient samples. Several DNA plasmids containing different sets of selected epitopes were designed, constructed, and evaluated for immunogenicity in HLA transgenic mice. Finally, epitopes were included in the candidate HCV polyepitope therapeutic vaccine based not only on their immunological properties but also their conservancy within and between HCV genotypes, as well as their HLA restriction. In addition, the polyepitope construct was expressed as protein in E. coli, purified using affinity chromatography and tested for immunogenicity.

 

Results and discussion:

A plasmid vector was constructed that contains 34 HCV-derived CTL epitopes, 13 HCV-derived HTL epitopes, and the pan-DR helper T-cell epitope PADRE®. Theoretical population coverage calculations show that the selected set of CTL and HTL epitopes can provide recognition of at least four CTL and three HTL epitopes in any HCV genotype 1-infected subject, irrespective of HLA type. Vigorous CTL and HTL responses could be induced using the pDNA or protein formats of the vaccine candidate in HLA-A01, HLA-A02, HLA-A11, and HLA-A24 transgenic mice.

 

Conclusion:

A set of HCV-derived CTL and HTL epitopes was identified that showed excellent affinity, immunogenicity, and cross-reactivity, and formed the basis for the development of a universal T-cell vaccine candidate for treatment of chronically infected HCV patients. The T-cell vaccine candidate has now been shown to be immunologically active both in the form of pDNA and protein.

 


Topic: Experimental Therapies - General

 

1389. Efficacy of Interferon β combined cyclosporine A treatment in the retreatment of chronic hepatitis C - Promising aspect of host factor targeting therapy.

K. Inoue; T. Watanabe; M. Yamada; M. Yoshiba 

 

Background/Aim

A significant proportion of chronic hepatitis C patients fails to achieve sustained virological response (SVR) even after the treatment with pegylated interferon (IFN) alpha combined ribavirin. The effective treatment for patients who previously failed combination standard IFN plus ribavirin or pegylated IFN plus ribavirin has not been well established. Management of these patients is the most challenging task and new compounds targeting NS3 protease or NS5B polymerase are now under evaluation. Cyclophilins are essential host factors for HCV replication. We have originally developed IFN combined cyclosporine A treatment and also reported its favorable anti-HCV effect. We report here the efficacy of divided administration of IFNβ plus cyclosporine A in the treatment of chronic hepatitis C patients who failed Peg-IFN or IFN combined ribavirin.

 

Patients and method

We prospectively included 59 patients (median age, 63) with 1) histologically proven chronic hepatitis C, 2) genotype 1b and 3) non-responders and relapsers to combination IFN plus ribavirin or combination pegylated IFN plus ribavirin. We conducted the present study to confirm the efficacy, safety and tolerability of our protocol. Serum HCV RNA level was 3900 KIU/ml. The treatments consisted of an induction therapy, an intensified therapy and a maintenance therapy. The induction therapy comprised intravenous 1 MU IFNβ every 4 hours for the first 3 days, 1.5 MU IFNβ every 6 hours for the next 4 days and 2 MU IFNβ every 8 hours for the following 3 weeks, totaling 168 MU of IFNβ. The intensified therapy was induction therapy shortened to 2 weeks. The maintenance therapy comprised of pegylated IFNα2b and ribavirin. CsA was given 4 times daily for a total dose of 200 mg during the induction and the intensified therapies. Ribavirin was given twice daily for a total dose of 800 mg (body weight over 60 kg) or a total dose of 600 mg (body weight equal to or less than 60 kg) during the maintenance therapy. The institute review board approved this protocol.

 

Results

The end treatment response and sustained virological response rate of the present study were 73%(43/59) and 59% (35/59), respectively. The relapse rate was 19%(8/43). SVR in previous combination therapy relapsers was 80% (32/40) and that in previous combination therapy non-responders was 16%(3/19). All adverse effects were completely reversible. The treatment protocol was well tolerable.

 

Conclusion

·        We concluded that our protocol should be effective in relapsers to the previous combination therapies.

·        Host factor targeting treatment will become a promising treatment option.

 


Topic: Experimental Therapies - TMC435350

 

1390. In Vitro Activity And Preclinical Pharmacokinetics Of The HCV Protease Inhibitor, TMC435350.

K. Simmen; O. Lenz; T. Lin; G. Fanning; P. Raboisson; H. de Kock; G. van't Klooster; Ĺ. Rosenquist ; M. Edlund; M. Nilsson; L. Vrang; B. Samuelsson 

 

Background:

As a class, HCV NS3/4A protease inhibitors have shown promise in clinical trials for the treatment of chronic hepatitis C virus infection. TMC435350 is a novel and potent macrocyclic NS3/4A protease inhibitor. To further assess the potential of TMC435350, we characterized the in vitro activity of TMC435350 alone or in combination with different classes of HCV inhibitors. The plasma pharmacokinetics and tissue distribution were also studied in vivo.

 

Methods:

The effect on HCV RNA level and the emergence of drug-resistant colonies was analyzed in the replicon model with TMC435350 alone, or in combination with interferon alpha, ribavirin, and different HCV polymerase inhibitors. Pharmacokinetic profiles were evaluated following single or repeated dosing in rats. The tissue distribution of TMC435350 was studied in male rats at time points from 0.5 up to 31 hours after a single oral dose of 40 mg/kg.

 

Results:

In biochemical HCV NS3/4a protease assays, TMC435350 exhibited Ki values <0.1nM for subtypes 1a (H77) and 1b (con1) enzymes. TMC435350 was found in the subgenomic genotype1b replicon model to have an EC50 of 8nM and a selectivity index (SI) of > 1000. The combination of TMC435350 with different classes of HCV inhibitors further increases its activity in reducing HCV RNA in an additive to synergistic manner, and further reduced the emergence of resistant replicon colonies.

After single oral administration of a PEG400-based solution of TMC435350 at 40 mg/kg the mean peak plasma concentration (Cmax) was 1430ng/ml and was observed at two hours post-dose (Tmax). The absolute bioavailability of TMC435350 was calculated at 44% after single oral administration of a 40 mg/kg dose. TMC435350 was found to be extensively distributed to the liver, small- and large intestines (tissue/plasma ratios >35). Concentrations in other organs were similar to plasma. Notably, TMC435350 was still quantifiable in the liver tissue up to 31 hours post-dosing.

 

Conclusions:

TMC435350 is a novel potent and specific HCV protease inhibitor, with good oral bioavailabilty and a favorable liver distribution. In addition, in vitro studies support the potential use of TMC435350 in combination with other HCV inhibitors.

 


Topic: Experimental Therapies - Boceprevir

 

1391. HCV Polymerase (NM107) and Protease (boceprevir) Inhibitors in Combination Show Enhanced Activity and Suppression of Resistance in the Replicon System

D. N. Standring; V. Bichko; R. Chase; M. LaColla; L. Lallos; A. Skelton; M. Soukasakos; M. Tausek; X. Tong; R. Ralston 

 

Background:

Combination of small-molecule antiviral agents directed against different molecular targets offer an attractive strategy for the effective therapy of hepatitis C. As monotherapies, valopicitabine (NM283) (Idenix/Novartis), an investigational nucleoside NS5B polymerase inhibitor, and boceprevir (SCH 503034) (Schering-Plough), an investigational NS3 protease inhibitor, have demonstrated antiviral activity against hepatitis C virus (HCV) in clinical studies. Using cell culture replicon studies we show that the combination of polymerase and protease inhibitors leads to greater anti-HCV activity, no cross-resistance and the suppression of treatment emergent-resistance, compared to monotherapy with each agent.

 

Methods:

The combined antiviral effect of the polymerase and protease inhibitors was evaluated in genotype 1b HCV replicon cells by real time RT-qPCR or ELISA. Possible cross-resistance of these compounds was evaluated using replicon variants carrying single protease inhibitor resistance mutations (T54A, A156S, V170A, A156T), or the polymerase inhibitor resistance mutation (S282T). The selection of resistant cell colonies was carried out for 3-4 weeks in the presence of various concentrations of one or both drugs.

 

Results:

The combination of SCH 503034 and NM107 showed dose-dependent enhancement of replicon inhibition, compared with the effect of each inhibitor used alone. No cytotoxicity was observed. In cross-resistance studies, NM107 showed similar antiviral activity (EC50 1.5-2 μM) against wild-type and SCH 503034-resistant replicons. SCH 503034 showed similar activity (EC50 0.3-0.4 μM) against wild type and NM107-resistant replicons. When tested against their known resistance mutations, each compound showed a 5- to 125-fold loss in susceptibility. In selection experiments, the combination of SCH 503034 and NM107 significantly reduced the frequency of resistant colonies in a dose-dependent manner, compared to each inhibitor used alone.

 

Conclusions:

In these in vitro studies, the combination of the polymerase and protease inhibitors showed enhanced anti-replicon activity with no cross-resistance and a greater genetic barrier to resistance. These results support clinical evaluation of this combination in patients with chronic hepatitis C.

 


Topic: Experimental Therapies - ANA598

 

1392. ANA598, a Novel Non-Nucleoside Inhibitor of HCV NS5B Polymerase, Exhibits Favorable Pharmacokinetic Properties in Multiple Preclinical Species

L. Kirkovsky; Y. Zhou; D. Norris; E. Okamoto; T. G. Nolan; D. Bartkowski; J. Khandurina; M. Sergeeva; D. Murphy; B. Ayida; A. Xiang; D. Ellis; J. Blazel; Z. Sun 

 

Introduction:  

Inadequate responses to current HCV therapy create an urgent unmet need for new antiviral agents to complement today’s standard of care, particularly for treatment of genotype 1 infections. Probable future HCV therapies will add multiple direct-acting antiviral agents taken from differing functional classes to enhance response and suppress the emergence of resistant HCV variants. The essentiality of the NS5B polymerase predicts that inhibitors of this enzyme should be attractive additions to current standard of care. However, first generation development candidates targeting this essential enzyme suffer notable defects in potency, metabolism, or pharmacokinetic properties that limit their potential. We describe here the superior pharmacokinetic properties of ANA598, a novel, orally available and potent “palm site” inhibitor of HCV genotype 1 NS5B polymerase.

 

Results:

ANA598 demonstrated high oral bioavailability in all four species evaluated. ANA598 plasma exposures were lower in the rat than the monkey; exposure did not differ significantly for solution and suspension formulations in these species. ANA598 demonstrated a greater than proportional increase in plasma exposures with increasing dose in monkey and rat; in the mouse exposures were approximately dose-proportional up to a 1000mg/kg. An oral dose of 5mg/kg ANA598 to monkeys provided C12 and C24 levels (21,600nM and 7,600nM, respectively) that were substantial multiples of the replicon EC50 (51nM for genotype 1a and 3nM for genotype 1b) even after adjustment for protein binding. ANA598 accumulated in rat liver and reached a liver-to-plasma ratio of ~20 at 12 hours after an oral 5mg/kg dose, suggesting significant additional antiviral coverage in the primary target organ for HCV replication.

 

Conclusion:

Preclinical studies of ANA598 in four species have demonstrated high oral bioavailability and plasma and liver trough levels that are substantial multiples of replicon EC50. Clinical studies of ANA598 in four species have demonstrated high oral bioavailability and plasma and liver trough levels that are substantial multiple of replicon EC 50.  These favourable antiviral, metabolic, pharmacokinetic and preliminary toxicologic properties clearly differentiate it from other molecules of this functional class and strongly support further evaluation of ANA598 for the treatment of HCV infection. 

Plasma PK parameters of ANA598 after a single oral dose of 5mg/kg

Species

Foral, %

AUCinf, h*μM

**C12, μM

**C24, μM

Cmax, μM

Tmax, h

T1/2, h

Cynomolgus Monkey

 

65

 

602

 

21.6

 

7.6

 

42

 

5.5

 

8

Beagle Dog

85

441

13.8

3.7

40

2

2

*CD-1 Mouse

45

42 (M) / 114 (F)

0.10 (M) / 0.74  (F)

 

11 / 22

0.5 / 4

3.4

*Sprague-Dawley rat

 

~115

 

94

0.3 / 2.0

 

 

24

 

0.4

 

5

* - mean values in rat and mouse are given separately for males and females, respectively ** - C12 and C24 - plasma levels at 12 and 24 hours post dose, respectively

 


Topic: Experimental Therapies - ME3738

 

1393. ME3738 inhibits hepatitis C virus replication by enhancing interferon-β

Y. Hiasa; Y. Tokumoto; I. Konishi; B. Matsuura; K. Michitaka; R. T. Chung; M. Onji 

 

Background/Aims:

We previously reported that ME3738, a derivative of soyasapogenol B, has effects against hepatitis C virus (HCV) in cells derived from hepatocytes. Our established model of full-length genotype 1a HCV replication supports replication not only in interferon-β (IFN-β) induction-deficient Huh7 cells, but also in HepG2 cells. Therefore, we used our model to examine whether or not ME3738 modifies innate antiviral activity. We also assessed the effects of ME3738 combined with interferon-α (IFN-α) on HCV.

 

Methods:

HepG2 or Huh7 cells were transfected with a full-length HCV cDNA plasmid (pH77), and infected with a replication-defective adenoviral vector expressing T7 polymerase (Ad-T7pol). Cells were infected with Ad-T7pol, then ME3738 (0.1-10 μM) and/or 100 IU/ml of IFN-α was added. Protein and RNA were harvested from the cells on day 1, 2, 3, 5, 7 and 9 post-infection. To knock down IFN-β expression, 20 nM of siRNA targeting IFN-β was transfected into the cells 1 day before pH77. We measured HCV positive and negative strands as well as mRNA levels of innate antiviral response-related genes using real-time RT-PCR. We assessed HCV core protein expression by ELISA. 

 

Results:

The anti-HCV effect of ME3738 was more pronounced in HepG2 than in Huh7 cells. ME3738 enhanced mRNA levels of IFN-β in HepG2 cells. The mRNA levels of 2′-5′ oligoadenylate synthetase and MxA were stimulated by IFN-β in HepG2 cells. When the IFN-β was knocked-down by siRNA, the anti-HCV effect of ME3738 was abrogated. In Huh7 cells, the IFN-β mRNA levels triggered by viral double-stranded RNA were increased slightly, and neither IFN-β nor IFN-stimulated gene mRNA expression by ME3738 was enhanced. ME3738 combined with IFN-α elicited synergistic anti-HCV effects in HepG2 cells (HCV/GAPDH copy ratio (Day 3); 2.585±1.600×10-6 (ME3738+IFN-α) vs. 3.557±1.560×10-5 (ME3738), p<0.05). 

 

Conclusions:

The anti-HCV effect of ME3738 was more potent in HepG2 cells than in cells deficient in IFN-β induction. The enhancement of endogenous IFN-β by ME3738 suggests that this agent exerts innate antiviral action more effectively along the type I IFN pathway. Adding IFN-α synergistically enhanced the anti-HCV action of ME3738. Thus, ME3738 might be a useful anti-HCV agent either with or without IFN-α.

 


Topic: Experimental Therapies - PF-00868554

 

1394. Preclinical Evaluations of PF-00868554, a Potent Non-nucleoside Inhibitor of the Hepatitis C Virus RNA Polymerase

S. Shi; K. Herlihy; R. Irvine; S. Binford; C. Lewis; J. Nonomiya; A. Patick 

 

Introduction:

PF-00868554 is a non-nucleoside inhibitor of the HCV RNA polymerase, which exerts its inhibitory effect by binding to the thumb-base domain of the protein. It is a potent and selective inhibitor of the enzyme, with a mean IC50 of 0.0096 µM against genotype 1 polymerases in biochemical assays.

 

Aim:

To determine the in vitro antiviral activity of PF-00868554 against various HCV laboratory and clinical strains, a panel of chimeric replicons was generated in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the genotype 1b (Con1 strain) subgenomic reporter replicon.

 

Results:

The antiviral activity of PF-00868554 was evaluated against this panel of chimeric replicons in the transient replication assay in Huh7.5 cells using the luciferase reporter endpoint. Results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1 replicons, with overall mean EC50 and EC90 values of 0.059. PF-00868554 showed no cytotoxic effect in several human cell lines up to the highest concentration evaluated (320 µM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins.   PF-00868554 displayed promising PK properties in rats and dogs.

 

Conclusions:

Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an antiviral agent in HCV-infected patients.

 


Topic: Experimental Therapies - GS-9190

 

1395. Mechanistic Characterization of GS-9190, a Novel Non-nucleoside Inhibitor of HCV NS5B Polymerase with Potent Antiviral Activity and a Unique Mechanism of Action

I. Shih; I. Vliegen; B. Peng; H. Yang; J. Paeshuyse; G. Purstinger; M. Fenaux; E. Mabery; G. Bahador; L. S. Lehman; S. Bondy; W. Tse; H. Reiser; W. A. Lee; J. Neyts; W. Zhong 

 

Background and Aims:

GS-9190 is a drug candidate currently being evaluated for safety, tolerability, pharmacokinetics, and antiviral efficacy in chronically infected HCV patients. It is a novel imidazopyridine analogue with potent antiviral activity in HCV replicon cells, especially against genotype 1 HCV. GS-9190 has lower potency against a genotype 2a (JFH1) subgenomic replicon or against the JFH1 infectious virus. The aim of this study was to define the mechanism of action of GS-9190.

 

Methods:

Chimeric replicons carrying sequences from genotype 1b (Con-1) and genotype 2a (JFH1) were used to identify viral determinants of susceptibility to GS-9190. A cell-based, strand-specific qRT-PCR replicase assay was employed to analyze the inhibitory profile of GS-9190. Drug resistance selection with GS-9190 was performed in Con-1 replicon cells.

 

Results:

To investigate the mechanism of action, we utilized the susceptibility difference between genotype 1b and genotype 2a to GS-9190 and constructed a chimeric replicon in which all viral genes were derived from genotype 1b except the NS5B gene, which was derived from genotype 2a. The antiviral activity of GS-9190 against the chimeric replicon was comparable to that observed for the genotype 2a replicon, suggesting that NS5B polymerase is the target of inhibition. Studies with additional 1b/2a chimeric replicons further indicated that the beta-hairpin in the thumb sub-domain of NS5B was involved in the interaction. Based on these results, a cell-based replicase assay utilizing strand-specific qRT-PCR was developed; analysis of positive and negative strand production indicated that GS-9190 affected viral RNA synthesis in a manner similar to that of non-nucleoside NS5B inhibitors. Characterization of replicons resistant to GS-9190 led to identification of multiple mutations across the viral genome including several inside the beta-hairpin of NS5B. Subsequent studies showed that only those mutations in NS5B were able to confer resistance to GS-9190 when introduced into a wild-type replicon, whereby the total number of mutations correlated with the degree of resistance.

 

Conclusion:

Collectively, these data demonstrate that GS-9190 represents a novel non-nucleoside NS5B inhibitor whose binding pocket involves beta-hairpin and is in close proximity to the catalytic active site of NS5B. Detailed mechanistic characterization of GS-9190 and its interaction with NS5B will be presented.

 


Topic: Experimental Therapies - General

 

1396. Modeling the potential cost-effectiveness of adding a novel STAT-C agent to current standard therapy in patients with genotype 1 chronic hepatitis C infection.

S. P. Galhenage; G. D. Sanders; K. Patel; K. A. Schulman; J. G. McHutchison 

 

Background:

Current standard of care for chronic hepatitis C (CHC) infection with peginterferon (PEG-IFN) and ribavirin (RBV) (P+R) is costly, and effective in only half of all treated cases. Recent data have shown that the addition of novel Specifically Targeted Antiviral Therapy for HCV (STAT-C) to standard of care has the potential to advance the treatment of genotype 1 CHC infection. Thus, we modeled this new strategy to assess the economic impact of improved viral response on costs and outcomes.

 

Methods:

A Markov model was developed to compare standard therapy with 4 treatment strategies (a STAT-C agent for 12 weeks combined with P +/- R for 12-48 weeks). The model followed treatment-naďve individuals with mild CHC infection (Metavir FO-F1) from treatment initiation until death [assuming base case age 40 years, 60% male, 48 week P + R sustained viral response rate (SVR) 46%]. Costs of PEG-IFN α-2a 180mcg weekly and RBV 1000-1200mg daily were based on average wholesale prices. Base cost of STAT-C therapy was assumed equivalent to 48 weeks of P + R. Rates of SVR and adverse effects were estimated. Natural history of CHC infection, treatment patterns, healthcare costs and utilities for all disease states were obtained from published data. Analyses adopted a societal perspective and applied a 3% annual discount rate. SVR and costs of STAT-C therapy were varied in sensitivity analyses.

 

Results:

Compared to standard therapy, STAT-C based regimens were associated with increased survival of 0.14-0.45 years and 0.31-0.90 quality-adjusted life years (QALYs). These additional health benefits however increased lifetime costs by $15,641-$39,757. Under base-case assumptions, a strategy of STAT-C + 24 weeks of P + R had an incremental cost-effectiveness ratio of $29,375/QALY compared with current standard of care for an SVR rate of 70%. Other strategies were either dominated or prohibitively costly. Results were most sensitive to treatment efficacy, cost, and patient age. Assuming a threshold of $50,000/QALY for cost-effectiveness, sensitivity analyses revealed that the STAT-C + 24 week P + R strategy would remain cost-effective if relative cost increased up to a factor of 1.44 or with SVR rates as low as 61%. If this regimen was priced to be cost neutral compared to current standard of care, lifetime costs increased by $4,482 and QALYs improved by 0.78 resulting in an incremental cost-effectiveness ratio of $5738/QALY.

 

Conclusions:

Our model suggests that STAT-C therapies that increase efficacy provide an opportunity to increase life expectancy and may enhance the value of treatment for patients with genotype 1 CHC infection, depending on the cost of these agents.

 


Topic: Experimental Therapies - General

 

1397. AM3 inhibits HCV replication through activation of peripheral blood mononuclear cells.

P. L. Majano; S. Martín-Vílchez; Y. Rodriguez-Munoz; P. Sanz Cameno.; F. Molina-Jimenez; J. L. Alonso; S. Gonzalez; M. Lopez-Cabrera.; R. Moreno-Otero 

 

Introduction:  

Inmunoferon® is a drug whose active principle is a glycoconjugate of natural origin composed of a glucomannan polysaccharide from Candida utilis and a storage protein from nongerminated seeds of Ricinus communis. The glycoconjugate that constitutes the active principle of Inmunoferon® (hereafter referred as AM3) has been shown to modulate regulatory and effector functions of the immune system by acting on peripheral blood mononuclear cells (PBMCs) and modifying the expression of extracellular mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta. Previously, it has been shown that AM3 has antiviral effect against HBV due to stimulation of secretion of molecules with antiviral properties by PBMC. 

 

Objective:

To analyze whether AM3 has antiviral properties against HCV replication in vitro.

 

Materials and Methods:

Reagents: AM3 was prepared according to the methods described in patents P9900408 (Spain) and PCT/ES99/00338. The phosphorylated glucomannan polysaccharide and the protein were combined in a 5:1 (wt/wt) polysaccharide/protein proportion.

Cell culture: We used two clones derived from Huh-7 cell with genomic bicistronic, full-length HCV genome. PBMCs were purified from peripheral blood cells from healthy donors by Ficoll density centrifugation and cultured at 106 cells/ml for 24 h prior to analysis. PBMC were stimulated or not with AM3 (1 μg/ml) for 48 or 96 h and then cell supernatants were collected. Huh7/HCV clones were treated for 24 or 48 h with the PBMC supernatant (conditioned medium; 1:2 proportion, with normal culture medium). To analyse whether AM3 has a direct antiviral effect on HCV replication, Huh7/HCV clones were incubated with various doses of AM3 for 48h. 

Methods: Total RNA Huh/HCV clones were isolated and HCV RNA was analyzed by real-time RT-PCR. Additionally, core and non-structural protein NS5a levels were determined by western blot.

 

Results:

HCV replicons cells treated with supernatant derived from AM3 stimulated PBMC exhibit lower HCV RNA and protein accumulation when compared to untreated controls. However, AM3 did not affect directly the expression of RNA or protein in any of the cell clones tested. 

 

Conclusion:

In this report, we found that AM3 inhibited HCV RNA and protein expression by an indirect mechanism. We found that AM3 lacked intrinsic antiviral properties, and that the antiviral effect of the glycoconjugate was due to stimulation of secretion of molecules with antiviral properties by PBMC. Our data suggest that the employment of AM3 as an adjuvant administered simultaneously with conventional antiviral drugs may potentiate the endogenous response against viral infection.

 


Topic: Experimental Therapies - GS-9190

 

1398. Preclinical Pharmacokinetic Characterization of GS-9190, a Novel Non-nucleoside HCV NS5B Polymerase Inhibitor.

C. Yang; Y. Wang; L. Wieman; E. Eisenberg; M. Lee; B. Murray; L. Tong; A. Ray; S. Bondy; W. Tse; A. Coluci; M. Wright; L. S. Lehman; W. A. Lee; G. Rhodes 

 

Background and Aims:

GS-9190 is a novel non-nucleoside HCV RNA polymerase inhibitor with potent in-vitro antiviral activity and a high selectivity index. GS-9190 is currently being evaluated for safety/tolerability, pharmacokinetics and antiviral efficacy in chronically infected HCV patients. It is a novel imidazopyridine analogue with potent antiviral activity against genotype 1 HCV replicon cells. The aim of these studies was to characterize the pharmacokinetic profile of GS-9190 in relevant preclinical models prior to administration in humans.

 

Methods:

Single dose pharmacokinetic studies were conducted following intravenous and oral administration of GS-9190 in rats, dogs and cynomolgus monkeys. The distribution and routes of excretion were determined in rats following oral administration of 14C-GS-9190. The absorption, metabolic stability, protein binding and the CYP450 inhibition and induction profile of GS-9190 were evaluated in vitro in systems derived from human and, where appropriate, preclinical species. 

 

Results:

GS-9190 was stable to in vitro metabolism in microsomal and S9 fractions derived from all species studied. Reaction phenotyping studies also suggested slow turnover by human CYP1A, CYP3A and CYP2C19. In all species, protein binding was extensive (> 98 %). GS-9190 demonstrated limited potential to alter human CYP function through either inhibition or induction. The absorption potential of GS-9190 was shown to be high based on its extensive Caco-2 cell monolayer permeation and lack of recognition by intestinal efflux proteins.

 

In vivo preclinical data are consistent with the in vitro profile of GS-9190. In all preclinical species GS 9190 displays low total body clearance and a volume of distribution comparable to total body water. Oral bioavailability was greater than 30 % in all preclinical species and was not limited by hepatic first pass extraction. In the rat, the majority of the 14C-radiolabelled dose was excreted slowly into the bile with only minor excretion in the urine. Recovery of radioactivity was essentially complete 48 hr after administration of 14C-GS-9190.

 

Conclusion:

The available human in vitro data project a favorable clinical pharmacokinetic profile, with high oral bioavailability for GS-9190 in human subjects. As a result it is predicted that plasma concentrations of GS-9190 sufficient to drive pharmacological effect can be achieved with relatively modest doses in humans.

 


Topic: Experimental Therapies - VCH-759

 

LB11. Antiviral activity of the non-nucleoside polymerase inhibitor, VCH-759, in chronic Hepatitis C patients:Results from a randomized, double-blind, placebo -controlled, ascending multiple dose study.

C. Cooper; E. J. Lawitz; P. Ghali; M. Rodriguez-Torres; F. H. Anderson; S. S. Lee; L. Proulx 

 

Background:

VCH-759 is a novel, orally bioavailable non-nucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. It has demonstrated sub-micromolar IC50s against the HCV replicons of genotype 1a and 1b. 

 

Methods:

This multiple ascending dose study was designed to assess the effect on viral kinetics, viral resistance, pharmacokinetics, safety and tolerability of VCH-759 given as monotherapy for 10 days with a 14-day follow-up period. Three cohorts of treatment-naive chronic hepatitis C patients infected with HCV genotype 1 received either placebo, 400 mg tid, 800 mg tid or 800 mg bid. Viral loads were determined using the Roche Amplicor assay (lower limit of quantification=600 IU/ml).

 

VCH-759 plasma levels were assessed over 6 hours for the tid regimen and over 12 hours for the bid regimen on Days 1 and 10 and daily, prior to the morning dose, on Days 1 to 11.

 

Results:

Thirty-two (32) subjects were enrolled and completed the study (9: placebo, 9: 400mg tid, 9: 800 mg tid, 5: 800 mg bid). VCH-759 was rapidly absorbed with peak plasma levels Day 1: 1857 ± 773 ng/ml, 4857.2 ± 4106.6 ng/ml and 4,627 ± 1688 ng/ml and Day 10: 71814.4  ± 3798.6, 22706.3 ± 26035.3, 21806.1 ± 19925.5 for the 400 mg tid, 800 mg tid and 800 mg bid doses respectively.

 

No serious adverse events or dose-limiting toxicities were reported.  All adverse events were mild to moderate.  The most frequently reported treatment-related AEs wer diarrheas, headache, flatulence, dyspepsia and fatigue.  The incidence of gastrointestinal AEs in the placebo group was comparable to that in the active treatment grups suggesting that the formulation vehicle (an aqueous mixture of Solutol HS 15 and Polyethylene glycol 400 which is known to affect the GIT).  Clincial laborator evaluations revealed no clinically significant effects of VCH-759 on blood chemistry, urialysis, vital signs and ECG measurement.

 

Conclusions:

·        VCH-759 demonstrated a rapid and significant antiviral response ewithin the first few days of treatment.  All subjects had more than one log 10 decrease in plasma HCV RNA with mean maximal decrease of 1.9, 2.3, 2.5 log 10 at 400 mg tid, 800 bid, and 800 tid, respectively.

·        The viral load response was similar for both HCV genotype 1a and 1b

·        Multiple administration of VCH-759 at difference dosing regimens for 10 days was well tolerated in treatment-naďve subjects with HCV

·        The pharmacokinetic results demonstrated no accumulation of VCH-759 after 10 days of treatment

·        VCH-759 plasma tough concentrations were at or above the replicon IC90 for the duration of treatment for the three different dosing regimens

·        Genotypic sequencing of the NS5B polymerase is ongoing to determine if mutations are associated with virologic rebound observed in some subjects prior to the final dosing day.

 


Topic: Experimental Therapies - Locteron

 

LB10. Phase 2a study to evaluate the safety and tolerability and anti-viral of 4 doses of a novel, controlled-release interferon-alfa 2b (Locteron) given every 2 weeks for 12 weeks in treatment-naive patients with chronic hepatitis C (genotype 1)

I. Dzyublyk; T. Yegorova; L. Moroz; O. Popovych; I. Zaytsev; V. Miroshnichenko; E. Herrmann; S. Zeuzem; E. J. van Hoogdalem; J. E. Humphries 

 

Background:

Controlled-release recombinant interferon-alfa 2b (Locteron) is a novel approach to delivery of interferon (IFN) given every 2 weeks with improved tolerability combined with a high level of hepatitis C virus (HCV)RNA reduction. 

 

Methods:

A phase 2a, open-label, dose-ranging study was conducted in treatment-naďve patients with genotype 1 chronic HCV infection to evaluate the safety, tolerability and anti-viral effect of Locteron. 32 patients were randomized to receive subcutaneous injections of Locteron 14 days apart over 12 weeks in 4 dose cohorts (8 per cohort) of 160, 320, 480 and 640 µg, with the 640 µg group starting after safety evaluation of the other cohorts. All subjects received weight-based ribavirin. HCV RNA reduction modeling was performed. 

 

Results:

The mean HCV RNA reduction at week 4 for the 160, 320, 480 and 640 µg groups were 1.1, 3.1, 2.9 and 3.1 logs, respectively. Percent of HCV negative subjects at week 4 were 0, 25, 38 and 25, respectively. Average viral reduction after 12 weeks for the 3 lower doses of Locteron (160, 320 and 480 µg) was 1.8, 4.5 and 4.2 logs, respectively. 63% of subjects at the 2 middle doses (320 & 480 µg) were HCV negative (LLOQ < 28 IU/mL) at 12 weeks. Early viral response (EVR: 12-week ≥ 2-log drop in HCV RNA) was achieved in 88% and 100% of subjects in the 320 and 480 µg Locteron dose cohorts, respectively. Modeling of HCV kinetics demonstrated dose-dependent biphasic kinetics reflected by mean and maximum efficiency in blocking viral production from day 1 to day 28 of treatment. Mean and maximum efficiency were 41%±23% and 54%±27%, respectively, in the 160 µg cohort, 58%±19% and 71%±21% in the 320 µg cohort, 72%±20% and 84%±11% in the 480 µg cohort, and 73%±24% and 80%±22% in the 640 µg cohort. The median T1/2 of free HCV RNA was 2 hours and the median T1/2 of infected cells was 2.8 days. Clinical adverse events were almost exclusively mild in intensity with only 1 severe adverse event in the 3 lower dose cohorts. The most common adverse events were arthralgia (50%), weakness (50%), myalgia (38%) and headache (33%), with chills, nausea and diarrhea each reported in fewer than 5% of subjects. Fever (Temp ≥ 38.0°C) occurred in only 1 subject in these first 3 cohorts. Full data on all 4 cohorts for all 12 weeks will be available by the AASLD meeting. 

 

Conclusions:

In this study, Locteron, a controlled-release formulation of unmodified IFN-alfa 2b, administered every 2 weeks to treatment-naďve patients with chronic hepatitis C (genotype 1) demonstrated strong anti-viral activity combined with an improved safety and tolerability profile compared to currently marketed IFNs and those in development.

 


Topic: Experimental Therapies - R7128

 

LB9. Antiviral Activity, Pharmacokinetics, Safety, and Tolerability of R7128, a Novel Nucleoside HCV RNA Polymerase Inhibitor, Following Multiple, Ascending, Oral Doses in Patients with HCV Genotype 1 Infection Who have Failed Prior Interferon Therapy

R. Reddy; M. Rodriguez-Torres; E. Gane; R. Robson; J. Lalezari; G. T. Everson; E. DeJesus; J. G. McHutchison; H. E. Vargas; A. Beard; C. A. Rodriguez; G. Z. Hill; W. Symonds; M. Berrey 

 

Background:

R7128 is a prodrug of PSI-6130, an oral cytidine nucleoside analog polymerase inhibitor, currently in development for the treatment of HCV. This multiple ascending dose study assessed safety, tolerability, pharmacokinetics, and preliminary antiviral activity of R7128 in subjects with HCV genotype 1 infection.

 

Methods:

Multiple oral doses of R7128 monotherapy were administered for 14 days to 40 HCV-infected patients (n=10 per cohort with 8 active + 2 placebo) of 750mg QD, 1500mg QD, 750mg BID & 1500mg BID. PK, safety and virology assessments were conducted throughout the study period. Data are available for the 750mg QD, 1500mg QD and 750mg BID cohorts. The 1500mg BID cohort is fully enrolled.

 

Results:

Demographics and Clinical Safety

·        Baseline demographics were similar across groups:  All subjects had HCV genotype 1 (29 – 1a; 11 – 1b), had previously failed alpha-interferon and were non-cirrhotic.

·        No serious adverse events were reported. No subjects discontinued R7128 due to an AE.

·        There was no trend of drug or exposure-related AEs.

·        The placebo group reported the highest number of AEs with 34 events in 7 of 8 subjects.

·        The most commonly reported AEs were headache, diarrhea, dry mouth, nausea.  The majority were mild in grade.

·        There were no clinically significant changes noted in the vital sign parameters across the treatment groups.

·        No trends in laboratory abnormalities were noted, and no treatment emergent grade 2 or higher labs were reported.

·        Of those receiving R7128 with abnormal ALT at baseline, 78% normalized by Day 14.

·        No clinically significant changes were reported for serial ECGs, including no QTc prolongation beyond 500ms.

 

Antiviral Activity

·        R7128 demonstrated dose-dependent HCV RNA decreases through 14 days of monotherapy in all dose groups

·        Viral nadir occurred at Day 15 with no evidence of clinically relevant rebound during therapy.

·        HCV RNA values in the placebo group remained at baseline.

·        The range at Day 15 in HCV RNA decrease from baseline in the 1500mg BID cohort was -1.2 to -4.2 log10 IU/mL with this subject having HCV RNA below the limit of detection.

·        Two subjects with ~1.2 log10 IU/mL decline included a prior null responder and

 

Pharmacokinetics

·        Oral dosing with R7128 resulted in dose-dependent but not dose proportional exposure to PSI-6130, the active moiety.

·        Plasma concentrations of the pro-drug, R7128, were below the limit of detection for all subjects

·        The monoester intermediate form was detected only at higher doses at tmax in a subset of subjects indicating efficient conversion of pro-drug to parent.

·        The terminal plasma elimination half-life (t1/2) of PSI-6130 was ~5 hrs, while

 

Summary

·        A mean 2.7 log10 decline and maximum 4.2 log10 decline was demonstrated following 14 days of monotherapy

·        R7128 was generally well-tolerated and demonstrated no evidence of acute target organ toxicity

·        78% of subjects receiving R7128 with abnormal ALT at baseline normalized

·        R7128 was effective as a pro-drug delivery of PSI-6130

·        Terminal plasma half-life of the parent compound, PSI-6130, was ~5 hrs; terminal plasma half-life of the metabolite, PSI-6206, was ~20 hrs

·        A maximum tolerated dose of R7128 has not been identified

 

Conclusions:

·        R7128 has provided positive proof-of-concept that a direct acting antiviral can deliver sufficient antiviral potency via monotherapy to suppress below the level of detection (<15 IU/mL) in a prior IFN non-responder population

·        BID dosing of R7128 was superior to QD dosing in this monotherapy trial

·        Lack of clinical rebound provides early evidence of high genetic barrier for nucleoside inhibitors of NS5b polymerase

·        The safety and efficacy of this monotherapy study support further development of R7128 in combination with the standard of care (pegylated interferon and ribavirin)

 

Dose

750mg QD (n=8)

1500mg QD (n=8)

750mg BID (n=8)

1500mg BID(n=10)

Mean baseline  

HCV RNA  

concentration  

(log10 IU/mL)

 

 

-0.90

 

 

-1.48

 

 

-2.11

 

 

-2.72

Mean(range)  

change from  

baseline on  

Day 15  

(log10 IU/mL)

 

 

-0.67

To

-1.10

 

 

-0.90

To

-2.50

 

 

-1.80

To

-3.00

 

 

-1.2

To

-4.21

Proportion  

with ≥1 log  

decline by  

Day 15

 

3 of 8

37.5%

 

7 of 8

87.5%

 

8 of 8

100%

 

8 of 8

100%

 


Topic: Diagnostic tools

 

1335. European Liver Fibrosis (ELF) panel of serum markers can predict clinical outcome in a cohort of patients from England with mixed aetiology chronic liver disease

J. Parkes; P. Roderick; S. Harris; C. Gough; M. Wheatley; G. J. Alexander; J. D. Collier; C. P. Day; D. J. Mutimer; J. Ramage; A. Burt; W. M. Rosenberg 

 

Introduction

The performance of non-invasive tests has been evaluated against fibrosis on biopsy but use of clinical outcomes as the reference standard would be ideal. The ELF panel of markers (TIMP1, HA, PIIINP) has been shown to have excellent ability to identify significant fibrosis on biopsy. To evaluate ELF performance in predicting clinical outcomes, the original ELF cohort was followed-up at 8-9 years. 

 

Methods

Patients recruited to the ELF study at 6 centres were followed up for liver morbidity and mortality by examination of clinical data. Those lost to follow up were followed up for morbidity by questionnaires to the family practitioner. Primary outcome measure was liver related morbidity or death; secondary outcome was all-cause mortality.

 

Results

448 patients were followed up after a median of 7.7 years representing 99% of those recruited at 6 sites. Median age=43 years, 67% male, 44% CHC and 17% ALD. 28% were lost to follow up and 13% were discharged. 85% of family practitioner questionnaires were returned reporting no liver outcomes. There were 57 liver outcomes (34 liver related deaths) and 61 deaths in total. Crude unadjusted analyses by Kaplan Meier plots showed that tertiles of baseline ELF score can predict liver outcomes and all-cause mortality (log rank test p= <0.001) (Figure 1). Histology was also predictive of outcome when classed as mild, moderate or severe fibrosis. Cox Proportional Hazards model analyses show that ELF remains predictive when adjusted for age, gender and disease aetiology (p=<0.0001); adjusted hazard ratio for the middle tertile ELF score versus lowest tertile ELF score= 4.06 (95% CI 1.55-10.624), and for highest tertile ELF score versus lowest tertile, HR=29.87 (95% CI 8.55-104.42)

 

Conclusions

ELF score can predict clinical outcomes in patients with chronic liver disease at least as well as liver biopsy, and is likely to be a useful prognostic tool in clinical practice.

 

Figure 1 

Kaplan-Meier plot for liver related outcome ELF tertiles

 


Topic Disease Progression

 

1336. Tracking the Course of Hepatitis C with Paired Biopsies - A Critical Analysis

M. Rajablou; A. S. Mugglin; K. P. Batts; C. I. Smith 

 

Purpose:

To determine if paired liver biopsies in following the course of patients with hepatitis C is of value.

 

Methods:

Blinded histologic re-examination of liver biopsy samples was undertaken from a cohort of 161 chronic hepatitis C patients who had undergone at least two (non-protocol) liver biopsies. Fibrosis was assessed using the Batts/Ludwig 0-4 staging system, with intermediate stages (e.g. 1.5) being used in an attempt to maximize the sensitivity. Grade and other co-morbid conditions were also recorded. The rate of fibrosis (stage/year) was determined both from the paired samples ("short-term rate") and from the estimated time of infection by hepatitis C (per history) to the first liver biopsy ("long-term rate"). Linear regression was used to assess the relationship of demographic variables to fibrosis rate. Linearity of long-term fibrosis change over time was assessed via polynomial regression.

 

Results:

Of the 161 paired biopsy patients, 136 had historical information allowing estimation of a long term rate of fibrosis prior to therapy: mean time interval to first biopsy 23.6 years; stages: <1 (17.6%, mean 21.4 yrs), 1-2 (71.3%, mean 24.0 yrs), >2 (11.0%, mean 24.8 yrs); overall fibrosis rate .06545 stages/year with "best fit" statistical analysis revealing non-linearity of the stages (p < 0.001). Body mass index (BMI) (p= 0.018) and increased age at infection (p<0.0001) were associated with accelerated rates of fibrosis. The mean interval between biopsy samples was 4.1 years; overall stage increased by just 0.168 stages (8.7% decreased, 67.1% stable, 10.6% increased by 0.5 stage and 13.7% by one stage or more), resulting in an overall short term fibrosis rate of 0.03995 stages/year; BMI (p=0.0032) was associated with more rapid fibrosis. No association between long-term and short-term fibrosis rates was detected (correlation = -0.018, p = 0.83). 

 

Conclusions:

Short-term (~4 years) follow up biopsy in hepatitis C patients uncommonly (13.7%) demonstrates a significant (one or more stage) increase in stage. Increased BMI is associated with more rapid progression. Short-term fibrosis rate cannot be used to predict long term fibrosis rate, perhaps in part because the individual 0-4 stages are likely not of equal time duration (non-linear), making comparison of long-term and short-term fibrosis rates problematic.

 


Topic: Disease Progression

 

1337. Long-term Morbidity and Mortality of HCV Infection: A 25 years Follow-up

S. Kamal; I. Nasser; S. El Kamary; M. Shardell; M. Hashem; A. Ibrahim; A. Moustafa; I. Fathy; M. Sobhi; A. Abdel Baky; H. Mansour 

 

Background/Aims:

The natural history of HCV is highly variable and not well characterized. Most cohort studies have not been well controlled with serial liver biopsies to estimate true disease progression. The aim of this study was to investigate the long-term clinical and histological outcome of a cohort of untreated and treated subjects followed for 25 years with a known onset of acute HCV.

 

Study design/methods:

In this retrospective-prospective longitudinal cohort study, archived serial serum samples from 420 subjects with non A-non B acute hepatitis between 1981-1982 were re-screened for HCV (ELISA, PCR). Of the 385 subjects with proven acute HCV, 36 subjects refused ebrollment, 45 had coinfections and were excluded, and 214 were enrolled and prospectively followed. Clinical, virological and HRQL evaluations were performed. Liver biopsies were either available at entry (n=49) or were performed at enrollment (n=96), Liver biopsies were repeated6-17 years after the initial biopsies in patients considered for treatment,. Ishak score and fibrosis progression rates were determined. The clinical end-points were end-stage disease, hepatocellular carcinoma (HCC), liver transplantation or death.

 

Results:

The disease duration ranged between 22-25 years. .Of the 385 patients with acute hepatitis C, 127 subjects (33%) had spontaneous persistant resolution. At baseline, none of the 214 patients with chronic hepatitis had clinical decompensation, HCC or significant impairment of HRQOL. Eighty-two patients (38%) had history of interferon therapy or were treated during the study. \ The baseline mean necroinflammatory and fibrosis scores were 2.8±3.9 and 0.5±0.02 respectively. Progression of fibrosis was detected in 123 untreated patients (57.4%), and 18 patients with no response to treatment. . The mean rate of fibrosis progression in untreated patients was 0.19± 0.08 in men and 0.08± 0.01 in women (p<0.05). Improvement in fibrosis scores was detected in all treated patients with sustained virologic response. The rate of progression was non linear and higher in older patients. During follow-up significant impairment of HRQOL was reported in 63 subjects (29.4%), end-stage disease in 41 (19%), liver transplantation in 23 (10.7%), HCC in 23 (10.7%). Death due to liver-related causes was reported in 23 patients (11%).

 

Conclusion:

Disease progression is non-linear in HCV with accelerated disease over time in untreated patients resulting in complications of chronic liver disease, hepatocellular carcinoma and death. Cohort studies and clinical decisions based on single biopsy estimates of disease progression may underestimate the risk of fibrosis progression.

 


Topic: Diagnostic Tools

 

1338. Diagnostic Accuracy of the APRI for the Prediction of Hepatitis C-Related Fibrosis: A Systematic Review

A. Shaheen; R. P. Myers 

 

Background:

The development of noninvasive markers of liver fibrosis is a clinical and research priority. The aspartate aminotransferase to platelet ratio index (APRI) is a promising tool with limited expense and widespread availability. Our objective was to systematically review the performance of the APRI in hepatitis C virus (HCV)-infected patients.

 

Methods:

An electronic search on Medline, EMBASE, and the Cochrane Library (01/1997-12/2006), supplemented with a manual search, identified studies comparing the APRI with liver biopsy for the assessment of HCV-related fibrosis. Random effects meta-analyses and areas under summary receiver operating characteristic curves (AUC) were examined to characterize APRI accuracy for significant fibrosis (stages 2-4) and cirrhosis. Random effects meta-regression was used to determine the impact of study and patient-related factors on APRI performance. 

 

Results:

In 22 studies including 4,266 patients (median age, 44 years; 61% male), the prevalence of significant fibrosis and cirrhosis were 47% (range 9-72%) and 15% (range 7-33%), respectively. The summary AUCs of the APRI for these outcomes were 0.76 (95% CI 0.74-0.79) and 0.82 (95% CI 0.79-0.86), respectively. For significant fibrosis, an APRI threshold of 0.5 was 81% sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this threshold had a negative predictive value (NPV) of 80%, but could reduce the necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was 76% sensitive and 71% specific. At a 15% cirrhosis prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had sub-optimal positive predictive values except in settings with a high prevalence of cirrhosis. APRI accuracy for significant fibrosis was not affected by the prevalence of advanced fibrosis, or study and biopsy quality. However, the accuracy for cirrhosis was greater in studies including HIV/HCV-coinfected patients. 

 

Conclusions:

The major strength of the APRI is the exclusion of significant HCV-related fibrosis. Future studies of novel markers should demonstrate improved accuracy and cost-effectiveness compared to this economical and widely available index.

 


Topic: Diagnostic tools

 

1339. Comparison of reproducibility of histology, blood tests and Fibroscan for liver fibrosis

P. Cales; J. Boursier; M. Rousselet; S. Michalak; F. Oberti; Y. Gallois; V. De Ledinghen; F. Lunel 

 

Aim:

Our aim was to compare the reproducibility of histology, blood tests and Fibroscan for liver fibrosis by comparing the intra-method and the inter-method agreements by taking as histological reference the reading by a senior expert pathologist.

 

Methods:

Several studies were used. All patients had chronic liver disease. Agreements were evaluated with kappa index (κ) and intraclas correlation coefficient (Ric).

 

Results:

1/ Intra method agreement. Blood tests. In study 1, 33 patients and 12 laboratories were included; Ric was: APRI: 0.897, FibroMeter: 0.942. In study 2, 20 patients and 10 laboratories were included; Ric was: APRI: 0.949, Fibrotest: 0.984, FibroMeter: 0.963. In study 3, 33 patients and 2 laboratories were included; Ric for FibroMeters was: virus: 0.991, alcohol: 0.976, NAFLD: 0.990. Liver biopsy. Intra center agreement. In study 4, the Metavir staging was evaluated in 44 patients by 4 pathologists from an academic hospital: κ=0.59. In study 5, agreement was evaluated between one senior and one junior expert in 157 patients: κ=0.48. Inter center agreement. In 1998 (study 6), agreement was evaluated in 26 patients between an academic senior expert and 10 non-expert out-pathologists: κ=0.13 and Ric=0.69. In 2003 (study 7), 33 patients were evaluated by 8 out-pathologists: κ=0.18 and Ric=0.69. In 2004, the agreement was between one expert from the Metavir group and 6 out-pathologists in 205 chronic hepatitis C (study 8): κ=0.336 and Ric=0.649. Fibroscan. 46 patients and 4 observers were enrolled into the study 9: Ric=0.93. 2/ Comparison between methods. Non invasive tests translated into Metavir F stages. The agreement of FibroMeters was: Ric=0.965, κ=0.874 (study 3). Agreement of Fibroscan was: Ric=0.84-0.89, κ=0.63-0.65 (study 9). Misclassification rates. The misclassification rates for significant fibrosis were: blood tests: FibroMeter: 23.3%, Fibrotest: 27.9%, Hepascore: 27.8% in 825 patients (study 10); liver biopsy: 22.9% against senior expert (study 8), 9.6% against consensus reading (study 5); Fibroscan: 16.5% in 194 patients (study 11), 20% in 65 patients (study 11) and 24.1% in 461 patients (study 13).

 

Conclusions:

Intra method reproducibility is as follows: blood test > Fibroscan > histology. Considering the liver interpretation by a senior expert or consensus reading as the reference, the agreement between measurements is as follows: blood test > Fibroscan > histology. In routine practice, the observed misclassification rate of non invasive tests is similar to that of liver biopsy. Finally, liver biopsy should be considered as a specialized tool read by experts whereas non invasive tests are more reproducible in clinical practice.

 


Topic: Disease Progression

 

1340. Histological Outcomes After 30 Years In Untreated Irish Women With Chronic HCV Genotype 1b, Do Genetic Factors Influence?

S. Barrett; J. A. Browne; C. O' Keane; R. A. Levine; J. P. Crowe 

 

Background and Aims:

The cohort of Irish women infected with Hepatitis C virus (HCV) genotype 1b in 1977, represent a unique homogenous group to investigate the natural course of HCV infection. We have previously demonstrated strong genetic associations with viral clearance in this cohort. More recently, we have demonstrated minimally progressive disease and histological improvement (after 27 years) in serial liver biopsies. To date we have not investigated whether genetic factors are responsible for the favourable histological outcomes observed in serial liver biopsies. In the current study we aim to describe the natural history of infection after 30 years and to investigate whether genetic factors including HLA Class I and Class II (DRB1 and DQB1) alleles or polymorphisms of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma genes could predict biochemical or histological outcomes.

 

Methods:

The study cohort comprised of 56 untreated women with persistent viremia who had paired or multiple liver biopsies. All were infected with HCV genotype 1b in 1977. Biochemical (alanine aminotransferase [ALT]) and histological assessments in serial liver biopsies were performed. Baseline and sequential biopsy specimens were assessed for grade (increase/decrease of 2 points) and stage change (increase/decrease of 1 point). Genotyping for the various genetic markers was carried out on genomic DNA using polymerase chain reaction sequence-specific primers. 

 

Results:

The mean age of the 56 women at the time of baseline biopsy was 44.3 [range 23-57]. The mean baseline grade and stage scores were 3.89 [range 2-9] and 0.72 [range 0-3] respectively. Mean number of biopsies was 2.73±0.7 and mean interval to last biopsy was 7.5 years [range 1-13]. Over this time period, grade scores remained unchanged in 51.8%, increased in 28.6% and improved in 19.6% patients; stage scores remained unchanged in 55.4%, increased in 17.9% and improved in 17.9% patients. The mean baseline ALT was 45.5 [range 11-110]. There were positive correlations between baseline ALT, grade and stage and between sequential grade and stage scores. Only DQB1 0203 was associated with increased ALT values (p<0.024). There were no significant associations between genetic factors and histological outcomes. 

 

Conclusion:

A benign course of HCV genotype 1b infection with 17.9% disease regression was observed in untreated women with paired or multiple liver biopsies 30 years after infection. Genetic factors including HLA Class I and Class II (DRB1 and DQB1) alleles or polymorphisms of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma genes do not account for this favourable histological outcome.

 


Topic: Disease Progression

 

1341. Higher Caffeine Consumption is associated with Milder Fibrosis in patients with Chronic Liver Diseases

A. A. Modi; J. J. Feld; Y. Park; J. Everhart; T. Liang; J. H. Hoofnagle 

 

Introduction:

Two recent population-based surveys (NHANES I and III) have reported that higher caffeine consumption was associated with lower risk of elevated ALT levels and lower risk of chronic liver disease (CLD). 

 

Aim:

To develop an instrument to assess caffeine consumption and evaluate the association of caffeine intake with severity of fibrosis in pts with CLD.

 

Methods:

A questionnaire aimed at measuring caffeine consumption over the previous month was developed and administered to all pts undergoing liver biopsy. Modified from a Nurses Health study questionnaire, it asked the frequency of consumption of caffeine-containing foods and beverages, including soft drinks, coffee, tea, cocoa as well as caffeine-fortified drinks, chocolate bars, caffeine-containing medications and alcohol intake. Caffeine consumption was quantified as the average mg of caffeine per day in which one 8 oz cup of coffee = 136 mg. Routine liver tests were obtained at the time of questionnaire completion, and liver histology was scored using a modified Ishak scoring system for activity and fibrosis. Logistic regression was performed to evaluate the association of caffeine with advanced liver fibrosis (Ishak score≥3).

 

Results:

Among the 182 pts (60% male, 58% Caucasian, mean age 48 years), 112 had HCV, 38 HBV, 3 HDV, 21 NASH, 4 PBC and 4 AIH. 137 pts underwent liver biopsy and 30% had advanced fibrosis. The average caffeine intake was 193 mg/day (~ 1.5 cups of coffee/day). No patient reported more than minimal alcohol intake. Repeat administration of the questionnaire (> 2 weeks after initial) demonstrated consistency in reporting of caffeine intake (Cronbach coefficient alpha = 0.97). Among the entire cohort, after adjusting for other factors known to be associated with fibrosis (age, sex and baseline ALT), caffeine intake ≥ 300 mg/day (~2.2 cups of coffee daily) was associated with reduced fibrosis compared to lesser amounts or no caffeine intake (OR=0.39, 95% CI 0.15-1.03, p=0.057). The effect of caffeine was even more pronounced in pts with HCV. HCV pts with caffeine intake ≥ 300 mg/d were 88% less likely to have advanced fibrosis than pts with lower consumption both by univariate and multivariate regression (adjusted OR=0.22, 95% CI 0.06-0.89, p= 0.03). Higher caffeine consumption was also independently associated with ALT values below the median (58 IU/l) for the HCV cohort (OR=0.37 95% CI 0.15-0.92, p=0.03).

 

Conclusions:

Higher caffeine consumption is associated with milder fibrosis in pts with CLD, particularly those with HCV infection.

 


Topic: Diagnostic Tools

 

1342. Large scale validation of the SAFE (Sequential Algorithms for Fibrosis Evaluation) biopsy in chronic hepatitis C

G. Sebastiani; P. Halfon; L. Castera; S. Pol; D. L. Thomas; A. Mangia; V. Di Marco; M. Pirisi; M. Voiculescu; M. Bourliere; A. Alberti 

 

Background:

Noninvasive methods have been proposed in hepatitis C as surrogates of liver fibrosis but their diagnostic performance is not such to completely substitute liver biopsy. Moreover, large validation studies are still pending. We have recently proposed sequential algorithms that combine AST/Platelets Ratio Index (APRI) and Fibrotest (FT) with liver biopsy, with excellent performance and >50% reduction in liver biopsy needed (J Hepatol 2006;44:686-93). These algorithms (SAFE biopsy) are based on sequential use of APRI and FT,restricting liver biopsy to cases in which these noninvasive markers show insufficient accuracy.

 

Aim:

Large-scale validation of the SAFE biopsy to identify significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4) in hepatitis C.

 

Methods:

International, multicenter study of 1978 HCV monoinfected cases (1112 males, 866 females; mean age: 46.9+11.9yrs). FT and APRI were measured at the time of liver biopsy,taken as gold standard. Subgroup analysis was conducted to determine whether age, gender, HCV genotype and BMI modify the performance of SAFE biopsy.

 

Results:

Performance of the SAFE biopsy using the cutoff for APRI and FT of the original studies is shown in table. Overall, SAFE biopsy for significant fibrosis saved 47.1% of liver biopsies with >95% accuracy. SAFE biopsy for cirrhosis also had excellent performance and saved 82% of liver biopsies. The performance of SAFE biopsy was excellent across all major HCV genotypes while it was somehow reduced for ≥F2 with age >50yrs (AUC=0.83, p=0.001 vs. overall AUC) and for F4 with BMI>30 (AUC=0.84, p=0.01). Therefore, specific cutoff for FT (0.57 for ≥F2 with >50yrs; 0.84 for F4 with BMI>30) were identified, allowing to optimise the performance of SAFE biopsy (AUC=0.87 for ≥F2 with >50yrs; AUC=0.90 for F4 with BMI>30). SAFE biopsy applied to HCV patients with normal ALT showed excellent performance (AUC=0.94 for ≥F2; AUC=0.89 for F4).

 

Ideal target populations for screening:

·        HCV patients aged > 60 years (5-15% Mediterranean population)

·        HCV carriers with normal ALT (20-25% have significant fibrosis)

·        Candidates to antiviral therapy with relative contraindications

·        HCV-1 patients with high virus loads. 

 

Conclusions:

This large-scale, multicenter validation study confirms that SAFE biopsy is a rational way of combining noninvasive markers with marked reduction in liver biopsies needed to correctly classify liver fibrosis in hepatitis C. This approach can be useful for large scale screening of HCV patients.

 

 

Overall

<50 yrs

>50 yrs

BMI<30

BMI>30

SAFE biopsy

≥F2

F4

≥F2

F4

≥F2

F4

≥F2

F4

≥F2

F4

Sens (%)

100

89.3

100

92.3

100

98.5

100

91.5

100

80

Spec (%)

88

94.6

86.3

97.6

66.4

92.6

83.2

95.5

69.2

89.4

PPV (%)

92.3

64.9

83.9

63.2

84.1

59.8

89.1

72

91.8

61.5

NPV (%)

100

98.8

100

99.7

100

99.8

100

99.1

100

95.4

Accuracy(%)

95.1

93.5

92

97.4

87.9

93.2

92.6

95

93.1

37.7

AUC

0.89

0.92

0.93

0.94

0.83

0.89

0.92

0.94

0.86

0.84

Saved biopsies (%)

47.1

82

31.8

89

58.9

73.8

41.4

72.5

45.2

71.9

 


Topic: Diagnostic Tools

 

1344. Interobserver Reproducibility of Liver Stiffness Measurement by Transient Elastography (FIBROSCAN®)

D. Lucidarme; G. Forzy; V. Gremaux; B. Filoche 

 

Background:

The results of transient elastography using FibroScan (Echosens, Paris, France) are expressed as a median value of 10 validated liver stiffness measurements (LSM). The purpose of this study was to evaluate the inter-observer reproducibility of LSM by transient elastography.

 

Patients and methods:

LSM was performed by 2 different operators who were blinded to the other’s result in 399 patients (mean age: 48 y; males: 63%, BMI: 24.0 Kg/m2) with chronic liver diseases of various causes (VHC: n = 167; VHB: n = 41; NASH: n = 85; alcohol: n = 39; other: n = 67). Thirty patients in whom one operator failed to obtain 10 successful acquisitions were excluded from the analysis. Results of 369 patients were analyzed. Variability between the 2 operators was evaluated by the inter-observer gap between LSM [(LSM operator 1 – LSM operator 2)/ (average LSM operators 1 and 2)]. Inter-observer agreement was analyzed using the intra-class correlation coefficient (ICC) and kappa index for the diagnosis of cirrhosis using a threshold of 14,6 KPa (1). The effect on agreement of age, gender, BMI, etiology of liver disease, rate of success, median value of LSM, interquartile range (IQR) and the ratio between IQR on the median value of LSM (IQR/LSM) was assessed by comparing 2 groups according to the median inter-observer gap.

 

Results:

The median inter-observer gap was 0.21. The overall inter-observer ICC was 0.87, and kappa index was 0.73. By univariate analysis, median value of LSM and IQR/LSM were associated with agreement (P < 0.10). In multivariate analysis, IQR/LSM was the only factor independently associated with the median inter-observer gap (P < 0,001). Four groups (Gr) were defined according to IQR/LSM. Gr1: Both operators found an IQR/LSM < 0,2 (n = 119): median inter-observer gap = 0,15; ICC = 0.99, and kappa index = 0,95; Gr2: At least one of the two operators found an IQR/LSM > 0,2 and < 0,3 (n = 124): median inter-observer gap = 0,19, ICC = 0.86, and kappa index = 0,64; Gr3: At least one of the two operators found an IQR/LSM > 0,3 and < 0,5 (n = 84): median inter-observer gap = 0,23; ICC = 0.84 and Kappa index = 0,60; Gr4: At least one of the two operators found an IQR/LSM > 0,5 (n = 42): median inter-observer gap = 0,41 ; ICC = 0.41, and kappa index = 0,58. The ICC and kappa index of Gr1 were different from those of the 3 other groups (P < 0.05).

 

Conclusion:

The reproducibility of transient elastography is excellent. However, IQR/LSM is a key factor of inter-observer agreement. The reproducibility of transient elastography is significantly reduced in patients with IQR/LSM > 0,2.

1) Ganne-Carrié et al. Hepatology 2006;44:1511-7.

 


Topic: Diagnostic Tools

 

1346. The result of liver stiffness measurement is influenced by the serum bilirubin level

Y. Seo; S. Suh; Y. Kwon; S. Park; B. Keum; B. Park; Y. Kim; Y. Jeen; H. Chun; C. Kim; H. Ryu; S. Um 

 

Background/Aim:

Although liver stiffness measurement (LSM) using FibroScan is usually well correlated with the fibrosis score on liver biopsy, discrepancies between the results of LSM and fibrosis score could appear in some patients. Until now, except fibrosis score, any factors which could influence the result of LSM were not identified. This study was performed to evaluate whether acute liver injury could affect the result of LSM.

 

Methods:

All consecutive patients with acute hepatitis who admitted to our hospital during 6 months were included. Patients with previous or family history of liver disease were excluded. These patients were subjected to FibroScan during admission and followed 1-6 months later. At the time of LSM, serum AST, ALT, ALP, GGT and bilirubin levels were examined. For validation, correlation between the LSM and fibrosis score were compared according to the results of biochemical tests in patients who undergone liver biopsy and LSM.

 

Results:

Seventy-five patients with acute hepatitis were enrolled (median age, 30 years; M:F, 40:35). The causes of acute hepatitis were acute hepatitis A in 61 patients, acute hepatitis B in 3, toxic hepatitis in 8, and others in 3. Baseline LSM was 10.6±6.9 kPa (median, 8.8). There was no difference in the results of AST, ALT, ALP and GGT between patients with higher LSM and lower LSM, but bilirubin level was significantly higher in patients with high LSM (P=0.024). Bilirubin level was the only significant correlated factor with LSM in bivariate correlation analysis (Kendall’s correlation coefficient, 0.331; P <0.001). LSM decreased to ≤6 kPa in 44 patients during follow-up. The duration for LSM ≤6 kPa was not different according to sex, age, cause of acute hepatitis, the levels of AST, ALT, ALP, and GGT, but it was significantly longer in patients with higher bilirubin level (80±11 days) than patients with lower bilirubin level (36±4 days; P <0.001). Similarly, bilirubin level was the only significant factor on multivariate analysis (OR, 0.265; 95% CI, 0.127-0.552). In 92 patients who performed liver biopsy, Kendall’s correlation coefficient between the results of LSM and fibrosis stage was 0.553 and AUROC for ≥F2, ≥F3, and F4 was 0.808, 0.877, and 0.913, respectively. When 7 patients with jaundice were excluded, the improvement of correlation and increase of AUROC were noted (Kendall’s correlation coefficient, 0.650; AUROC for ≥F2, ≥F3, and F4, 0.891, 0.915, and 0.923, respectively).

 

Conclusion:

Serum bilirubin level seems to affect the result of LSM. Caution is required when interpret the result of LSM in patients with jaundice.

 


Topic: Disease Progression

 

1347. Obesity is an Independent predictor of fibrosis progression in patients with chronic Hepatitis C Virus (HCV) using paired liver biopsy specimens

A. A. Pillai; L. M. Yerian; R. Lopez; I. A. Hanouneh; N. N. Zein 

 

Introduction:

Obesity is a contributing factor to the development of steatosis and in treatment failure in chronic HCV.

 

Aims:

Evaluate the interaction between obesity and fibrosis progression in a cohort of HCV patients with paired liver biopsies.

 

Methods:

We identified all HCV patients with at least two liver biopsies (1997-2006). Patients with insufficient tissue (<10 portal tracts) or lack of body mass index (BMI) were excluded. A hepatopathologist scored 215 biopsies from 102 patients for necroinflammation (modified histologic activity index (HAI)) and fibrosis (Ishak, stage 0-6). A change by at least one histologic stage was used to define progression or regression. Univariable and multivariable logistic regression analysis was performed to assess the association of baseline factors with advanced fibrosis on each of the paired biopsies separately. To assess factors associated with progression between the two biopsies, a Cox regression model was used. Backward elimination method was used to select factors included in the final model.

 

Results:

Time between 1st and 2nd biopsy was 1-13.5 years in which 43% of subjects had progression, 29% had no change and 27% had regression. Rate of change between 1st and 2nd biopsy was -0.16 to 0.49 units annually. Older age, higher HAI score and diabetes were independently associated with advanced fibrosis in 1st and 2nd biopsy. Obesity (BMI >30) was the only factor found to be significantly associated with fibrosis progression between 1st and 2nd biopsy by univariable (P=0.023) and multivariable (P=0.006) analysis, independent of antiviral therapy. A Kaplan-Meier plot was constructed (Figure) to outline the association between obesity and fibrosis progression.

 

Conclusions:

1)Older age, higher HAI score and diabetes in chronic HCV patients are independently associated with advanced fibrosis in a cross-sectional single time point biopsy. 2)Using paired biopsy specimens, obesity is a strong predictor of fibrosis progression over a defined time interval between biopsies.

 

 


Topic: Diagnostic Tools

 

1348. Accurate Identification of Liver Fibrosis Using the Point-Of-Care Continuous 13C Methacetin Breath Test: A Decision Making Tool in the Treatment of Patients with Chronic HCV Infection

G. Lalazar; O. Pappo; Y. Ilan 

 

Introduction:

Current treatment of chronic HCV infection is based on the degree of hepatic fibrosis. Liver biopsy has been the gold standard for this assessment. The point-of-care non-invasive BreathID® continuous online 13C methacetin breath test (MBT) reflects hepatic microsomal function (CYP1A2) and was shown to correlate accurately with the degree of hepatic fibrosis.

 

Aim:

To develop a treatment algorithm for patients with chronic HCV infection based on detection of the degree of liver fibrosis using MBT.

 

Methods:

100 patients with chronic HCV infection and 100 healthy, age and sex-matched controls underwent 13C MBT following ingestion of 75 mg methacetin. All HCV patients had undergone a liver biopsy within 6 months of performing the MBT. Breath test parameters tested included PDR Peak (percentage dose recovered), PDR Peak Time, and both PDR and CPDR (cumulative PDR) 10, 20, 30 and 60 minutes after ingestion of methacetin, respectively. The correlation between breath test parameters and the Ishak modified histological activity index (HAI) fibrosis score, age, weight and BMI was determined. The ability of MBT to correctly identify liver fibrosis was assessed. Patients with a HAI fibrosis score ≤ 2 or > 2 were defined as non-significant or significant fibrosis, respectively.

 

Results:

MBT parameters were significantly correlated with the stage of fibrosis (p<0.0001). By using an algorithm that includes age, PDR Peak, PDR Peak Time, PDR30 and CPDR20-60, 67% of liver biopsies performed in the patient group could have been avoided. This algorithm achieved an area under the curve (AUC) of 0.92, with a sensitivity of 91% and a specificity of 88%, a PPV of 88% and NPV of 91%. Thirty three patients were identified as having significant fibrosis, including 4 false positives; two with a HAI fibrosis score of 2 and an additional two with a score of 1. Thirty four patients were identified as having non-significant fibrosis including 4 false negatives; two with a HAI fibrosis score of 3 and one with a score of 5. There was no correlation between age or BMI and MBT scores for patients with the same histological score.

 

Conclusions:

The BreathID® continuous online 13C MBT accurately detects liver fibrosis in patients with chronic HCV infection enabling a non-invasive alternative to liver biopsy. Using the above algorithm, liver biopsy could have been avoided in two thirds of this patient population. MBT is a practical non-invasive tool for decision-making in the evaluation of patients with chronic HCV infection.

 


Topic: Diagnostic Tools

 

1349. Iron overload does not effect the quantification of fibrosis by Liver Stiffness Measurement

V. Di Marco; F. Bronte; D. Cabibi; F. Barbaria; Z. Borsellino; G. Alaimo; V. Calvaruso; S. Ciminnisi; M. Capra; A. Maggio; P. Almasio; A. Craxě 

 

Background and aims:

Several studies report a close relation between liver stiffness measured by FibroScan (Echosens, France) and fibrosis evaluated by liver biopsy (LB), but the influence of iron overload on liver stiffness measurement (LSM) is unknown. Aim of our study was to evaluate the correlation between liver fibrosis, iron overload and LSM in patients with Homozygous β- Thalassemia (HβT) and in patients with chronic hepatitis C.

 

Methods:

52 patients with HβT (mean age 27 years; 18 HCV-RNA positive and 34 HCV-RNA negative) and 104 non-thalassemic adults with chronic hepatitis C (mean age 55±10.6 years, mean BMI 27.3±4.7 Kg/m2) underwent LB (mean length of biopsy 17 mm) and simultaneous LSM. Liver inflammation and fibrosis were scored according to METAVIR, steatosis according to Brunt’s score and LIC was measured on fresh tissue cores by atomic absorption spectrometry and was expressed as mg/gr of liver dry weight (normal values < 1.6 mg/gr).

 

Results:

The degree of liver fibrosis, the LSM expressed as KPa, and the LIC in patients with HBT and in patients with chronic hepatitis C are reported in the table 1.

LSM increased proportionally to the METAVIR stage, with a highly significant relation to fibrosis (rho= 0.70; p >0.001 by Spearman’s test) independently of LIC values (r= 0.16; p= 0.07 by Spearman’s test), both for thalassemics and non-thalassemics patients. At univariate analysis, LSM correlated with histological grading (95% CI: 3,0–37,5; p < 0.0001), presence of steatosis (p< 0.0001) and degree of fibrosis (95% CI: 2,8–37,5; p < 0.0001). At multivariate analysis, presence of steatosis (r= 0.362; p < 0.0007 and fibrosis (r= 0.684; p < 0.0001) remained factors associated with LSM. LSM had excellent value in discriminating patients with F4 fibrosis (i.e. cirrhosis), but was less performing at lower stages of fibrosis.

 

Conclusion:

LSM by FibroScan is an adequate and reliable non-invasive tool to diagnose advanced liver fibrosis even in subjects with severe liver iron overload.

Liver fibrosis, LSM (expressed as KPa) and the LIC (expressed as mg/gr of liver dry weight) in patients with HβT and in patients with chronic hepatitis C

Liver Fibrosis (METAVIR)

HβT patients (52)

LSM  

(median, range)

LIC  

(median, range)

Chronic Hepatitis C patients (104)

LSM  

(median, range)

LIC (median, range)

F0/F1

23

4.9 (3.2-10.1)

3.51 (0.50-10.71)

18

6.0 (3.1-10.3)

0.46 (0.10-3.66)

F2

14

5.1 (2.8-6.8)

2.86 (0.77-22.03)

48

6.7 (3.8-16.9)

0.48 (0.12-2.69)

F3

8

7.1 (4.7-10.4)

2.73 (0.23-6.96)

21

13.6 (6.6-25.8)

0.36 (0.05-4.04)

F4

7

15.9 (13.1-21.3)

6.66 (0.66-11.73)

16

17.6 (8.0-37.7)

0.52 (0.16- 6.78)

 


Topic: Diagnostic Tools

 

1351. Serum levels of sH2a, a secreted form of the asialoglycoprotein receptor, as a non-invasive sensitive marker for liver function

E. Veselkin; M. Kondratyev; E. Ron; M. Santo; S. Reif; I. Elashvili; L. Bar; Y. Lurie; R. Oren; G. Z. Lederkremer 

 

Purpose:

We have evaluated the possible use of a soluble secreted form of the human asialoglycoprotein receptor (ASGPR sH2a) as a new non-invasive marker for the sensitive assessment of liver function. The current markers (prothrombin time, albumin and others) can only detect liver dysfunction in advanced disease. On the other hand, blood levels of enzymes such as alanine and aspartate aminotransferases (ALT and AST) indicate liver damage and not function and can appear normal in many cases of liver disease or abnormal in a wide range of non-hepatic diseases. sH2a is liver-specific as it is secreted to the serum exclusively by hepatocytes. 

 

Methods:

We have measured sH2a levels in serum using a monoclonal antibody and an ELISA assay that we developed, comparing with routine liver function tests. 

 

Results:

We determined in a series of double blind studies that sH2a was present at very constant levels in serum from 57 out of 63 healthy control individuals. The <10% of controls that showed abnormal levels of sH2a also revealed borderline levels for one or more of the established liver function markers. A study of 43 HCV patients showed abnormal sH2a values in 25% of those at fibrosis stage 0, 37% of those at stage 1, 57% at stages 2-3 and 100% at stage 4 (cirrhosis). The combined analysis of sH2a levels and those of ALT and AST allows prediction of fibrosis stage. 

 

Conclusions:

sH2a appears to be a uniquely sensitive marker of liver function with potential widespread use. In combination with routine markers it could also be used for non-invasive determination of fibrosis stage.

 


Topic: HIV/HCV Coinfection

 

1353. Natural history of hepatitis C virus infection in HIV-infected individuals in the era of HAART: systematic review and meta-analysis

H. Thein; Q. Yi; G. J. Dore; M. D. Krahn 

 

Objectives:

Our objectives were to estimate stage-specific hepatic fibrosis progression rates in HIV/hepatitis C virus (HCV) coinfected individuals and to determine factors associated with fibrosis progression in this population, including the impact of HIV on HCV disease progression.

 

Methods:

A systematic review of published prognostic studies was undertaken. Study inclusion criteria were: i) HIV and HCV infections determined by serological assays; ii) information about age at assessment of liver disease or HCV acquisition; iii) duration of HCV infection; and iv) histological fibrosis staging (F0-F4) and/or clinical diagnosis of cirrhosis. Annual stage-specific transition probabilities (F0→F1, F3→F4) were derived using the Markov maximum likelihood estimation method and a meta-analysis was performed using both fixed and random effects models. The impact of covariates – study design (cross-sectional/retrospective, prospective, retrospective-prospective), study setting (clinical-/community-based), age at/duration and mode of HCV infection, gender, alcohol consumption, HCV genotype and RNA, CD4 cell count, and highly active antiretroviral therapy (HAART)) on fibrosis progression was evaluated using meta-regression models. Pre-HAART and HAART era cirrhosis rates were compared in studies reporting both HCV groups. Sixteen of 65 studies reviewed fulfilled the inclusion criteria. Mean (95% CI) fixed effects annual transition rates of the HIV/HCV coinfected individuals (82% injection drug users) were: F0→F1 0.119 (0.114, 0.125); F1→F2 0.118 (0.112, 0.125); F2→F3 0.156 (0.145, 0.169); and F3→F4 0.122 (0.109, 0.137). Random effects estimates showed comparable results.

 

Results:

The mean (95% CI) probability of cirrhosis after 20 and 40 years was 25% (22%, 27%) and 77% (74%, 79%), respectively. All covariates of interest were significantly associated with fibrosis progression from F0→F1, while study setting and HCV RNA positivity were associated with progression from F3→F4. Overall, the rate ratio (95% CI) of cirrhosis between HIV/HCV coinfected and HCV monoinfected individuals was 2.1 (1.8, 2.5): 1.7 (1.1, 2.7) in the pre-HAART era (n=6); and 2.2 (1.9, 2.6) in the HAART era (n=10).

 

Conclusion:

In conclusion, our predicted estimates for cirrhosis in HIV/HCV coinfected individuals appear to be higher than published estimates for HCV monoinfection. This study improves on previous studies by using a method that does not require the assumption of constant transition rates between stages and taking into account the effects of study design and setting, clinical factors, and HAART on disease progression.

 


Topic: HIV/HCV Coinfection

 

1354. Validation of simple indexes (FIB-4, APRI, Forns index) and platelet count for non invasive prediction of liver fibrosis in HIV-HCV coinfected French patients.

L. Castera; M. Loko; F. Dabis; B. Le Bail; M. Winnock; G. Coureau; D. Neau 

 

Background:

Several non-invasive indexes using routinely available parameters have been proposed recently for the prediction of liver fibrosis in patients with chronic hepatitis C. However, little information regarding the validity of these indexes in human immunodeficiency virus (HIV)-HCV coinfected patients is available. 

 

Aim:

To determine the diagnostic performance of FIB4, APRI, Forns index and platelet count for the prediction of liver fibrosis in HIV/HCV coinfected patients.

 

Methods:

200 HIV/HCV co-infected patients (male 66%, age 40±6 yrs) of the ANRS CO3 Aquitaine Cohort who underwent liver biopsy between 1999 and 2005 and had complete data to validate all the considered tests, were studied. Liver fibrosis was assessed using METAVIR scoring system and diagnostic performance by measuring areas under the ROC curve (AUROC).

Results: Significant fibrosis (F2-F3-F4) was present in 157 patients (78.5%) and cirrhosis (F4) in 19.5%. Performance of the different methods using the published cut-offs are shown in the table.

 

Conclusion:

Overall, the diagnostic accuracy of these indexes was lower in HIV-HCV coinfected patients than in HCV monoinfected patients, particularly for the diagnosis of significant fibrosis. However, the use of FIB-4, APRI or platelet count may obviate the need for liver biopsy for the diagnosis of severe fibrosis-cirrhosis in up to 55% to 85 % of cases in HIV-HCV coinfected patients.

 

End-point

Significant fibrosis  

F2-F3-F4

Severe fibrosis  

F3-F4

Cirrhosis  

F4

Indexes

Forns

APRI

Fib-4

APRI

Platelet

Cut-offs

<4.2

>6.9

<0.5

>1.5

<1.45

>3.25

<1.0

>2.0

<130

Se(%)

83

23

78

28

73

31

77

41

59

Sp(%)

35

100

65

98

70

93

71

91

91

PPV(%)

86

100

89

98

57

71

39

53

62

NPV(%)

30

21

44

27

83

72

92

86

90

AUROC

0.75

0.77

0.77

0.80

0.78

Saved biopsies(%)

25

35

56

65

85

 


Topic: Diagnostic Tools

 

1355. Can platelet count or APRI be the poor man’s Transient Elastography in HCV patients?

V. Calvaruso; S. Maimone; F. Bronte; L. Marelli; V. Di Marco; P. Manousou; A. Corbani; E. Xirouchakis; A. Sigalas; G. M. Dusheiko; A. Craxi'; A. K. Burroughs 

 

Background:

Non invasive tests for fibrosis are being evaluated extensively in many clinical settings, to substitute for liver biopsy, particularly in HCV disease. Transient elastography (TE) is the major indirect test for fibrosis with good accuracy to identify cirrhosis.

 

Aim:

To assess TE measurements (Fibroscan) in relation to platelet count and APRI score (AST(/ULN)/PLATELET(109/L) x 100) in two independent cohorts of HCV patients. 

 

Patients and methods:

333 HCV-RNA PCR positive patients (having excluded 16 patients due to TE technical failure), not receiving antiviral therapy, nor co-infected, nor alcohol abusers (198 in Palermo, 135 in London) had TE, liver function tests and platelet count assessed contemporaneously. Main patient characteristics are shown in the table. Correlations were evaluated by linear regression analysis. 

 

Results:

There was a similar and significant correlation between platelet count and stiffness measurement: r = 0.69(Palermo) and 0.63(London), both p < 0.001. APRI had a correlation of r = 0.74, p<0.001, in each group evaluated independently. 

 

AUROC curve for platelets was 0.82 for Stiffness ≥ 8.3KPa (Metavir ≥ F2) and 0.88 for Stiffness ≥ 14KPa (Metavir = F4). The best platelet cut off values were 195.000 for Stiffness ≥ 8,3 and 160.000 for Stiffness ≥ 14 with sensitivity 77% and 80%; specificity 73% and 83%; PPV 74% and 67%; NPV 75% and 91%; diagnostic accuracies 75% and 82% respectively.

 

AUROC curve for APRI was 0.88 for both cut off stiffness values. APRI cut off values were 0.6 for Stiffness ≥ 8.3 and 1.0 for Stiffness ≥ 14 with sensitivity 84% and 83%; specificity were 74% and 78%; PPV 76% and 62%; NPV 82% and 91% respectively; Diagnostic accuracies 79% for both cut offs. 

 

Conclusion:

Easily available serum markers of platelet count and AST have good correlation with liver stiffness measurements across the spectrum of HCV liver disease including cirrhosis. The AUROC values for platelet count are similar to those for indirect fibrosis markers for F2 or more or F4(Coco J Viral Hep 2007;14:360). The use of APRI is better than platelet count for non cirrhotic fibrosis, but has the same AUROC as platelet count in cirrhosis.

Characteristics of Patients

 

All patients (333)

Palermo pts(198)

London pts (135)

p

Males

187(56%)

109(55%)

78(58%)

n.s.

Age Mean(range)

55  

(9-84)

56  

(9-77)

54  

(24-84)

n.s.

AST(U/l)  

Mean(range)

71  

(11-262)

74  

(11-262)

67  

(15-261)

n.s.

ALT (U/l)  

Mean(range)

92  

(11-373)

96  

(11-375)

86  

(12-373)

n.s.

Platelet count  

Mean(mm3/L)  

(range)

189  

(20-457)

168  

(20-345)

218  

(48-457)

< 0.001

APRI

1.3

1.5

1.0

0.001

Stiffness (Kpa)  

Mean(range)

13.0  

(3-75)

14.6  

(3-75)

10.8(3.2-53)

0.001

Cirrhosis

106(32%)

74(37%)

32(24%)

0.009

 


Topic: Epidemiology

 

1358. Evolution of hepatitis C virus (HCV) viremia in prospectively followed intravenous drug users (IVDU:s) with documented anti-HCV antibody seroconversion participating in a Swedish needle-exchange program

M. Alanko; P. Björkman; V. Molnegren; L. Flamholc; A. Widell 

 

Background:

The dynamics of HCV viremia following acute HCV infection have mostly been studied in cases of symptomatic acute hepatitis C, which represent a minor proportion of incident HCV infections. We used sera drawn approximately every 3-6 months for surveillance of blood-borne viruses among participants in a needle-exchange program (NEP) to assess the longitudinal evolution of HCV viremia in incident HCV infection. 

 

Methods:

Out of 1150 newly registered participants in a NEP in Southern Sweden, 1997-2005, 198 cases of anti-HCV antibody seroconversion were identified during longitudinal follow-up. The last anti-HCV negative, the first anti-HCV positive, and one sample obtained one year after seroconversion , were tested for HCV RNA load using real-time PCR (Roche Taqman) at 1/10 serum dilution (detection limit 150 IU/mL).

 

Results:

HCV RNA was detected in 81 (41%) of anti-HCV negative pre-seroconversion sera. HCV viremia was detected in the 1 year sample in 145 cases (73%), indicating probable establishment of chronic infection.

Eight patterns of longitudinal HCV viremia were observed (Median viral load, see Table): 

 

1)     undetectable HCV RNA in all samples (17; 8.6%) 

2)     undetectable HCV RNA pre-seroconversion and at one year, detectable HCV RNA in seroconversion sample (16; 8.1%)

3)     undetectable HCV RNA in first two samples, detectable HCV RNA at one year (19; 9.6%) 

4)     undetectable HCV RNA pre-seroconversion, detectable HCV RNA in both later samples (65; 33%)

5)     detectable HCV RNA pre-seroconversion, both later samples undetectable HCV RNA (7; 3.5%)

6)     detectable HCV RNA in first two samples, undetectable HCV RNA one year later (13; 6.6%)

7)     detectable HCV RNA pre-seroconversion and at one year, undetectable HCV RNA in first post-seroconversion sample (17, 8.6%)

8)     detectable HCV RNA in all samples (44; 22%).

 

Conclusions:

Several different patterns of HCV viremia were observed in acute hepatitis C in this cohort of IVDU:s, most of whom had subclinical acute HCV infection. Chronic infection developed in 73% of cases and HCV viremia was detected in 41% of the last anti-HCV negative pre-seroconversion samples.

 

Median viral HCV RNA load*(IU/mL) during follow-up in IVDU:s with anti-HCV antibody seroconversion.

 

No

Last anti-HCV neg

First anti-HCV pos

One year later

A

17

-

-

-

B

16

-

810

-

C

19

-

-

24 700

D

65

-