Parallel Session 08: HCV Treatment: Clinical Trials  Moscone West –General Session Room  11/13/2005 4:45 PM - 6:15 PM  11/13/2005


4:45 PM - 5:00 PM

Poster 55

Abstract ID: 66913

Category: JO7: HCV: Treatment

Treatment of chronic Hepatitis C virus (HCV) genotype 1 with peginterferon alfa-2b(PEGIFN), high weight based dose ribavirin (RVN) and Epoetin alfa (EPO) enhances sustained virologic response (SVR).

M. L. Shiffman, Virginia Commonwealth University Medical Center, Richmond, VA,A. Price, Virginia Commonwealth University Medical Center, Richmond, VA, S. Hubbard, Virginia Commonwealth University Medical Center, Richmond, VA, M. Wilson, Virginia Commonwealth University Medical Center, Richmond, VA, J. Salvatori, Virginia Commonwealth University Medical Center, Richmond, VA, R. K. Sterling, Virginia Commonwealth University Medical Center, Richmond, VA, R. T. Stravitz, Virginia Commonwealth University Medical Center, Richmond, VA, V. A. Luketic, Virginia Commonwealth University Medical Center, Richmond, VA, A. J. Sanyal, Virginia Commonweakth University Medical Center, Richmond, VA



Successful treatment of chronic HCV with PEGIFN and RVN is hampered by adverse events (AEs). One of the most common AEs is anemia and this frequently requires that RVN either be dose reduced or prematurely discontinued. RVN dose reduction, particularly during the first 24 weeks of therapy, is associated with a significant reduction in SVR; particularly in patients with HCV genotype 1. Our HYPOTHESIS was that utilizing EPO at the onset of PEGIFN and RVN therapy would reduce the frequency

of anemia, the need to dose reduce RVN, allow for use of higher RVN dosing and this in turn could enhance SVR.



150 patients with HCV genotype 1, naïve to prior treatment, were randomly assigned to one of three treatment groups (50/group);

·       Group 1: PEGIFN alfa-2b (1.5 mcg/kg/wk) + weight based RVN (WBRBN) 13.3 mg/kg/day (800-1400 mg/day);

·       Group 2: PEGIFN alfa-2b + WBRVN + EPO (40,000 U/wk) or

·       Group 3: PEGIFN alfa-2b + a higher dose of WBRVN (HDWBRVN) 15.2 mg/kg/day (1000-1600 mg/day) + EPO.


In groups 2 and 3 EPO was initiated at the onset of therapy and titrated

between 10,000 –60,000 U/wk to maintain the hemoglobin (Hb) between 12-15 gm/dl. In all groups, the RVN dose was reduced by 200 mg increments if the Hb declined below 10 gm/dl or for management of other side effects as needed. All patients underwent liver biopsy prior to treatment. HCV RNA was assessed by Taqman PCR.



The mean age of the patient population was 48 years; 60% were male and 34% African American (AA). Mean body weight was 82.4 (49-149) kg, serum Log HCV RNA 5.5 + 0.32 IU/ml and Knodell score was 7.0 + 2.3; 6% of the patients had cirrhosis. Early virologic response (EVR), end-of-treatment response (ETVR), SVR, mean RVN dose and the % of patients in each group that required RVN dose reduction are listed (Table).



No significant difference in either EVR or ETVR was observed between the three groups. In contrast, SVR was higher (p=0.05) in patients who received HDWBRVN + EPO (Group 3) despite the need for dose reduction in 27% of patients. This increase in SVR resulted from a decline in relapse; from 43-48% in Groups 1-2 to only 19% in group 3. Although EVR, ETVT and SVR were all lower in the 51 AA patients; SVR in both AA(31 vs 18%) and non-AA (53 vs 30%) patients were higher in Group 3 (HDWBRVN) compared to Groups 1.



A significant increase in SVR can be achieved in HCV genotype 1 patients if treated with higher doses of RVN along with EPO to limit dose reduction.

Poster 56


Abstract ID: 64296

Category: JO7: HCV: Treatment

Is shorter treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) possible in HCV genotype 1 ‘super-responders’? Preliminary results of a prospective randomized clinical trial.

P. Ferenci, Medical University of Vienna, Vienna, Austria, U. BERGHOLZ, Department of Internal Medicine 4, Medical University of Vienna, Vienna, Austria, H. LAFERL, Kaiser Franz Josef Hospital, Vienna, Austria, C. GURGUTA, Department of Internal Medicine 4, Medical University of Vienna, Vienna, Austria, A. MAIERON, Krankenhaus der Elisabethinnen, Dept. of Medicine 4, Linz, Austria, M. GSCHWANTLER, Wilhelminenspital, Dept. of Medicine 4, Vienna, Austria, H.BRUNNER, Krankenhaus Lainz, 1. Dept. of Medicine, Vienna, Austria, R. HUBMANN, General Hospital, 2nd. Dept. of Medicine, Linz, Austria, C. DATZ, Krankenhaus Oberndorf, Dept. of Medicine, OBERNDORF, Austria, M. BISCHOF, Krankenhaus Rudolfstiftung, Dept. of Medicine 4, Vienna, Austria, R. STAUBER, Department of Internal Medicine, Medical University of Graz, Graz, Austria, P. STEINDL-MUNDA, Department of Internal Medicine 4, Medical University of Vienna, Vienna, Austria



We designed a prospective randomized multicentre trial to determine if response rates in genotype 1 patients could be improved by individualizing therapy based on viral kinetic responses at wk 4 and 12 to treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®). Here we present data from patients with undetectable HCV RNA at wk 4, the most responsive subgroup.



Interferon-naïve adults with quantifiable HCV RNA genotype 1 were enrolled. All received peginterferon alfa-2a (40KD) 180 μg/wk plus ribavirin 1000/1200 mg/d prior to allocation to one of 4 treatments based on HCV RNA testing at wks 4 and 12 (Figure). At wk 4, ‘super-responders’ (HCV RNA <50 IU/mL) were assigned to group D and received a further 20 wks of therapy. At wk 12, remaining patients who with HCV RNA

<50IU/mL received a further 36 wks therapy (group C). Patients with detectable HCV RNA at wk 12 but a 2-log drop over baseline were randomized to group A (48wk) or B (72wk).



Data are now available from group D. Of 366 patients, 79 (22%) ‘super-responders’ were assigned to 24 wks therapy. To date, 48 patients have completed the study (Table). An SVR [HCV RNA <50 IU/mL after 24 weeks’ of untreated follow-up] was recorded in 32 of these patients (67% ITT analysis). Group D had a very low drop-out rate (6%).

Complete arm D data will be presented.




Analyses now indicate that treatment duration in genotype 1 patients might be best individualized based on HCV RNA levels at wk 4. In this study, initial data indicate that shorter treatment (24 wks) with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) provide substantial benefit in genotype 1 ‘super-responders’, with an SVR rate of 66%.

Poster 57


Abstract ID: 64291

Category: JO7: HCV: Treatment

Does Treatment-Induced Recovery from Hepatitis C Result in the Same Immunological Memory as Spontaneous Recovery?

C. Weiler-Normann, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, T. Heller, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, Y. Sobao, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, G. Lutchman, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, B. Borg, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, M. Ghany, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, T. Liang, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, J. Hoofnagle, Liver Diseases Branch, NIDDK,

NIH, Bethesda, MD, B. Rehermann, NIDDK, National Institutes of Health, Bethesda, MD



Spontaneous HCV clearance is associated with vigorous T cell responses that remain detectable for decades after recovery. In the non-human primate model, these T cell responses mediate protective immunity upon rechallenge.



Studying 51 patients, we have assessed whether successful interferon-based therapy results in the same type of immunological memory as spontaneous HCV clearance. Peripheral blood lymphocytes (PBL) were collected prospectively from 9 patients who cleared HCV spontaneously after acute infection and from 42 patients who responded to treatment in the acute (n=12) or chronic phase of infection (n=30). PBL were tested for proliferation and IFN-gamma production in response to HCV proteins and 600 overlapping peptides spanning the complete HCV sequence.



All patients with acute hepatitis C displayed vigorous and multispecific IFNgamma production by CD4 and CD8 T cells, which decreased after initiation of therapy in all treatment responders. Nine of twelve treatment responders were prospectively followed after cessation of therapy for up to 3 years. T cell responses to HCV peptides increased again in most of them. Despite these increasing IFN-gamma responses, proliferative responses to HCV proteins remained significantly weaker than in spontaneously recovered patients (mean stimulation indices 7.1 versus 25.8 respectively; p<0.05). For comparison, we cross-sectionally studied 30 patients 4 months to 17 years after successful treatment of chronic hepatitis C. Proliferation and IFN-gammaproduction of HCV-specific memory T cells after treatment-induced recovery from chronic hepatitis C were comparable to those after treatment-induced recovery from acute hepatitis C.



In summary, these results suggest differences in function and/or differentiation of HCV-specific memory T cells after treatment-induced and spontaneous HCV clearance. Epitopes have been mapped and tetramer-studies are currently in progress to investigate the underlying mechanisms at the single cell level. The relatively weaker memory T cell response of treatment-recovered patients may affect the degree of immune protection upon reexposure to HCV.

Poster 58


Abstract ID: 66553

Category: JO7: HCV: Treatment

Utility of TMA Testing During Antiviral Treatment of Advanced Hepatitis C

C. Morishima, University of Washington, Seattle, WA, T. R. Morgan, University of California-Irvine, VA Medical Center, Long Beach, CA, D. R. Gretch, University of Washington, Seattle, WA, E. C. Wright, New England Research Institutes, Watertown, MA, J. E. Everhart, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, f. Group, University of Washington, Seattle, WA




Qualitative HCV RNA assays with improved analytical sensitivity are available, but their added clinical benefit is not clear. The Bayer VERSANT© HCV RNA Qualitative (TMA) Assay* (lower limit of detection (LOD) ~10 IU/mL) was evaluated for its ability to predict sustained virologic response (SVR) using stored serum from the HALT-C trial.



Patients with chronic hepatitis C, prior non-response to interferon, and advanced liver disease were treated with peginterferon alfa-2a and ribavirin for 24 weeks. Patients with undetectable HCV RNA using the Roche COBAS Amplicor © HCV Test, v. 2.0 assay (LOD 100 IU/mL in serum) at week 20 (W20) continued therapy for a total of 48 weeks and were assessed for SVR (absence of serum HCV RNA by the Amplicor test at W72). Serum aliquots from 1070 subjects at W20 and in fewer numbers at other weeks were tested by TMA.



1044 of 1045 Amplicorpositive samples from different timepoints were also positive by TMA. The single discrepant sample had additional testing that indicated HCV RNA negativity. Among 1293 Amplicor-negative samples, 279 (21.6%) were TMA-positive, with the rate of TMA positivity decreasing during therapy. The majority of subjects with Amplicornegative/TMA-positive discordant results subsequently developed treatment breakthrough or relapse (defined using Amplicor results): 84% from W20, 87% from W24, and 89% from W48. Patients who were TMA-negative at W12, W20, or both were more likely to achieve SVR (74%, 62% and 82%, respectively) than were patients who were Amplicor-negative at these timepoints (58%, 48%, 61%, respectively). The added benefit of TMA testing to the early virologic response (EVR, defined as at least a 2 log drop of HCV RNA level at W12) was evaluated in subjects with EVR who were Amplicornegative at W20 and received 48 weeks of treatment. Of 48 patients with two consecutive TMA-positive results at W20 and W24, none achieved SVR (95% CI: 0- 7.4%). By contrast, 67% of subjects with consecutive TMA-negative results at W20 and W24 did achieve SVR.



Among patients treated with combination therapy for chronic hepatitis C, the TMA test detects HCV RNA in all specimens that are Amplicor-positive, as well as an additional 21.6% that are Amplicor-negative. The increased sensitivity of the TMA test can be helpful in identifying patients with low levels of HCV RNA who are likely to relapse when therapy is stopped. Furthermore, among patients with EVR and a negative Amplicor test at W20, persistent detection of HCV with the TMA test during therapy predicts failure to achieve SVR.

*FDA-approved for detection of HCV RNA as evidence of active infection.

Poster 59


Abstract ID: 64255

Category: JO8: HCV Therapy: Phase 3, 4 Trials

Weight Based Ribavirin in Combination with Pegylated Interferon Alpha 2-B Does not Improve SVR In HCV Infected Patients who Failed prior therapy: Results in 454 patients.

P. Gaglio, Columbia University P & S, New York, NY, J. Choi, CLDT PH-14, NY, NY, D. Zimmerman, CLDT PH-14, NY, NY, L. Heller, None, Flushing, NY, R. S. Brown, CLDT ph-14, NY, NY



Eradicating HCV in the majority of infected patients remains elusive, particularly in patients who failed or relapsed following prior therapy. The present prospective study was designed to determine the efficacy and safety of treatment with pegylated interferon alfa-2b 1.5 mcg/kg/wk and either fixed or weight based Ribavirin in patients who failed prior standard interferon therapy with or without Ribavirin.



454 patients were enrolled in this multi-center study. The first 247 enrolled patients (cohort A) were treated with 1.5 mcg/kg of PEG-Intron sc q week, and Ribavirin 800 mg po qd. 207 patients (cohort B) received 1.5 mcg/kg PEG-Intron and weight based doses of Ribavirin (100-1200 or 800-1400/day). SVR data is available for all patients and is based on intention-to-treat.



There were no differences when comparing cohort A to cohort B related to genotype distribution, prior history of non response to therapy, type of therapy (combination interferon plus ribavirin vs interferon monotherapy), BMI, grade and stage of histologic injury, and viral load. A greater percentage of women and African Americans were represented in cohort B. Dose reduction was required in 19% of pts most commonly due to leukopenia and anemia. A greater number of patients in cohort A required dose reduction.


Serious adverse events: (1.8% of pts) Included one patient each with: neutropenia/MRSA sepsis, optic neuritis with monocular blindness, perirectal abscess, cellulitis with multiorgan failure, cutaneous and pulmonary sarcoidosis, pneumonia, homicidal ideation, and suicide.


SVR: 1) Overall SVR was 19% (17% cohort A, 20% cohort B (p= NS)) 2) ETR was 32%, however, 52% of patients who achieved an ETR relapsed. 3) SVR in G1 combo NR was 11% in White and 10% in AA 4) In all patient groups studied, weight based Ribavirin (cohort B) was not associated with improvement in SVR when compared to fixed dosing of Ribavirin (cohort A) 5)




SVR is ~20% in retreatment and is not improved with higher ribavirin dosing Response rates may be higher for G non 1, prior monotherapy and relapsers, Optimal therapy in patient who failed prior therapy with standard Interferon and Ribavirin remains to be established

Poster 60


Abstract ID: 67881

Category: JO8: HCV Therapy: Phase 3, 4 Trials


J. Gross, Mayo Clinic, Rochester, MN, S. Johnson, Mayo Clinic, Rochester, MN, P.Kwo, Indiana U. Schoo of Medicine, Indianapolis, IN, N. Afdhal, Beth Israel DeaconessMedical Center, Boston, MA, S. Flamm, Northwestern U. Department of Medicine,Chicago, IL, T. Therneau, Mayo Clinic, Rochester, MN, T. Investigators, Mayo Clinic, Rochester, MN



Three large trials have shown that patients with hepatitis C who did not respond to treatment with interferon and ribavirin have a 10-12% chance of a sustained viral response (SVR) if they are subsequently treated with peginterferon and ribavirin.



Among non-responders to previous interferon and ribavirin, to assess the efficacy and safety of doubling the dose of peginterferon alfa-2b (PEG-2b) and using an aggressive weight-based ribavirin schedule.



RENEW is an investigator-initiated study that was carried out at 100 academic and community sites in the US. Entry was limited to patients who never cleared HCV RNA during previous combination interferon + ribavirin treatment and who had compensated liver disease. Patients were randomized to 48 wk of treatment with PEG-2b 0.5, 1.5, or 3.0 mcg/kg weekly + ribavirin 12-15 mg/kg/day (800-1400 mg/day). Treatment assignment was stratified for sex, race (Afr-Amer vs. other), genotype (1 vs. other), and fibrosis (F0/1 vs. F2/3/4). Treatment was discontinued at 24 wk if serum was HCV RNA (+). Doses were reduced 33% for toxicity. Growth factors were not allowed. The primary endpoint was absence of HCV RNA 24 wk after treatment (SVR).



963 patients were enrolled; 818 were confirmed to have started treatment. Enrollment in the low-dose arm was stopped when the FDA approved higher doses of PEG-2b, leaving 704 treated patients (352 in each of the other two arms). Patients were 91% genotype 1, 70% male, 40% F3/4, and 16% Afr-Amer. On an intent-to-treat basis, the rate of SVR was 17% on PEG-2b 3.0 mcg/kg/wk, compared to 12% on 1.5 mcg/kg/wk (p = 0.03). Overall, SVR was less likely among patients with F3/4 fibrosis (OR = 0.53) and Afr-Americans (OR = 0.61), but on PEG-2b 3.0 mcg/kg these groups had SVR rates equivalent to the rest of the patients. SVR was not related to baseline body weight, on this fully weight-based treatment. Although there was a trend toward a higher frequency of adverse effects on the higher dose of PEG-2b, the differences were not clinically significant. Rates of dose reduction were 37% vs. 45%; rates of discontinuation for adverse events were 11% vs. 13%.



Among patients who never cleared HCV RNA on previous interferon and ribavirin:

1) PEG-2b 3.0 mcg/kg weekly, combined with ribavirin 12-15 mg/kg daily, was more effective than 1.5 mcg/kg weekly, especially among African-Americans and those with advanced fibrosis.

2) The safety and tolerability of PEG-2b 3.0 mcg/kg weekly and 1.5 mcg/kg weekly were similar.

3) High-dose antiviral treatment deserves further study as initial therapy for patients with inherently low response rates.


November 15th , 2005

Parallel Session 29: HCV Clinical Trials and Therapeutic Developments  Moscone West - Room 3016/3018/3020 (1000pp) 

11/15/2005 11:15 AM - 12:45 PM 


11/15/2005 11:15 AM - 11:30 AM 

Poster 199

Abstract ID: 62985

Category: JO7: HCV: Treatment

Peginterferon Alfa-2a and Ribavirin in African American and Caucasian Patients withChronic Hepatitis C, Genotype 1.

H. S. Conjeevaram, UNIVERSITY OF MICHIGAN, Ann Arbor, MI, M. W. Fried, University of North Carolina, Chapell Hill, NC, L. J. Jeffers, VA Medical Center, Miami, FL, N. Terrault, UCSF, San Francisco, CA, T. E. Wiley-Lucas, Rush University Medical Center, Chicago, IL, N. Afdhal, Beth Israel Deaconess Medical Center, Boston, MA, R. S. Brown Jr, New York Presbyterian-Columbia Presbyterian Center, New York, NY, S. H. Belle, University of Pittsburgh, Pittsburgh, PA, P. R. Robuck, NIDDK, NIH, Bethesda, MD, C. D. Howell, University of Maryland, Baltimore, MD



Compared to Caucasian Americans (CA), African Americans (AA) with chronic hepatitis C virus (HCV) infection are less likely to respond to interferon-based antiviral therapy. The biological bases for this racial difference in response are not known. Virahep-C is a prospective, multi-center clinical study, designed to compare the effects of peginterferon and ribavirin therapy between AA and CA pts and determine predictive factors for non-response to treatment.



196 AA and 205 CA treatment-naïve pts with genotype 1 infection were treated with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). Pts who were HCV RNA negative at wk 24 were treated for an additional 24 wks and followed thereafter for evidence of SVR. Pts who were HCV RNA positive at wk 24 were considered nonresponders, and therapy stopped.



Baseline features were similar among AA and CA including age, gender, histologic severity but AA had higher average BMI, higher rates of diabetes and hypertension, and lower mean ALT, neutrophil, and hemoglobin levels (p< .001 for all). AA were also more likely to have HCV subtype 1b than CA (46% vs. 28%, p=.0004) and less likely to have 1a (47% vs. 58%, p=.04) but HCV RNA levels were similar. Virological response rates are shown below, representing final data on 94% of pts. Complete results are expected by October 2005.



Breakthrough responses between wk 24 and wk 48 occurred in 14% AA and 6% CA (p=.03). Relapse rates following treatment were similar between AA and CA (34% vs. 27%, p=.30). Frequencies of serious adverse events, dose reductions/discontinuations were similar among AA and CA. Multiple logistic regression analyses demonstrated that CA race was independently associated with a higher SVR rate compared to AA [OR 3.40 (95% CI 2.07-5.61)]. Other factors independently associated with lower SVR included male sex, higher baseline HCV RNA level, higher Ishak fibrosis score and compliance (< 80/80/80); none of these accounted for racial differences in response.



In pts with HCV genotype 1 infection, AA have significantly lower rate of virological response to peginterferon and ribavirin therapy than CA. The differences in response are evident soon after starting therapy and persist. Analyses of other clinical, viral, immunological, and genetic differences between responders and non-responders in this cohort are ongoing.

Poster 200


Abstract ID: 63276

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Cross-reactive epitopes identified in hepatitis C virus E1E2 proteins induce antibodiesthat capture virions from infected patients’ sera and inhibit HCV/HIV pseudo virus entryinto susceptible cells.

J. Torresi, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia, L. Grollo, University of Melbourne, Parkville, Australia, O. Stock, University of Melbourne, Parkville, Australia, A. E. Fischer, The University of Melbourne, Parkville, Australia, H. Drummer, Burnet Institute, Prahran, Australia, W. Zeng, University of Melbourne, Parkville, Australia, D. Jackson, University of Melbourne, Parkville, Australia



A vaccine aimed at preventing HCV infection is not available. Potential neutralising epitopes have been reported in the E2 glycoprotein, including hypervariable region 1 (HVR1), and these hold promise as targets for a prophylactic vaccine. Despite this the difficulty in targeting the viral envelope and in particular HVR1 lies in accounting for its extreme variability.



(1) Human serum containing anti-hepatitis C virus (HCV) antibody was used to isolate epitopes from a library of synthetic peptides encompassing the sequences of the surface glycoproteins E1 and E2. Peptides isolated by the process of epitope extraction were identified by mass spectrometry. Epitopes identified in this way were assembled into synthetic peptides incorporating a promiscuous T helper epitope (TH) (2) We also investigated an approach to address the challenges of hypervariability. A peptide library, of 288 individual HVR1 decapeptides, was assembled and incorporated into multideterminant polymeric immunogens with and without the TH epitope and/or lipid groups (Pam2Cys), to act as an endogenous adjuvant and used to immunize mice. Antibodies raised with these 2 types of immunogen were analysed by (1) ELISA (2) immune capture (ic) RT-PCR (3) neutralisation of HCV/HIV pseudotypes (HCVpp) and (4) FACS for immunofluorescence of cell surface expressed E2.



(1) Epitopes identified by Ab extraction and subsequent mass spectrometry allowed construction of an antigenic map of three distinct antigenic sites. The amino acid sequences of four peptide epitopes were conserved within at least 3 HCV genotypes indicating that these are cross-reactive. When assembled into vaccine candidates the HCV epitopes elicited antibodies capable of capturing HCV virions from the serum of viremic patients; inhibiting HCVpp entry into Huh7 cells and binding to E1E2 glycoproteins expressed on the surface of HEK 293T cells. (2) Mice inoculated with the self-adjuvanting lipidated polymer generated antibody that was capable of capturing virions of different HCV genotypes from the sera of chronically infected patients in an ic RT-PCR and bound cell-surface expressed E1E2. The polymer antigens also bound to antibody present in the sera of chronically infected patients.



Our approach to epitope discovery exploits the information inherent in the binding sites of pathogen-specific antibodies and represents a novel method for the design of synthetic epitope-based vaccines. In addition, polymeric lipidated peptidebased immunogens offer the potential to deliver broad cross-reactive epitopes.

Poster 201


Abstract ID: 67627

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Combination Therapy with the HCV Protease Inhibitor, SCH 503034, Plus PEG-Intron inHepatitis C Genotype-1 PEG-Intron Non-responders: Phase Ib Results.

S. Zeuzem, Saarland University Hospital, Homburg, C. Sarrazin, Saarland University Hospital, Homburg, F. Wagner, Research Unit im Bettenhaus der Charite,, Berlin, R. Rouzier, Centre Cap, Montpelleir, N. Forestier, Saarland University Hospital, Homburg, S. Gupta, Schering-Plough Reserach Institute, Kenilworth, NJ, M. Hussain, Schering-Plough Research Institute, Kenilworth, NJ, A. Shah, Schering-Plough Research Institute, Kenilworth, NJ, D. L. Cutler, Schering-Plough Research Institute, Kenilworth, NJ, J. Zhang, Schering-Plough research Institute, Kenilworth, NJ



SCH 503034 is a novel HCV protease inhibitor that delivers potent antiviral activity in an oral capsule formulation. In this study we compared the anti-HCV activity of SCH 503034 in combination with PEG-Intron vs SCH 503034 or PEG-Intron alone in HCV-1 PEG-Intron non-responders.



In this multi-center, open-label study, adults with HCV-1 and prior PEG-Intron ± Ribavirin failure (<2 log reduction in HCV RNA (VL) after 12 wks) received in random sequence, A) SCH 503034 oral capsules (200 mg or 400 mg) as a monotherapy for 7d, B) PEG-Intron 1.5 mg/kg/QW SC as monotherapy for 14d, and C) A + B for 14d, in a 3-way crossover design with a 3-wk washout between treatments. HCV RNA was determined daily by qRT-PCR (Taq-Man™/LOQ= 29 IU/ml).



HCV RNA was substantially reduced by SCH 503034 + PEG-Intron. 4/10 patients in the 400 mg combination group became HCV RNA non-detectable (<29 IU/ml) during treatment vs. 0/22 patients receiving PEG-Intron alone. Mean max log10 reductions were 2.4 (range, 1-4.5) and 2.9 (range, 2.3-4.1) for 200 mg and 400 mg SCH 503034 + PEG-Intron, respectively, Vs 1.1 for PEG-Intron alone. SCH 503034 monotherapy for 7d reduced HCV RNA 0.4-1.77 log10, at 200 mg TID and 0.5-2.5 log10, at 400 mg TID.


The AE profile for combination treatment was similar to PEG-Intron alone, except for a slight increase in the incidence of headache.



SCH 503034 plus PEG-Intron demonstrated potent antiviral activity in HCV-1 PEG-Intron non-responders and thus may represent a new therapeutic option for this patient population. This is being further evaluated in Phase II studies assessing 24 and 48 wks of combination treatment.


Poster 202


Abstract ID: 64046

Category: JO1: HCV: Pathogenesis


K. Krawczynski, Division of Viral Hepatitis, NCID, CCID, CDC, Atlanta, GA, B. Bartosch, Ecole Normale Superieure de Lyon, Lyon, France, J. Meunier, NIAID, NIH, Bethesda, MI, L. Basham, Nabi Pharmaceuticals, Inc., Rockville, MD, D. Culver, DVH, CDC, Atlanta, GA, D. Lavillette, Ecole Normale Superieure de Lyon, Lyon, S. Kamili, DVH, CDC, Atlanta, GA, F. Cosset, Ecole Normale Superieure de Lyon, Lyon, A. Fattom, Nabi Pharmaceuticals, Inc., Rockville, MA



Antiviral effect of anti-HCV antibodies has been suggested but their effect on HCV clearance remains unclear. We have passively transferred anti-HCV (HCIg, Civacir™) to acutely or chronically HCV-infected chimpanzees and used a recently designed assay that measures neutralization of infectivity of retroviral particles carrying HCV E1E2 heterodimer (HCVpp) to evaluate the occurrence of HCVpp neutralizing antibodies (HCVppNtAb) and assess antiviral effect of anti-HCV immunoglobulin. The HCIg had a titer of HCVppNtAb > 1:2000 and contained 682 &#61549;g/mL of anti-E2 globulin. Acute HCV infection was induced in two pairs of chimpanzees infected with either 3-30 or 3-30x103 chimpanzee infectious doses (CID) of HCV genotype 1a. The animals were treated with multiple intravenous infusions of HCIg for 13 weeks (2x per week, 100mg of Ig/kg body weight), beginning as early as 1 or 24 hours after inoculation.



HCVppNtAb and anti-E2 levels reached a plateau within 14 days after beginning the infusions; the level of antibodies gradually decreased and disappeared 80 to 100 days after the infusions were discontinued. HCV viremia lasted 39 to 42 days, and there was no evidence of acute hepatitis. In another chimpanzee, infected with 3-30x103 CID, which received two 13-week series of HCIg infusions, level of HCV RNA decreased after the first series of HCIg infusions and transiently disappeared from serum during the second series of infusions. In control chimpanzees infused with anti-HCV-negative immunoglobulin (IVIG), HCV viremia lasted from 73 to 300 days and was followed by or concordant with acute hepatitis. Three chronically HCV genotype1a infected chimpanzees were treated with HCIg: 2x per week, 100mg of Ig/kg body weight for 15 weeks. The level of anti-E2 reached a plateau after three weeks of HCIg infusions, remained essentially unchanged for the next 80 days, and gradually decreased when the infusions were terminated. Unlike anti-E2, HCVppNtAb were detected in all three animals before HCIg infusions and their level increased slightly during the infusions. The HCV RNA load declined during the infusions by 1.37 log (p<0.0001; two-tail t test) in a linear fashion in two of three chimpanzees. Alanine aminotransferase values were significantly decreased during HCIg infusions in all three animals.



The results of chimpanzee experiments suggest that HCV neutralizing antibody contained in HCIg modulated the level and length of HCV viremia and prevented hepatitis in acutely infected animals. The HCIg infusions changed the rate of HCV replication and ameliorated liver pathology in chronically infected chimpanzees.
Poster 203

12:15-12:30 PM

Abstract ID: 66839

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Consensus Interferon in combination with Gamma Interferon and/or Ribavirin leads to a significant response in treatment-naive Hepatitis C Genotype 1 patients.

S. Kaiser, University Hospital of Tuebingen, Tuebingen, Germany, H. Hass, Dept. of Medicine, University Hospital of Tuebingen, Tuebingen, Germany, M. Gregor, Dept. of Medicine, University Hospital of Tuebingen, Tuebingen, Germany



Treatment with pegylated interferon alfa and ribavirin has an efficacy in chronic hepatitis C patients with sustained response rates of about 50%. However, response in genotype 1 patients is between 41-44%.  Recent in vitro studies have suggested a synergistic antiviral effect of alpha and gamma interferons. Furthermore, a pilot trial with consensus (CIFN) and gamma interferon (Gamma IFN) has shown enhanced antiviral efficacy in PEG interferon nonresponders.



The efficacy of CIFN daily dosing combined with either gamma IFN and/or ribavirin (RBV) in 60 treatment-naive patients with chronic hepatitis C and genotype 1 was evaluated. All patients had histologically proven hepatitis. Patients were treated with CIFN of 9 ug QD for 48 weeks. Treatment was supplemented with gamma IFN at 50ug TIW and / or weight-based RBV with 11 mg/kg BW.



At 48 weeks therapy (ETR) an undetectable HCV-RNA was observed in 74% of the CIFN/RBV group, in 71% of the CIFN/gamma IFN group and 82% of the CIFN/RBV/gamma IFN group.


At 24 weeks post treatment (SVR) an undetectable HCV-RNA was observed in 59% of the CIFN/RBV group, in 31% of the CIFN/gamma IFN group and 71% of the CIFN/RBV/gamma IFN group.


Due to side effects CIFN had to be dose reduced in 7% and discontinued in 3% of all patients. RBV had to be dose reduced in 11% of all patients, while gamma IFN was not dose reduced, but discontinued in 9% of all patients.


Safety Analysis

o      All patients have tolerated both drugs well with no discontinuations or dose reductions through week 12

o      All patients had flu-like symptoms and fatigue typical of therapy with Interferons

o      No patients had reductions in ANC that required growth factor support

o      Patients with CIFN / Gamma IFN treatment had a significantly lower drop of Hemoglobin levels as compared to the other treatment arms

o      All patients have tolerated both drugs well through week 12

o      All patients had flu-like symptoms and fatigue typical of therapy with Interferons

o      No patients had reductions in ANC that required growth factor support

o      Patients with CIFN / IFN-γ treatment had a significantly lower drop of Hemoglobin levels as compared to the other treatment arms


Preliminary Conclusions

o      Gamma Interferon has additive antiviral effects when being combined with interferon alfa and ribavirin therapy in HCV

o      Triple therapy with alfa and gamma interferon together with ribavirin may be an emerging option for difficult-to-treat patients with HCV Genotype 1 and high viral load

o      In special patients with intolerability to ribavirin combination therapy with alfa and gamma interferon may be an alternative therapeutic option


Parallel Session 10: Pediatric Liver Disease  Moscone West - Room 3014 (300pp)  11/13/2005 4:45 PM - 6:15 PM


11/13/2005 5:30 PM - 5:45 PM

Abstract ID: 65163

Category: JO3: HCV: Diagnosis and Natural History


The Natural History of Hepatitis C Virus (HCV) Recurrence in Pediatric Liver Transplant Recipients: An Analysis of National Data.

N. R. Barshes, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, I. W. Udell, Baylor College of Medicine, Houston, TX, T. C. Lee, Baylor College of Medicine, Houston, TX, C. A. O'Mahony, Baylor College of Medicine, Houston, TX, S. J. Karpen, Texas Children's Liver Center, Houston, TX, B. A. Carter, Texas Children's Liver Center, Houston, TX, J. M. Vierling, Baylor College of Medicine, Houston, TX, J. A. Goss, Baylor College of Medicine, Houston, TX



The natural history of HCV infections in pediatric patients differs from the natural history in adults, as pediatric patients generally have a more benign course and occasional spontaneous clearance of the virus. The natural history of the disease following liver transplantation has never been described, however, and only extrapolations of adult studies have given guidance to clinicians offering liver transplantation to pediatric patients with HCV.



All pediatric patients (age <17 y.o.) that have undergone liver transplantation for HCV were enrolled in this study through the United Network for Organ Sharing liver transplant database. Survival analysis was performed by the Kaplan-Meier product limit estimate.



A total of 75 pediatric patients have undergone liver transplantation for HCV in the United States since 1988. Median age was 14 y.o. (range <1 y.o. to 17 y.o.). Approximately 75% were 12 y.o. or older. 85% represented de novo cases of HCV, and the remaining 15% occurred after liver transplantation done for a non-HCV indication (including biliary atresia and metabolic liver disease). Fifty-five (73%) represented primary transplants, while 20 (27%) represented retransplants (including two patients who had received 3 transplants each). Patient survival at 5 years was 81% for primary transplants and 53% for retransplants (p=0.003). Recurrent hepatitis or hepatoma accounted for 25% of patient deaths. Graft survival at 5 years posttransplant was 59% for primary transplants and 37% for retransplants (p=0.02). Overall, 20% of patients required retransplantation a median of 308 days (range 1 to 5,186 days) after initial liver transplantation. Of these, 86% were due to HCV recurrence or other complications of HCV. Only 6 (8%) received liver allografts from living donors; the survival of these

grafts and their respective donors did not differ significantly from those of deceased donors.



HCV is a rare indication for liver transplantation in pediatric patients. While the natural history of HCV in pediatric patients is typically more benign

than in adult patients, 24% of patients who undergo liver transplantation for HCV experience HCV-related death or retransplantation. Rates of patient and graft survival is significantly worsened after in the case of retransplantation for HCV. More treatment strategies are needed to prevent HCV recurrence after liver transplantation in children.