Abstract ID: S1531

 

Interim Results From the PACT-Trial: High Antiviral Efficacy Of Daily Consensus Interferon/ribavirin Compared To Peg-Interferon Alfa2b/ribavirin in Treatment-Naive Patients With Chronic Hepatitis C and Serotype-2 or -3

 

W. Bocher, M. Fuchs, P. Buggisch, S. Kaiser, R. Link, J. Nalop, C. Antoni, J. Schlaak, T. Witthft, P.R. Galle, H.F. Lhr

 

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 peg-IFNa2b plus ribavrin.

 

Methods

400 patients with chronic HCV infection and serotype-2 or -3 will randomly be assigned to treatment with 9 mcg qd CIFN sc. (group A) or peg-IFNa2b (1,5 mcg/kg body weight once weekly, group B), each in combination with ribavirin (>10,6 mg/kg body weight) for 24 weeks. Treatment is interrupted for primary non-response, if viral load drops by less than 2 log until week 12 or drops by more than 2 log but remains positive at week 16. Follow up includes further 24 weeks. Viral response rates are analysed by the Roche COBAS Amplicor HCV Monitor v2.0 test. 129 patients out of 199 patients enrolled before November 2004 reached at least the end of treatment at week 24 and represent the base of this interim analysis. At the Meeting, ETR data of 170 patients will be presented.

 

Results

There were no significant differences in patient baseline characteristics between both treatment groups concerning age, gender, genotype and viral load. The virological response rates analysed as intend-to-treat are shown in the Table:

 

 

 

Group

A

 

Group

B

 

wk 12

(n=67)

wk 24

(n=68)

wk 48

(n=43)

wk 12

(n=60)

wk 24

(n=61)

wk 48

(n=38)

PCR neg

99%

93%

95%

92%

94%

95%

 

Thus, end-of treatment response (ETR) rates as well as sustained virological response (SVR) rates were very high and identical in both treatment groups. This was also true for all subgroup analyses, including analysis according to baseline viral load (< vs. ≥ 800.000 IU/ml) gender, body weight (< vs. ≥ 75 kg) and age (< vs. ≥ 60 yrs). Treatment was rather well tolerated in both treatment groups, as there were no significant differences in the numbers of serious adverse events or preterm treatment discontinuations.

 

Conclusions

In treatment-naive patients with chronic hepatitis C and serotype-2 or -3 infection, daily treatment with CIFN combined with ribavirin has the same antiviral efficacy and safety profile as weight adjusted peg-IFNa2b. Further analyses will show, whether some subgroups might preferentially benefit from one or the other interferon.


Abstract ID: S1546

The Efficacy Of Two Different Doses Of Peginterferon -2b and Ribavirin Combination Therapy in HIV/HCV Coinfected African American Patients

 

G. Hammoud, J. Li, K. Vega, P. Wludyka, B. Rodwick, D. Parks, M. Davis, R. Berggren, R. Emgunsnov, R. Eng, D. Lintz, K. Casey, D. Mayorga, L. Lambiase

 

Background

African American monoinfected patients are known to have a lower response to hepatitis C virus therapy in comparison to Caucasian patients. Moreover, HIV/HCV coinfected patients have a lower response to HCV therapy than monoinfected patients. We investigated the difference in response to HCV combination therapy using two different doses of peginterferon α-2b in HIV-infected African American (AA) patients.

 

Aim

To evaluate the efficacy of the standard dose peginterferon α-2b versus the low dose peginterferon α-2b in addition to a weight based ribavirin in HIV/HCV coinfected nave and non-responder African American patients.

 

Methods

Originally, this study was designed to investigate the response to two different doses of peginterferon α-2b among different racial groups. We present a sub-analysis of the response among African American subjects in the two arms. Sixty three patients were enrolled and randomized to low dose (LD, n=32) peginterferon alpha-2b 1.0 mcg/kg administered once/week and standard dose (SD, n=31) peginterferon alpha-2b 1.5 mcg/kg administered once/week. Both groups received ribavirin at 132 mg/kg administered twice daily for 48 weeks. Five Latino patients were excluded from this analysis (SD=3, LD=2). The remaining 58 patients are (African American = 31, males=20, LD=15, SD=16, nave=20, genotype 1=29, median HCV viral load 850,000 IU/ml), (Caucasians=27, males=20, LD=15, SD=12, nave=18, genotype 1=20, median HCV viral load=837,140). HCV was measured by a quantitative PCR assay at baseline, week 12, 24, 48 and 72. Sustained virologic response (SVR) is defined as undetectable HCV six months post therapy.

 

Results

Seven patients (12%) achieved sustained viral response (AA = 2 (3%) and Caucasians = 5 (9%), p = 0.16). None of the AA patients with genotype non-1 (6%) achieved SVR while only two Caucasian patients (7%) with genotype non-1 had SVR on low dose (22%), (p=1.0). One previous non-responder AA patient (3%) achieved SVR on HD (2%), while non of the previous non-responder Caucasian patients had SVR and only four nave Caucasian patients (15%) achieved SVR on low dose (p=0.09).

 

Conclusion

African American patients had a better response with standard peginterferon α-2b especially in a previous non-responder to standard interferon, while Caucasian patients had a better response with low dose peginterferon α-2b, however, this did not reach statistical significance due to the small number of patients with SVR in both arms.


Abstract ID: 5

Sustained Virologic Response (SVR) With PEG-Interferon-Alfa 2b/ribavirin Weight Based Dosing in Previous Interferon/ribavirin HCV Treatment Failures; Week 12 Virology As a Predictor Of SVR in the EPIC3 Trials

 

T. Poynard, E. Schiff, R. Terg, F. Goncales, S. Flamm, M. Diago, J. Reichen, R. Moreno, H. Tanno, J. McHutchison, H. Fainboim, T. Berg, A. Mattos, K. Burak, P. Mukhopadhyay, P. Bedossa, L. Griffel, M. Burroughs, C. Brass, J. Albrecht

 

Introduction

EPIC3 is a large, prospective, controlled trial designed to understand 1) the efficacy of treatment with PEG-Interferon a2b and ribavirin weight based dosing for 48 weeks in previous treatment failures to any interferon-a and ribavirin therapy and 2) for non-responders to PEG-Interferon a2b and ribavirin, to determine the efficacy of PEG-Interferon a2b 0.5 mg/kg/week compared to no treatment in either delaying progression of hepatic fibrosis or preventing end stage liver disease in cirrhotics.

 

Aim

The SVR rate in a similar population (HALT-C) retreated with PEG-Interferon alfa-2a plus ribavirin was low (12%). This led us to examine the SVR to PEG-Interferon a2b and ribavirin weight based dosing in the first 575 patients in EPIC3. Additionally, we evaluated the ability of early virologic response (EVR [>2 log10 decrease or undetectable HCV-RNA at week 12]) to predict the likelihood of achieving SVR (undetectable HCV-RNA at follow up [FU] weeks 12 or 24).

 

Methods

HCV + patients that did not respond (NR) or had relapsed after previous treatment with any interferon-a and ribavirin received PEG-Interferon a2b 1.5 mg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day weight based dosing for up to 48 weeks. All patients had pre-treatment biopsies scored by a single reviewer using METAVIR criteria. Plasma HCV-RNA was determined at weeks 12, 24 and 48 of therapy and FU 12 and 24 using a quantitative Taq-Man assay (SPRI; sensitivity 29 IU/mL). Genotype was determined by sequencing the PCR product.

 

Results

Of the first 575 patients enrolled in the combination therapy trial, 21% achieved SVR. Of those who attained EVR, 38% achieved SVR: 61% of those that were HCV-RNA (-) at week 12 achieved SVR, but only 5% of those who attained EVR with detectable viral load. SVR was higher in genotype 2/3 patients (54%) compared to genotype 1 patients (16%) and greater in previous relapsers (39%) compared to NRs (15%). SVR was higher in F2/3 (27%) patients compared to F4 patients (14%). NRs and relapsers who were HCV(-) at week 12 were equally likely to achieve an SVR (61% vs. 59%). SVR was higher in G2/3 than G1 NRs (47% vs. 12%) and relapsers (58% vs. 29%).

 

Conclusions

Retreatment with PEG-Interferon a2b plus weight based ribavirin achieves sustained virologic response in a substantial proportion of interferon-a and ribavirin treatment failures who are HCV-RNA (-) at treatment week 12.

 

Abstract ID: S1575

Comparison Of the Early Viral Kinetics Between CHC Genotype 1, 3a, and 4a Patients Under Peginterferon Alfa-2a Combination Therapy, and Relationship With Cellular Immune Reactivity

 

K. Tang, E. Paulon, E. Herrmann, N. Tatman, s. Zeuzem, R. Williams, N. Naoumov

 

Background

Hepatitis C virus (HCV) genotype is the major determinant for the duration and success rate of antiviral therapy in chronic hepatitis C (CHC). Better understanding of viral and host factors associated with these differences is needed to develop more effective treatment regimens.

 

Aims

To analyse and compare early HCV kinetics and HCV-specific T-cell reactivity during peginterferon-a2a/ribavirin treatment (P2aR) in patients with CHC-G1, G3 and G4.

 

Methods

Twenty, treatment-nave, non-cirrhotic patients with CHC (10 HCV-G1; 5 HCV-G3a; 5 HCV-G4a) were treated with P2aR. HCV viral load was quantitated by real-time RT-PCR at days: 0, 1, 2, 3 and weeks 1, 2, 4, 8, 12 after treatment initiation. Peripheral blood lymphocytes were obtained serially and CD4+ T-cell reactivity to HCV Core, NS3 and NS4 antigens was assessed by IFNg ELISpot assays. Mathematical modelling was employed to determine the patterns of viral kinetics. Results: Similar baseline characteristics existed between the 3 genotype groups. The mean (SEM) antiviral efficacy e (phase 1 viral decline) was significantly lower for G1 (72.1%6.0) compared with G3 (94%3.6, p=0.002) and G4 (76.4%19.1, p=0.01). Infected cell loss (Md) was greatest among G3 patients (1.50.8/day), followed by G4 (0.70.3/day), then G1 (0.30.3/day). A further analysis, using a previously determined threshold Md value correlating with SVR (0.25/day), identified two subsets of G1 patients: 5 fast responders (G1-FR) and 5 slow responders (G1-SR). All 5 G3 and 3/5 G4 patients were fast responders. The mean Md value of G1-FR (0.50.1) was similar to G4 (0.70.3; p=0.6), whereas the Md of G1-SR (0.10.04) was significantly lower than G3, G4 and G1-FR (all p<0.01). During therapy no changes in HCV-specific T-cell reactivity were detected in G3 or G4 patients, but temporal enhancement of T-cell reactivity was demonstrated amongst G1-FR, peaking at TW12, compared to baseline reactivity (p = 0.016), but not in G1-SR patients who had persistent viremia.

 

Conclusions

Early viral kinetic profiles differ markedly between HCV genotypes during P2aR combined therapy. The early on-treatment HCV decline is greatest in G3, followed by G1-FR and G4, and lastly G1-SR. Rapid early HCV clearance, rather than strong antiviral immunity, appears to be the main determinant for a high treatment response in CHC G3; however, enhanced cellular immunity is associated with early viral clearance only in the subset of CHC-G1 fast-responders.

 

 


 

Abstract ID: S1578

 

Factors Associated With Increased Risk Of Anemia in HIV/HCV Subjects on Pegylated Interferon and Ribavirin.

 

A.J. Uriel, Dr, L. Moorehead, J. Park, Dr, D. Carriero, J. Lucas, M. Sulkowski, Dr, D.T. Dieterich

 

Background

Use of Pegylated Interferon (Peg-IFN) and Ribavirin (RBV) for chronic Hepatitis C Virus (HCV) infection is commonly associated with a reversible hemolytic anemia. Individuals co-infected with Human Immunodeficiency Virus (HIV) and HCV, due to the myelotoxic effects of HIV and/or antiretroviral therapy (ART), may be at increased risk for developing anemia during HCV therapy.

 

Aim

To assess the factors associated with fall in hemoglobin (Hb) in a cohort of HIV/HCV patients (pts) undergoing therapy with Peg-IFN and RBV

 

Methods

A retrospective analysis of 89 HIV/HCV pts enrolled in a HCV re-treatment study (HRN 004) using Peg-IFN a2a and optimized weight based RBV was undertaken. Nadir Hb levels in the first 8 weeks were compared to baseline. Glomerular filtration rate (GFR) was estimated using the MDRD formula of Levey et al, and proteinuria on baseline urinalysis was noted. Incidence of severe anemia (Hb < 10 g/dl), RBV dose reduction and treatment cessation due to anemia during the first 24 weeks of therapy were recorded. Linear regression was utilized to investigate the risk factors for fall in Hb on therapy.

 

Results

Mean age of the cohort was 48.5 years (+/- 6.1), 75 (84%) were male, 77 (87%) had HCV genotype 1 or 4, median HCV RNA was 694812 IU/ml (IQR 449,004-5,266,006). Median CD4 count was 539 cells/mm3, 85% of the cohort was on ART, 30% were on zidovudine (AZT). Median RBV dose was 13.1 mg/kg/day (IQR 12.4 13.6). Median GFR was 96.7 mls/min (84.8 112.4), 4 pts had proteinuria. Mean baseline Hb was 14.7+/- 1.4 g/dl; mean fall in Hb by week 8 of therapy was 2.63g/dl +/- 1.47 with mean time to Hb nadir of 4 weeks. Using an intention to treat analysis of outcomes at week 24 of therapy, 12.5% of pts had a fall in Hb to < 10g/dl, 18% required RBV dose reduction, and 3 pts discontinued therapy due to anemia. On multivariate analysis, female gender (p=0.0118) and GFR (p=0.041) were significant negative predictors of anemia, whilst AZT use (p<0.0001) and proteinuria (p=0.015) were significant positive predictors. RBV dose was not a significant predictor of anemia.

 

Conclusion

In this HIV/HCV cohort on Pegasys plus ribavirin:

1.     The incidence of severe anemia was similar to that reported in the HCV moninfected (12.5%)

2.     Only 3% required discontinuation of therapy due to anemia

3.     Males and subjects with lower baseline GFR and/or proteinura had a greater risk of anemia

4.     AZT use was a highly significant risk factor with fall in HgB on therapy.

Patients with these risk factors may require closer monitoring during therapy with Peg IFN and ribavirin. Consider switching patients to a non-AZT containing regimen prior to starting HCV therapy.

 


Abstract ID: S1568

 

Peginterferon Alfa-2a/ribavirin Treatment in Patients With Chronic HCV Genotype 1: Efficacy Is Improved in Patients With Early Stages Of Fibrosis

 

M.L. Shiffman, M.W. Fried, P. Marcellin, S. Govindarajan, J. Lopez-Talavera, P.J. Pockros

 

Introduction

Treatment with peginterferon and ribavirin (PEGIFN/RBV) is the standard of care for patients with hepatitis C virus (HCV) infection. Patients with chronic HCV and advanced fibrosis or cirrhosis (CX) are at risk for developing disease progression and hepatic decompensation and are therefore candidates for treatment. In contrast, the risk:benefit ratio of PEGIFN/RBV therapy is controversial for patients with mild or no fibrosis (NoF), particularly patients with HCV genotype 1 who have a lower overall rate of sustained virologic response (SVR). We therefore examined the relationship between liver histology, SVR and the incidence of Laboratory abnormalities (LA) during treatment with PEGIFN alfa-2a/RBV in patients with HCV genotype 1.

 

Methods

Data were reviewed from 328 patients with chronic HCV genotype 1 treated with PEGIFN alfa-2a (180 mg/week) plus RBV (1000/1200 mg/day) for 48 weeks in two registration trials. All patients had a baseline liver biopsy. A subset of the biopsies were assessed for fibrosis by a local pathologist and staged as either NoF, portal (PF), incomplete septa (IS) or CX. HCV RNA titer was determined by Roche Amplicor. SVR and LAs were examined as a function of baseline fibrosis score.

 

Results

The number of patients and SVR for each fibrosis group are listed in the TABLE. Patients with NoF/PF had an SVR of 56% (136/241) whereas 43% (37/87) of patients with IS/CX achieved SVR (p<0.03). No significant differences in gender (73% male), race (82% Caucasian), or baseline HCV RNA titer >800,000 IU/ml (67%) were present between the 2 groups. In contrast, patients with IS or CX were older (p<0.001). Only grade 3 thrombocytopenia was more frequent in patients with IS/CX than noF/PF (10 % vs 2%; p<0.001). No grade 4 thrombocytopenia was observed.

 

Conclusion

o      Among patients infected with HCV genotype 1, those with early fibrosis achieved a superior SVR rate compared with patients with advanced fibrosis when receiving treatment with peginterferon alfa-2a and ribavirin

o      These findings suggest that patients infected with HCV genotype 1 and NoF/PF may benefit from early treatment with peginterferon alfa-2a plus ribavirin therapy because fibrosis progression appears to reduce the probability of SVR

o      These findings support earlier reports of higher fibrosis score predicting a lack of virologic response.

o      The risk of hematopoietic adverse events was lower in patients with early-stage fibrosis (NoF/PF) than in patients with late-stage fibrosis (IS/CX)

Baseline Fibrosis score, N=328

N (%)

SVR

Age, Mean SD

ALT, Mean SD

NoF

65

34 (52%)

38 10

84 50

PF

176

101 (57%)

43 10

114 113

IS

51

25 (49%)

48 10

133 99

CX

36

12 (33%)

50 8

151 134

 

 

Abstract ID: S1540

 

Correlations Between Rapid Virologic Response, Early Virologic Response and Sustained Virologic Response in HCV Genotype 1 Patients Treated With Pegylated Interferon Alfa-2a and Ribavirin

 

K. Reddy, J. Rakela, J. Lopez-Talavera, P.J. Pockros

 

Background

In patients with chronic hepatitis C treated with peginterferon alfa-2a plus ribavirin, a rapid virological response (RVR) is frequently an indication of early virologic response (EVR) at week 12, and can predict sustained virological response (SVR). Previous studies have shown that patients who do not have a rapid and early decrease in HCV RNA may profit from more extended treatment [Berg, et al AASLD 2004; Sanchez-Tapias, AASLD, 2004]. We have analyzed the relationship between HCV RNA response at week 4 and week 12 and SVR.

Patients and Methods

Data from 569 treatment-nave patients infected with HCV genotype 1 and randomized to 48 weeks of treatment with peginterferon alfa-2a 180 mg/week plus ribavirin 1000/1200 mg/day were analyzed. HCV RNA was assessed by quantitative assay and qualitative PCR at weeks 4 and 12 and by qualitative PCR at weeks 24 and 72.

Results

The overall EVR rate for the patients in this analysis was 80.3% (457/569). The SVR rate for patients with EVR was 59.7% (273/457). The relationships between week 4 and week 12 virologic responses and SVR are shown in the Table. Patients with markedly lower SVR rates were those with a 1 and <2 log decrease in HCV RNA at week 4 and those with a 2 decrease in HCV RNA but ongoing viremia at 12 weeks. An additional 133 patients had a > 2 log decrease at week 12, 80 of whom were HCV RNA negative by 24 weeks; this group had the lowest SVR rate.

 

Conclusions

o      EVR (12-week viral response) is a better predictor of SVR than RVR 4-week viral response)

o      Patients who have a greater than or equal to 2 log decrease but still have detectable HCV RNA at week 12 have a high rate of viral re-emergence

o      Additional clinical studies may determine the benefit of prolonged treatment with peginterferon alfa-2a plus ribavirin in those patients who have a greater than or equal to 2 log decrease but still have detectable HCV RNA at week 12.

 

Virologic Response

N=569

n, (%)

HCV RNA undetectable at Week 24, n (%)

SVR, n (% )

Week 4

 

 

 

>1 and <2 log decrease, HCV RNA+

121 (21.3)

66 (54.5)

34 (28.1)

>2 log decrease, HCV RNA+

242 (42.5)

215 (88.8)

151 (63.4)

Undetectable HCV RNA

90 (15.8)

83 (92.2)

78 (86.7)

Week 12

 

 

 

>2 log decrease, HCV RNA+

133 (23.4)

80 (60.2)

37 (27.8)

Undetectable

324 (56.9)

301 (92.9)

236 (72.8)