Additional Tuesday Poster Sessions,  November 4, 2007

 

Topic: Current Treatment - Pegasys

 

164.  HCV Patients with Genotype 2 or 3 Who Do Not Achieve a Rapid Virologic Response (RVR) with Peginterferon alfa-2a (40KD)(PEGASYS®) and Ribavirin (COPEGUS®) Are Not Easy to Treat: An analysis of non-RVR patients from the ACCELERATE study

M. L. Shiffman; D. R. Nelson; G. Hooper; D. Messinger; S. Zeuze

 

Background:

Patients with HCV genotypes (GT) 2 or 3 have traditionally been referred to as “easy to treat”. However, data from the ACCELERATE trial have demonstrated that this is not true for all of these patients.

In this study 1463 treatment-naive patients with HCV genotype 2 or 3 were randomized to receive either 16 or 24 weeks of peginterferon alfa-2a (40KD) 180 µg/week and ribavirin 800 mg/d. Overall 66% of these patients were HCV RNA undetectable at treatment week 4; defined as a rapid virologic response (RVR). These patients had an SVR of 79% and 85% with 16 and 24 weeks of treatment respectively. In contrast, patients with HCV genotype 2 or 3 who had detectable HCV RNA at week 4 (non-RVR) had an SVR rate of only 45% with 24 weeks of treatment. This analysis explores baseline (BL) factors that may identify those non-RVR patients who are more likely to achieve an SVR with either 16 or 24 weeks of therapy.

 

Methods:

All patients who received at least one dose of study drug and who did not achieve an RVR were included in this analysis (ITT population). Patients were dichotomised by BL factors and rates of SVR calculated as a function of treatment duration.

 

Results:

466 non-RVR patients were included in this analysis (Table). Patients with a BL HCV RNA <400,000 IU/mL had similar rates of SVR with 16 and 24 weeks of treatment. For all other BL characteristics non-RVR patients treated for 24 weeks had a higher SVR rate compared to patients treated for 16 weeks (overall 44.7 vs 26.4%). In patients treated for 24 weeks GT 2 (vs GT 3), absence of cirrhosis and younger age were associated with at least 10% higher rates of SVR.

 

Conclusions:

Patients with HCV GT 2 or 3 who do not achieve an RVR are not “easy to treat” and have low rates of SVR. The SVR in those patients treated for 24 weeks with GT 2, absence of cirrhosis and younger age is consistently above 50%, but this is still significantly inferior to that observed in patients with an RVR. RVR remains the strongest predictor of SVR and studies to evaluate the impact of prolonging treatment to 48 weeks in patients with HCV GT 2 or 3 who do not achieve an RVR are warranted.

Rate of SVR in non-RVR pts (ITT)

Characteristic

16wks (n=220)

24wks (n=246)

Geographical region

Non-US

US

18/62 (29.0%)

40/158 (25.3%)

29/66 (43.9%)

81/180 (45.0%)

Genotype 2

Genotype 3

27/103 (26.2%)

31/117 (26.5%)

53/99 (53.3%)

57/145 (39.3%)

HCV RNA (IU/mL)

≤400 000

>400 000

14/28 (50.0%)

44/192 (22.9%)

17/32 (53.1%)

93/214 (43.5%)

HCV RNA (IU/mL)

≤800 000

>800 000

19/46 (41.3%)

39/174 (22.4%)

27/57 (47.4%)

83/189 (43.9%)

Cirrhosis

No

Yes

47/146 (32.2%)

11/74 (14.9%)

90/174 (51.7%)

20/72 (27.8%)

Age (years)

<45

≥45

30/85 (35.3%)

28/135 (20.7%)

44/83 (53.0%)

66/163 (40.5%)

BMI (kg/m2)

≤30

>30

45/139 (32.4%)

13/81 (16.0%)

75/157 (47.8%)

35/89 (39.3%)

 


Topic: Experimental Therapies - R1626

 

167. Robust Synergistic Antiviral Effect of R1626 in Combination with Peginterferon alfa-2a (40KD), with or without Ribavirin – Interim Analysis Results of Phase 2a Study

P. J. Pockros; D. Nelson; E. Godofsky; M. Rodriguez-Torres; G. Everson; M. W. Fried; R. H. Ghalib; S. A. Harrison; L. M. Nyberg; M. L. Shiffman; G. Z. Hill; A. Chan

 

Introduction:

The novel nucleoside, R1626, is a potent inhibitor of the HCV RNA polymerase. When administered as monotherapy to patients with chronic hepatitis C, R1626 demonstrates dose-dependent decreases in HCV RNA blood levels.

 

Method:

This Phase 2a study evaluated the safety and efficacy of R1626 administered for 4 weeks in combination with 180 µg peginterferon alfa-2a (PEG-IFNα-2a) ± 1000–1200 mg ribavirin (RBV) in HCV genotype 1 treatment-naive patients. 104 patients were randomized to: Dual Low: 1500 mg bid + PEG-IFNα-2a (n=21); Dual High: 3000 mg bid + PEG-IFNα-2a (n=32); Triple Low: 1500 mg bid + PEG-IFNα-2a + RBV (n=31); SOC: PEG-IFNα-2a + RBV (n=20). Virological response was measured by Roche COBAS TaqMan (undetectable <15 IU/mL).

 

Results:

At 4 weeks HCV RNA was undetectable in 81% of patients treated with Triple Low (mean reduction of 5.2 log10 IU/mL), 69% treated with Dual High (mean reduction of 4.5 log10 IU/mL), and 33% treated with Dual Low (mean reduction of 3.6 log10 IU/mL), compared to only 5% of patients treated with SOC (mean reduction of 2.4 log10 IU/mL). Synergy was observed between R1626 and SOC (additional 2.8 log10 IU/mL, Triple Low vs. SOC), and between R1626 and RBV (additional 1.6 log10 IU/mL, Triple Low vs. Dual Low) (Figure). ALT normalized in approximately 50% of patients in R1626 treatment groups.

 

Most adverse events (AEs) were mild or moderate. Six patients had 8 serious AEs during the 4-week period: 4 in Dual High, 1 in Triple Low and 1 in SOC. The incidence of Grade 4 neutropenia was 48%, 78%, 39% and 10% in Dual Low, Dual High, Triple Low and SOC, respectively and was the main reason for dose reductions.

 

Conclusion:

In conclusion, a robust synergistic antiviral effect was observed when R1626 is combined with PEG-IFNα-2a ± RBV, with up to 81% of patients undetectable by week 4. Dosing of R1626 may be limited mainly by neutropenia; additional studies of different dosages of R1626 in combination with PEG-IFNα-2a and RBV are underway.

 


Topic:  Current Treatment – Consensus Interferon

  

168. The DIRECT Trial (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy): Treatment of Non-Responders to Previous Pegylated Interferon plus Ribavirin: Sustained Virologic Response Data

B. Bacon ; A. Regev; R. H. Ghalib; G. Morelli; K. D. Rothstein; M. L. Shiffman; T. Hassanein; J. Hammond

 

Background:

Approximately 50% of HCV treatment-naïve patients treated with pegIFN/RBV fail therapy. A controlled trial of re-treatment of pegIFN/RBV non-responders with a subsequent course of pegIFN/RBV resulted in only a 3% sustained response. Daily use of consensus interferon (CIFN), which in vitro has been shown to be more effective than IFN alfa-2a and IFN alfa-2b, allows constant pharmacologic pressure on HCV and, when combined with RBV, may be an effective treatment option for previous pegIFN/RBV non-responders.

 

Methods:

The DIRECT clinical trial was a Phase 3, open-label, multi-center US-based study that enrolled 343 patients who were previous non-responders to pegIFN/RBV therapy. Patients were randomized to receive 48 weeks of CIFN 9μg/day or CIFN 15μg/day both with RBV (1.0-1.2 g/day). Prior to study entry, patients had to have <2log10 decline in viral load (VL) while undergoing at least 12 weeks of previous pegIFN/RBV therapy or have detectable VL at end of treatment after completing at least 24 weeks of therapy with ≥80% adherence. Patients had a negative VL if virus was undetectable by both bDNA and TMA assays. No adjunctive growth factors were used.

Results:

Patient demographics included mean age 50 yr, 71% male, 68% high viral load, 94% genotype 1, mean weight 89 kg, 17% African American, and 67% Caucasian. Other important patient characteristics included 59% with evidence of bridging fibrosis or cirrhosis on biopsy and 79% null responders (<2log10 drop in VL during their previous pegIFN/RBV). In the intent-to-treat analysis, SVR rates were 5% and 10% for CIFN 9μg/day and CIFN 15μg/day, respectively. SVR rates by previous response to therapy and fibrosis score for available patients are listed in Table 1. Discontinuations due to adverse events occurred in 11% and 17% in the CIFN 9μg/day and CIFN 15μg/day arms, respectively.

 

Conclusions:

Use of daily CIFN plus RBV in patients with advanced liver disease who were primarily null responders to previous pegIFN/RBV therapy resulted in viral clearance in a dose-dependent manner. Non-cirrhotic patients who achieved a partial response on their previous pegIFN/RBV treatment achieved the best outcomes, which approached 30% SVR. Daily CIFN up to 15μg/day and RBV was well tolerated in this population of pegIFN/RBV non-responders.

Table 1: Sustained Virologic Response (%) By Previous Response to Therapy and Fibrosis Score

 

 

 

Fibrosis Score (within 3 yr of study entry)

 

 

F0-F3

F4

 

 

9μg CIFN

15μg CIFN

9μg CIFN

15μg CIFN

Previous Response to Therapy

<2 log10

6/106(6%)

11/98(11%)

1/28(4%)

1/41(2%)

>2 log10

1/18(6%)

4/14(29%)

0/7(0%)

0/7(0%)

 


Topic:  Experimental Therapies - Telaprevir

 

175. Final Results of Patients Treated with Peg-Interferon-Alfa-2a (Peg-IFN) and Ribavirin (RBV) Follow-on Therapy After 28-Day Treatment with the Hepatitis C Protease Inhibitor Telaprevir (VX-950), Peg-IFN and RBV

M. Rodriguez-Torres; E. J. Lawitz; J. G. McHutchison

 

Purpose:

Telaprevir (TVR, VX-950) is an orally administered, highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3-4A protease. The VX05-950-102 study was designed to assess the safety of telaprevir when given in combination with Peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV) and to evaluate the antiviral response during 28 days of dosing. After completion of the 28-day study, all subjects received off-study therapy with Peg-IFN/RBV under the clinical care of their physicians. Here we report the outcome of treatment after this post-study therapy.

 

Methods:

This study included 12 treatment-naïve, mostly Latino (10/12),patients infected with genotype 1. All subjects received TVR (750 mg q8h), Peg-IFN alfa-2a (180 µg weekly), and RBV (1000 or 1200 mg daily). At the completion of the 28 days, patients began off-study follow-on therapy with Peg-IFN alfa -2a/RBV.

 

Results:

TVR/Peg-IFN/RBV was well tolerated in the 28-day study, with no serious adverse events. The adverse event profile was consistent with the profile commonly seen with Peg-IFN/RBV therapy. All subjects demonstrated a response to the study drug regimen, with 2 subjects reaching undetectable (< 10 IU/mL, Roche Taqman® Assay) levels of plasma HCV RNA within 8 days of the start of dosing, and all subjects had undetectable HCV RNA at the end of the 28-day study dosing period. At 12 weeks of follow-on therapy after completing the 28-day study dosing, 11 subjects had undetectable HCV RNA. All subjects continued on Peg-IFN/RBV therapy, and were followed for response in accordance with standard practice. Seven patients received a total of 48 weeks of treatment and achieved SVR. One patient received Peg-IFN/RBV for only 18 weeks (total treatment 22 weeks) before discontinuing, but also achieved SVR. Two patients had viral breakthroughs at 12 weeks and 24 weeks of treatment.Two patients were lost to follow up and were undetectable at last assessment. In total, 8/10 patients for whom results are available, achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy.

 

Conclusions:

The rapid and substantial initial antiviral effect of telaprevir was maintained by the majority of patients during post-study therapy with PegIFN/RBV. The observation that SVR was achieved in eight patients, including 1 who completed only 22 weeks of treatment, suggests that telaprevir-based regimens may allow increased SVR rates as compared to current therapies.

 


Topic:  Current Treatment - General

 

176. Pre-treatment PD-1 expression on HCV-specific CTLs predicts early and long-term response to combination therapy in African Americans but not Caucasian Americans

J. Klarquist; L. Golden-Mason; A. S. Wahed; H. R. Rosen

 

Introduction:

African Americans (AA) with chronic HCV are less likely to have a sustained virological response (SVR) to IFN-based antiviral therapy than Caucasian Americans (CA), but mechanisms for these differences are not fully elucidated. Host immune responses are postulated to affect viral kinetics and ultimate outcome of treatment.

 

Aim:

To asses the association of PD-1, recently shown to be an important marker for CTL exhaustion, with early viral decline and ultimate response to treatment in AA and CA with chronic HCV. Methods: 72 genotype 1 patients (30 AA, 42 CA) with chronic HCV were selected from the Virahep-C study based upon presence of relevant HLA alleles. All patients received peginterferon and ribavirin for 24-48 weeks; 31 (43%) experienced SVR. Poor viral decline was defined as less than 1.4 log10 drop in HCV RNA levels between baseline and day 28 (n=28); intermediate, 1.4-3.5 log10 drop (n=24); and marked, >3.5 log10 drop (n=18). Pentamers incorporating 10 HCV epitopes were synthesized to stain PD-1 on a total of 168 pre-treatment, individual, HCV-specific CTL responses.

 

Results:

AA with poor kinetics demonstrated significantly higher pretreatment PD-1 on HCV-specific CTLs than those with marked or intermediate responses (p=.0005). Remarkably, PD-1 on HCV-specific CTLs was 15% higher among AA poor responders compared to the intermediate group. Among CA, pretreatment PD-1 was not significantly associated with early viral kinetics. PD-1 as a predictor of SVR was examined using Poisson regression analysis, with adjustment for race. Among AA, PD-1 expression on HCV-specific CTLs was significantly, inversely associated with SVR (RR=0.95; 95% CI 0.93-0.97; p<.0001). This association, however, was not significant in CA (Figure).

 

Conclusions:

In this large cohort of prospectively characterized patients, pre-treatment PD-1 expression on HCV-specific CTLs was associated with early and long-term virologic response to combination antiviral therapy in AA but not CA patients. These findings suggest that immune factors may contribute to the poor antiviral responses found among AA patients with hepatitis C and provide potential immune targets for manipulation.


Topic:  Experimental Therapies - Telaprevir

   

177. Interim Analysis Results from a Phase 2 Study of Telaprevir with Peginterferon alfa-2A and Ribavirin in Treatment-naïve Subjects with Hepatitis C

I. M. Jacobson; G. T. Everson; S. C. Gordon; R. Kauffman; L. McNair; A. Muir; J. G. McHutchison

 

Background:

The VX05-950-104 study (PROVE1) is a randomized, placebo-controlled Phase 2 study of telaprevir (TVR, VX-950), an HCV protease inhibitor, with Peg-IFN-2a and RBV, in naive subjects with genotype 1 hepatitis C. We report the results of a planned interim analysis.

 

Methods:

Subjects were randomized into 4 groups; 3 groups received TVR 750 mg q8h, Peg-IFN-2a 180 μg/week, and RBV 1000-1200 mg/day for 12 weeks followed by 0 (n=20), 12 (n=80) or 36 (n=82) weeks of Peg-IFN-2a and RBV (TVR/PR groups). The control group (n=81) received up to 48 weeks of Peg-IFN-2a/RBV (PR). This analysis was performed when all treated subjects had completed 12 weeks of dosing. Follow-up information was also obtained for the subjects who completed the 12-week dosing arm. Plasma HCV RNA was isolated for viral sequencing at baseline and at each HCV RNA assessment in samples that contained greater than 1,000 IU/mL.

 

Results: 

The proportion of subjects with undetectable HCV RNA (LOD 10 IU/mL) at Week 4 was 79% (TVR/PR group), and 11% (control group) (p<0.001), and at Week 12 was 70% (TVR/PR group), and 39% (control group) (p<0.001). Viral breakthroughs (increase of > 1-log above HCV RNA nadir) with previously described TVR resistant variants were observed in 12 of 175 (11 genotype 1a and 1 genotype 1b) subjects in the TVR/PR groups. In the group assigned to 12 weeks of treatment, 6 of 9 subjects with RVR and completing 12 weeks of treatment achieved SVR. The remaining 3 subjects relapsed with TVR resistant variants (genotype 1a: R155T/I). Discontinuations due to adverse events were more frequent in the TVR/PR group (11% vs. 3%). Rashes, gastrointestinal events and anemia were more common, and rashes more severe in the TVR/PR groups. An additional interim analysis will be conducted when all subjects have completed 36 weeks on-study, including 12-week post-treatment follow-up for the 24-week study arm subjects.

 

Conclusions:

Compared with standard therapy, significantly more subjects receiving a TVR/PR regimen achieved undetectable HCV RNA at Weeks 4 and 12, and some subjects achieved an SVR after 12 weeks of TVR/PR. Other patients relapsed with TVR-resistant variants, suggesting that 12 weeks of TVR/PR may be adequate to eliminate wild-type virus. The post-treatment follow-up results in the 24-week group will evaluate whether the additional 12 weeks of PR is sufficient to eliminate the remaining TVR-resistant variants.

 

* for the PROVE1 study team

 


Topic:  Experimental Therapies - NTZ

  

178. Interim Data from a Randomized Controlled Trial of Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and Peginterferon-Ribavirin in the Treatment of Patients with Chronic Hepatitis C Genotype 4

J. Rossignol1; A. Elfert; Y. El-Gohary; E. B. Keeffe; J. Glenn

 

Introduction: 

Nitazoxanide (NTZ), a thiazolide anti-infective agent approved in the United States for treating emerging intracellular protozoan infections, blocks viral protein synthesis at a cellular level by selectively inhibiting dephosphorylation of eukaryotic initiation factor 2α (eIF2α). A randomized controlled clinical trial was conducted to evaluate the efficacy and safety of NTZ added to peginterferon α-2a (PegIFN) plus ribavirin (RBV) or PegIFN without RBV in treating chronic hepatitis C genotype 4.

 

Methods:

120 patients with chronic hepatitis C genotype 4 were enrolled in the trial at two centers in Egypt. Liver biopsy was obtained from each patient before enrollment. Patients were sequentially randomized to one of three treatment groups: (a) PegIFN-RBV for 48 weeks (standard of care), (b) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN for 36 weeks, and (c) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN-RBV for 36 weeks. Eleven interferon-experienced patients were allowed to be enrolled in each of the two NTZ groups. NTZ was administered one 500 mg tablet twice daily with food; RBV was administered 1000 mg (weight <75kgs), or 1200 mg (≥75 kgs) daily in divided doses; and PegIFN was injected by clinical investigators once weekly (180 µg). Evaluations performed every 4 weeks during treatment included physical examination, standard laboratory hematologic and chemistry tests and determination of HCV viral load by RT-PCR. The primary endpoint of the study is SVR (HCV RNA <10 IU/mL 24 weeks following end of treatment). Secondary endpoints include RVR (HCV RNA <10 IU/mL after 4 weeks of combination therapy), EVR (≥2 log10 drop in HCV RNA after 12 weeks of combination therapy) and ETR (HCV RNA <10 IU/mL at end of treatment). Analysis is intent to treat.

 

Results:

Baseline viral loads, BMI, fibrosis, age, sex and other demographic and disease-related characteristics were similar across the three groups. RVR, EVR and ETR rates are presented in the table below. Adverse events were similar across the three treatment groups except that the rate of anemia was significantly reduced in the group that did not receive RBV.

 

Conclusions:

The addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates compared with PegIFN-RBV therapy without increase in adverse events. Patients are being followed to evaluate SVR rates. Further trials are being conducted in the United States in patients with genotype 1.

 

Treatment-naive

Treatment-experienced

 

RVR

EVR

ETR

RVR

EVR

ETR

PegIFN-RBV

14/40 (35%)

26/40 (65%)

20/40 (50%)

-

-

-

NTZ-PegIFN

18/29 (62%)

22/29 (76%)

20/29 (69%)

5/11 (45%)

5/11 (45%)

5/11 (45%)

NTZ-PegIFN-RBV

21/29 (72%)

26/29 (90%)

27/29 (93%)

3/11 (27%)

4/11 (36%)

4/11 (36%)

 

 


Topic:  Current Treatment - General

 

179. Importance of a Minimal Residual Viremia for the Relapse Prediction in HCV Type 1 Patients Receiving Standard or Individualized Treatment Duration

T. Berg; V. Weich; G. Teuber; H. Klinker; B. Möller; J. Rasenack; H. Hinrichsen; T. Gerlach; U. Spengler; P. Buggisch; H. Balk; M. Zankel; C. Sarrazin; S. Zeuzem

 

Introduction:

The exact estimation of early virologic response rates in the course of antiviral therapy is an important goal in order to improve individualized therapeutic strategies in HCV infection. The sensitive TMA test could provide better advantage to distinguish at early stages sustained from non-sustained responders.

 

Method:

We evaluated HCV type 1 patients who took part in a prospective study asking whether the application of TMA in bDNA-negative patients may be a better indicator to predict long-term outcome of the HCV infection.

 

433 patients were randomized to receive either 1.5ug/kg PEG-INFa-2b plus 800-1400 mg RBV for 48 weeks (n=225, group A) or an individualized tailored treatment duration (n=208, group B). In the latter group treatment duration was calculated by the time required to become for the first time HCV RNA negative as defined by bDNA assay (detection limit 615 IU/mL) multiplied by the factor 6. HCV RNA levels were quantified weekly until week 8, at week 12 and 24. For all those patients who were bDNA negative the more sensitive TMA test (detection limit 5.3 IU/mL) was also prospectively assessed. The different response groups were classified according to the HCV RNA levels at week 4 and 12 (Table).

 

Results:

Table shows the relevant data and refers to the relative relapse rates in group A and B at week 4 and 12 in relation to the treatment schedule. There is clear evidence for a high relapse rate in patients with a positive TMA within the first 12 weeks of therapy being more pronounced when treatment duration shortened in the individualized treatment group. In contrast patients shown to respond as early as week 4 evidenced by a negative TMA test had relapse rates below 10% irrespectively from treatment group.

 

Conclusion:

The application of the highly sensitive HCV RNA tests must be considered to be now mandatory because this new test helps to evaluate in a much more refined way treatment response as well as relapse rates and provides better clues for an individualized tailored treatment strategy. Thus our study clearly indicates that patients even with a minimal amount of HCV RNA detected at week 12 can suffer from relapse rates greater than 50%. These patients may indeed benefit when their treatment duration is adapted to their individual needs.

 

Response groups

Relative relapse rate (%)

 

 

 

week 4

response

>= log decline,

bDNA positive

36%

(all patients)

19%

(group A)

63%

(group B)

bDNA negative,

TMA positive

38%

(all patients)

22%

(group A)

49%

(group B)

bDNA negative,

TMA negative

4%

(all patients)

0%

(group A)

8%

(group B)

week 12

response

>= 2log decline,

bDNA positive

77%

(all patients)

78%

(group A)

75%

(group B)

bDNA negative,

TMA positive

64%

(all patients)

56%

(group A)

69%

(group B)

bDNA negative,

TMA negative

20%

(all patients)

9%

(group A)

32%

(group B)

 


Topic:  Current Treatment - Pegasys

 

180. Sustained Virologic Response rates with albinterferon alfa-2b plus ribavirin treatment in IFN-naïve, chronic hepatitis C genotype 1 patients

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

 

Aim/Background:

This Phase 2b study evaluates the efficacy and safety of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of IFNa-2b genetically fused to human albumin, in combination with oral ribavirin (RBV) in IFN-naïve, chronic hepatitis C genotype 1 patients.

 

Methods:

458 patients were randomized to 4 treatment arms: PEG-IFNa-2a 180mcg Q1w (PEG-IFN) or one of 3 alb-IFN arms (900mcg Q2w, 1200mcg Q2w or 1200mcg Q4w), all in combination with weight-based oral RBV1000-1200 mg/d (Table). HCV RNA was measured by real-time PCR (limit of detection [LOD]: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (SVR) defined as HCV RNA

 

Results:

By ITT analysis, SVR rates were 58.5% for the 900Q2, 55.5% for 1200Q2, 50.9% for 1200Q4 and 57.9% for PEG-IFN (Table). In patients with ≥80% adherence to therapy, SVR rates were 71.6% for the Q2w alb-IFN arms compared to 66.7% for PEG-IFN. Of note, in heavier patients (≥75 kg) adherent to therapy, SVR rates were maintained for the alb-IFN arms and declined for PEG-IFN. Discontinuations due to adverse events in the alb-IFN arms were 9.3% in the 900Q2, 18.2% in the 1200Q2 and 12.1% in the 1200Q4 compared with 6.1% for PEG-IFN. Hematologic reductions were lowest in the Q4w arm and comparable across other arms. Quality-of-life as measured by SF-36v2 and missed work was significantly more favorable for the 900Q2w arm.

 

Conclusions:

These data suggest that the Q2w alb-IFN may offer comparable efficacy, with an improved dosing schedule and quality-of-life compared with current standard of care with PEG-IFN.

 


Topic: Diagnostic Tools

 

181. Ratio Interquartile Range / Median Value of Liver Stiffness Measurement is a Key Factor of Accuracy of Transient Elastography (FIBROSCAN®) for the Diagnosis of Liver Fibrosis

D. Lucidarme; J. Foucher; B. Le Bail; L. Castera; S. Villars; G. Forzy; B. Filoche; P. Couzigou; V. de Lédinghen

 

Background:

The result of transient elastography using FibroScan is expressed as a median value of 10 liver stiffness measurements (LSM). To our knowledge, the role of the interquartile range (IQR) and the ratio IQR/LSM for the performance of FibroScan has not been studied. The aim of this study was to evaluate the influence of these 2 parameters on the accuracy of transient elastography for the diagnosis of liver fibrosis and cirrhosis.

 

Patients and methods:

A total of 254 consecutive HCV patients (mean age 52 y; males 60%, BMI 25.0 Kg/m2) had LSM using FibroScan and liver biopsy (LB) > 15mm (median 22 mm, range 15-50 mm) within one month. Liver fibrosis was staged according to the METAVIR scoring system and cut-off values of LSM according to those previously reported (1). Discordances of at least 2 stages between LSM and histological assessment were observed in 28 cases (11 %). The effect of age, gender, BMI, LB length, activity grade, LSM, success rate of LSM, IQR and IQR/LSM on discordances was assessed by comparing the 28 misclassified cases to the 226 others. The influence of one or several possible predictive factors of discordances was assessed by using the receiver operating characteristics (ROC) curves after assessment of the most significantly discriminant cut-off values.

 

Results:

By univariate analysis, LSM and IQR/LSM were associated with discordances (P< 0.10). By multivariate analysis, IQR/LSM was the only factor independently associated with discordances (P < 0.01). The most significantly discriminant cut-off value was IQR/LSM = 0.2. For IQR/LSM < 0.2 versus > 0.2, discordances of at least two stages of fibrosis were observed in 8/127 cases (6.3 %) versus 20/127 cases (15.7 %), P < 0.02, respectively. In patients with IQR/LSM > 0.2 versus < 0.2, for the diagnosis of liver fibrosis F > 2, F > 3 and cirrhosis, AUROCs were 0.77 versus 0.83 (P = 0.18), 0.79 versus 0.91 for (P < 0.01) and 0.86 versus 0.95 (P = 0.11), respectively.

 

Conclusion:

IQR/LSM is a key factor of accuracy of FibroScan for the diagnosis of liver fibrosis. This ratio significantly improves the performance of FibroScan for the diagnosis of extensive fibrosis (F3). In case of IQR/LSM > 0.2, a new measurement of LS or a LB should be proposed.

 

1) Castera et al. Gastroenterology 2005;128:343-50.

 


Topic:  Diagnostic Tools

 

182. Performance of non-invasive methods in the assessment of disease severity in routine clinical practice in patients with chronic hepatitis C

S. M. Martinez; M. Domínguez; G. Fernandez-Varo; P. Gonzalez; R. Bataller; E. Sampson; W. Jimenez; X. Forns; J. M. Sánchez-Tapias

 

Background:

Prediction of liver fibrosis by means of noninvasive tests is intended to replace liver biopsy in the assessment of disease severity in chronic hepatitis C (CHC).

 

Aim:

The aim of this study was to evaluate the diagnostic performance of several noninvasive methods, alone or in combination, in the detection of significant liver fibrosis or cirrhosis in patients with chronic hepatitis C.

 

Methods:

The performance to predict liver fibrosis was investigated in a cohort of 373 patients with CHC who were candidates to antiviral therapy by the following non-invasive methods: Forns score, AST to platelet ratio index (APRI), liver stiffness measurement (LSM) by transient elastography, and the extracellular matrix markers hyaluronic acid (HA), collagen IV(Col4), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of matrix metalloproteinase 1(TIMP-1). The latter markers were combined in two models: ELF Scheuer (age, PIIINP, TIMP-1 and HA) and 4-marker (PIIINP, TIMP-1, Col4 and HA) (Rosenberg et al. Gastroenterol 2004). Liver fibrosis stage was assessed according to Scheuer classification. Diagnostic accuracies of each method were determined by the area under the ROC curve (AUROC). The predictive value of combinations of these methods was assessed by multiple regression.

 

Results:

Mean age was 47,26 (17-69) years, and 251 (62,6%) were male. The distribution of liver fibrosis stages was: F0: 11,5% , F1: 25,9%, F2: 25,7%, F3: 9,5% and F4: 27,4%. The AUROCs of the different methods for F ≥2 and F4 are shown in table 1. The best diagnostic performance was obtained with combination of APRI index and FibroScan for F ≥ 2 (AUROC = 0,88), and Forns Score and FibroScan (AUROC= 0,90) for F4.

 

Conclusions:

These results show that non-invasive methods are accurate in the prediction of significant fibrosis and cirrhosis. Combinations of these methods improve the diagnostic accuracy, with best diagnostic performance obtained with combination of transient elastography and indirect markers of fibrosis.

 


Topic: Diagnostic Tools

 

184. Comparison of MR elastography, ultrasound elastography and APRI for the non-invasive assessment of liver fibrosis

L. Huwart; C. Sempoux; N. Salameh; L. Annet; Y. Horsmans; B. Van Beers

 

Introduction:

Recently, magnetic resonance (MR) elastography has emerged as a non-invasive method to assess the fibrosis stage. The purpose of our study was to prospectively compare the diagnostic accuracy of MR elastography, ultrasound elastography, and aspartate aminotransferase to platelets ratio index (APRI) for the staging of fibrosis in patients with chronic liver disease.

 

Materials and methods:

Ninety-six patients who had liver biopsy for suspicion of chronic liver disease had MR elastography, ultrasound elastography and APRI within 2 days. Fibrosis stage was assessed by two pathologists according to the METAVIR score (from F0 to F4) that served as reference. MR elastography was performed with a 1.5 Tesla scanner using a motion-sensitized sequence and a transducer that applied mechanical waves into the liver. Ultrasound elastography was performed with the commercially available FibroScan. The measurements of MR elasticity, ultrasound elasticity and APRI were analyzed with receiver operating characteristic curves.

 

Results:

The distribution of fibrosis stage was F0 in 22/96 patients (23%), F1 in 22 (23%), F2 in 19 (20%), F3 in 15 (15%) and F4 in 18 (19%). The areas under the receiver operating characteristic curves of MR elastography (0.994 for F ≥ 2, 0.985 for F ≥ 3 and 0.998 for F = 4) were significantly (P < 0.05) larger than those of ultrasound elastography, APRI and the combination of ultrasound elastography and APRI (respectively 0.837, 0.709 and 0.849 for F ≥ 2; 0.906, 0.816 and 0.936 for F ≥ 3; 0.930, 0.820 and 0.944 for F = 4). The most discriminant cut-off values of MR elasticity were respectively 2.5 kPa for F ≥ 2, 3.1 kPa for F ≥ 3, and 4.1 kPa for F = 4.

 

Conclusion:

The results of this study show that MR elastography is more accurate than ultrasound elastography and APRI to stage liver fibrosis and suggest that MR elastography can be used for the assessment and follow-up of liver fibrosis.

 

F ≥ 2

F ≥ 3

F = 4

Cut-off (kPa)

2.49

3.13

4.13

Sensitivity

1.0 (0.93-1.0)

0.91 (0.76-0.98)

1.0 (0.81-1.0)

Specificity

0.91 (0.78-0.97)

0.97 (0.89-1.0)

0.96 (0.89-0.99)

Positive predictive value

0.93 (0.83-0.98)

0.94 (0.79-0.99)

0.86 (0.64-0.97)

Negative predictive value

1.0 (0.91-1.0)

0.95 (0.87-0.99)

1.0 (0.95-1.0)

Table. Most discriminant MR elasticity cut-off values (kPa) and corresponding sensitivities, specificities, positive and negative predictive values with 95% confidence intervals in parentheses for METAVIR scores F ≥ 2, F ≥ 3 and F = 4.


Topic: Diagnostic Tools

  

185. Fibrotest versus liver biopsy: An independent multicenter evaluation of performance

M. Guido; A. Alberti; G. Bellati; G. Colloredo; A. Craxì; V. Di Marco; S. Fagiuoli; M. Fassan; L. Giacomelli; A. Mangia; G. Sebastiani; M. Rugge

 

BACKGROUND AND AIMS:

Algorithms based on indirect biochemical markers of fibrosis are becoming increasingly popular. Though the Fibrotest (FT) is accredited for the non-invasive assessment of liver fibrosis, its validation against liver biopsy comes mainly from data generated by the center where it was originally developed. In an independent nationwide multicenter study, we aimed to assess the diagnostic accuracy of FT in a large series of patients with chronic hepatitis B and C undergoing liver biopsy (LB) for disease grading and staging. This is the first multicenter study in which all liver biopsies were reviewed at a single center by the same experienced liver pathologist.

 

METHODS:

In all, 496 consecutive patients with chronic HBV (55 cases) or HCV hepatitis were enrolled at five centers where liver biopsies and biochemical markers were collected on the same day. All subjects were HIV negative. The diagnostic value of the FT was assessed, applying logistic regression as a discriminant function, in terms of area under the receiver operating characteristic (ROC) curves (AUCs), sensitivity, specificity, PPV, NPV, general agreement, and kappa score.

 

Liver biopsies more than 2 cm long & with ≥ 11 complete portal tracts (= 277 cases) were considered the “platinum” standard: all analyses were repeated in these biopsies to test the hypothesis that FT might significantly improve its diagnostic accuracy with a better gold standard, assuming that the discrepancy between FT and LB is due mainly to poor biopsy quality.

 

RESULTS:

73% of the biopsy samples were ≥ 2 cm long (median 2 cm; range: 0.5–6.5). According to the METAVIR score, histological fibrosis was F0 in 8% (39/496) of cases, F1 in 29% (142/496), F2 in 35% (176/496), F3 in 13% (63/496), and F4 in 15% (76/496). FT proved scarcely able to discriminate between single fibrosis stages and 34% of cases had intermediated values and cannot be classified. Table 1 summarizes the diagnostic value of FT in discriminating between absent/mild fibrosis and severe fibrosis/cirrhosis. The results did not change when the analysis was restricted to the “platinum” standard biopsies.

 

CONCLUSIONS:

FT performs best in discriminating severe fibrosis/cirrhosis from absent/mild fibrosis, but it does not accurately predict the various intermediate stages of fibrosis. Its performance does not improve significantly with better-quality liver biopsies.

Table 1

 

AUC-ROC

SENS

SPEC

NPV

PPV

Agreement

k

F0/F1 vs. F2/F4

0.77

0.71

0.72

0.59

0.82

71.98

0.42

F0/F2 vs. F3/F4

0.82

0.64

0.83

0.85

0.64

78.43

0.47

 


Topic:  Diagnostic Tools

 

186. Prospective comparison of two algorithms combining non invasive tests for staging of liver fibrosis in chronic hepatitis C

L. Castera; G. Sebastiani; B. Le Bail; V. de Ledinghen; P. Couzigou; A. Alberti

 

Background:

Non invasive assessment of liver fibrosis is a challenging area. Numerous markers are available but their performance may be better when combined. Two algorithms have been proposed recently in patients with chronic hepatitis C, combining either transient elastography (Fibroscan) and Fibrotest (Castera et al. Gastroenterology 2005) or Fibrotest and AST to Platelet Ratio (APRI) (Sebastiani et al. J Hepatol 2006).

 

Aim:

to prospectively compare the diagnostic performance for significant fibrosis and cirrhosis of these 2 algorithms in the same population.

 

Methods:

302 consecutive HCV patients (58% male, mean age 52±12 yrs) who undergone liver biopsy (>10mm and 6 portal triads) were studied. Fibroscan, Fibrotest and APRI were performed in the same lab the day of liver biopsy taken as reference. Fibrosis was scored according to the Metavir scoring system. Diagnostic performances were assessed by measuring area under the ROC curve (AUROC).

 

Results:

Significant fibrosis (F2-F3-F4) was present in 76% of patients and cirrhosis (F4) in 24%. The mean liver biopsy length was: 20±8 mm. Fibroscan failure was observed in 8 cases (3%). Performance of the 2 algorithms using the cutoffs for APRI and fibrotest of the original studies are shown in the table.

 

For significant fibrosis, Castera algorithm saved 23% more liver biopsies than Sebastiani algorithm but its accuracy was lower (AUROC 0.91 vs. 0.94; accuracy 87.1% vs. 97.0%, respectively). Regarding cirrhosis, Castera algorithm was slightly more accurate (AUROC 0.93 vs. 0.87; accuracy 95.7% vs. 88.7%, respectively) and saved 4% more liver biopsies. However, Castera algorithm was less cost-effective (using both 100% Fibroscan and Fibrotest) than Sebastiani algorithm (using 100% APRI (virtually no cost) and around 50% Fibrotest).

 

Conclusion:

Both algorithms are effective for the non invasive staging of liver fibrosis in chronic hepatitis C. Their use in clinical practice could avoid the need for liver biopsy in 48 to 71% of cases for the diagnosis of significant fibrosis and in 74 to 78% of cases for cirrhosis.

 

 

Castera algorithm

Sebastiani algorithm

End Point

F2-F3-F4

F4

F2-F3-F4

F4

APRI performed

none

none

100

100

Fibrotest performed

100

100

43.7

61.9

Fibroscan performed

100

100

none

none

Sensitivity (%)

85.1

89.4

100

86.4

Specificity (%)

97.2

98.2

87.3

89.7

PPV (%)

98.9

95.0

96.3

77.6

NPV (%)

66.9

95.9

100

94.1

Accuracy (%)

87.1

95.7

97.0

88.7

AUROC

0.91

0.93

0.94

0.87

Saved biopsies (%)

71.9

78.8

48.3

74.8