PEGINTERFERON ALFA 2-B THERAPY IN ACUTE HEPATITIS C: IMPACT OF ONSET AND DURATION OF THERAPY ON SUSTAINED VIROLOGIC RESPONSE

S. Kamal, Q. He, A. Al Tawil, K. Khalifa, S. Hakam, W. Saleh, M. Omar, J. Rasenack, M. Koziel, M. Madwar  

 

Background

The role, onset and duration of peginterferon treatment have not been evaluated in acute hepatitis C. 

 

Objective

To assess the efficacy, safety, onset and duration of peginterferon alfa  (PEG IFN) in acute hepatitis C. 

 

Methods

In this intent to treat study patients with acute HCV genotypes 1 and 4 (n=98) were enrolled and prospectively followed. Patients were screened for 8 weeks after seroconversion or first positive PCR. Fifteen subjects refused treatment but were followed through the study. Patients without spontaneous recovery were randomized to begin PEG IFN-alpha monotherapy at wks 8, 12, 20 respectively for either 12 or 24 weeks. A subset of subjects who failed to achieve a virologic response after 12 wks of treatment continued therapy for additional 12 wks.

 

Results

Five untreated subjects had spontaneous recovery and another 4 subjects scheduled to start treatment at weeks 12 or 20 resolved spontaneously before therapy. 79 subjects with persistent viremia were randomized to 3 groups (Table). The end of treatment response was 94% and the overall SVR was 82%. The SVR was better for genotype 4 compared to genotype 1. Earlier treatment (week 8 or 12) was associated with higher SVR particularly in genotype 1. Twelve week therapy was sufficient for genotype 4 while higher SVR rates in genotype 1 patients were achieved with 24 wks treatment (86%). Peginterferon alfa-2b monotherapy was well tolerated and associated with significant improvement in the quality of life.

 

Conclusion

Peginterferon alfa-2b monotherapy improves sustained virologic response for acute hepatitis C virus with genotype 1 and 4 infection. Earlier treatment leads to increased virologic response.  HCV genotype 1 may require longer treatment duration.

 


 

FINAL RESULTS OF ANRS HC02 - RIBAVIC: A RANDOMIZED CONTROLLED TRIAL OF PEGYLATED-INTERFERON ALFA-2B PLUS RIBAVIRIN VS INTERFERON ALFA-2B PLUS RIBAVIRIN FOR NAIVE HCV-HIV CO-INFECTED PATIENTS

S. Pol, F. Carrat, F. Bani-Sadr, E. Rosenthal, F. Lunel, P. Morand, D. Salmon, G. Pialoux, P. Cacoub, C. Perronne  ANRS HC02-RIBAVIC Group

 

Background

Hepatitis C may be severe in HIV-infected subjects evidencing the need to treat.

 

Aim

To compare the safety and efficacy of the standard (IFNa2b: 3 MIU x3/w, n=207) (INF group) to the pegylated (PEG-IFNa2b: 1.5 mg/kg x1/w, n=205) interferon (PEG group) both combined with ribavirin (800mg/d, approx. 12 mg/kg/d) during 48 weeks.

 

Methods

A randomized, multicenter, parallel-group, open-label trial. Inclusion criteria were: HCV-RNA positive and abnormal liver histology, CD4>200, stable HIV-RNA, off or stable HAART.

 

Results

The 412 patients (40 y, 74%M, 79% IVDU) were given HAART in 82%. Mean CD4 cell count was 514 ± 229/ml, HIV RNA<400 in 66% (mean HIV load in others: 3.7±0.7 logs). The mean pre-treatment Metavir score was A 1.8±0.7, F 2.3 ± 1.0 and 39% of pts had F3-F4 of which 17% had sustained normal ALT. Baseline variables were not different between groups. Treatment discontinuation occurred in 167 pts (42%) (86 IFN & 81 PEG) and severe adverse events in 127 (31%) (64 IFN & 63 PEG), including 6 mitochondriopathies. SVR was achieved in 20% of IFN pts vs 27% of PEG pts (p=0.047). In those who did not discontinue treatment, virological response rates were at W4 (12 vs 20%), W12 (34 vs 41%), W24 (41 vs 54%), (W48: 34 vs 52%) and W72 (6 vs 35%), respectively. Virologic response at W12 predicted SVR with 87% Positive Predictive Value and its absence had a 99% Negative Predictive Value. SVR varied with genotypes 1 or 4 (11%) vs 3 or others (43%), but not with the Metavir score or the adjusted ribavirin dose. Response-associated pretreatment characteristics included genotypes other than 1 or 4 (OR=5.9), no protease-inhibitor therapy (OR=2.0), age = 40 years (OR=1.9) and elevated ALT (OR=1.8). Necro-inflammation significantly decreased in the PEG pts (-0.20 vs 0.02, p=0.0008). Fibrosis stabilized in virological responders and worsened in non responders. Steatosis improved significantly in patients infected by genotype 3 who had a SVR (p= 0.017).

 

Conclusion

In HIV-HCV coinfected pts, the combination of pegylated IFNa2b and ribavirin is associated with a superior HCV virologic response than standard combination with a quite similar adverse-event profile.


 

COMBINATION THERAPY OF PEGINTERFERON ALFA-2B AND ADEFOVIRDIPIVOXIL IN CHRONIC HEPATITIS-B LEADS TO A STRONG SUPPRESSION OF CCCDNA AND HIGH RATES OF HBE AND HBS SEROCONVERSION

K. Wursthorn, P. Buggisch, B. Zoellner, M. Zankel, C. Fischer, S. Xiong, C. Brosgart, G. Currie, J. Petersen  

Background

HBV targeted antiviral therapy with adefovir dipivoxil (ADV) results in a significant reduction of intrahepatic HBV cccDNA, serum HBsAg, and serum HBV DNA (Werle-Lapostolle, Gastroenterology 2004). Pegylated interferon alfa (Peg IFN) improves serological outcome in HBeAg positive and HBeAg negative patients (Lau, AASLD 2004; Marcellin, New Engl J Med 2004).

 

Aim

The aim of this study was to determine the virological and serological outcome in patients with chronic Hepatitis B treated with combination therapy of Peg IFN alfa 2b and ADV. 

 

Methods

26 patients with chronic Hepatitis B were included in a single center open label pilot study. Patients received a 48 week course of antiviral combination therapy with 12kDa pegylated interferon alfa 2b 1.5µg/kg bw qw and ADV 10mg qd. 23/26 patients were analyzed at the time of abstract submission, final data will be available as of December 2004.  Intrahepatocellular cccDNA, serum HBsAg, and serum HBV DNA was quantified as described previously (Werle-Lapostolle, Gastroenterology 2004). 

 

Baseline characteristics:

Median age, years                                    33

Male                                                         14

Caucasian                                                 21

Asian                                                        5

HBeAg +                                                  15

HBeAg –                                                  11

HBV DNA, PCR                                      5 x 106

(log10 copies/ml, median)

ALT (xULN, median)                               3,1 

 

Results

At week 48, compared to week 0:

cccDNA reduction (median, paired biopsies)             -2.2log

Serum HBsAg titer reduction (median)                       -44%

Serum HBV DNA reduction (median)                         -4.7log

Serum HBV DNA <100 copies/ml                              12/23(52%)

(LLoD, LightCycler, Roche)                   

HBeAg loss                                                                 7/13 (54%)

HBeAg seroconversion                                               5/13 (38%)

HBsAg seroconversion                                               4/23 (17%)

ALT normalisation                                                      10/23 (43%)

ALT improvement                                                       19/23 (83%)

METAVIR histology score improved                         13/21 (62%) 

 

Conclusion

Administration of 48 weeks of Peg IFN alfa 2b and adefovir dipivoxil resulted in a strong suppression of cccDNA, high rates of HBsAg seroconversion, HBeAg seroconversion and loss, respectively. Combination therapy was safe and well tolerated. No unexpected adverse events were reported. All patients are continuing in study on additional 96 weeks of ADV monotherapy followed by a third liver biopsy.


 

ENHANCED ANTIVIRAL EFFICACY FOR VALOPICITABINE (NM283) PLUS PEG-INTERFERON IN HEPATITIS C PATIENTS WITH HCV GENOTYPE-1 INFECTION:  RESULTS OF A PHASE IIA MULTICENTER TRIAL

N. Afdhal, M. Rodriguez-Torres, E. Lawitz, E. Godofsky, G. Chao, B. Fielman, S. Knox, N. Brown  

 

Background

Only 40-50% of HCV-1 infected hepatitis C patients respond to pegylated interferon (peg-IFNα) plus ribavirin therapy.  NM283 is a novel nucleoside analog that as monotherapy reduced serum HCV RNA by a mean 1.2 log10 (94%) in a recent 15-day trial in HCV-1 patients, most of whom had previously failed antiviral therapy for HCV infection.  NM107, the parent compound of NM283, and interferon alfa exhibit synergistic antiviral effects against BVDV models in vitro, prompting the current investigation of  NM283 combined with peg-IFNα in treatment naďve patients with chronic hepatitis C.

 

Methods

A multicenter, open-label phase IIa trial is evaluating whether NM283 plus peg-IFNα-2b has enhanced antiviral activity compared to NM283 alone in HCV-1 infected patients.  Key entry criteria are:  HCV RNA >5 log10 IU/mL, ALT <5 xULN, compensated liver disease, treatment naďve.  Eligible patients are randomized 2:3 to NM283 or peg-IFNα + NM283 (combinationRx).  NM283 is dosed orally QD for 24 weeks in both groups, escalating to 800 mg/day over the first week and then continuing at that dose. The group randomized to combinationRx receives peg-IFNα-2b (1.0 μg/kg weekly) starting on Day 8.

 

Results

Presently 19 of 30 planned patients (age 22-65, 68% males) are enrolled and have received 10 or 12 weeks of treatment.  Tolerance of both treatments has been satisfactory.  Mean HCV RNA reductions (log10 IU/mL) from baseline to the last patient visit are 1.0 for the NM283 monotherapy group and 3.2 for the combinationRx group.  Eleven of twelve combinationRx patients treated for at least 10 weeks have had substantial HCV RNA reductions (range 1.2-6.2 log10), and 8 of 12 patients have achieved >2 log10 decrease in HCV RNA, which has been associated with sustained response to current standard Rx. Presently 4 patients are PCR-negative (<10 IU/mL).  12-week early virological response data will be presented at the meeting.

 

Conclusions

NM283 combined with peg-IFNα shows consistent, rapid and marked anti-HCV activity in patients with HCV-1 infection, a historically difficult-to-treat group.  Initial EVR rates with combinationRx are encouraging and support continued investigation of NM283 and NM283 + peg-IFNα, which may offer improved efficacy and tolerability for patients with HCV-1 infection.


 

EFFECT OF MAINTENANCE PEG-INTRON THERAPY ON PORTAL HYPERTENSION AND ITS COMPLICATIONS: RESULTS FROM THE COPILOT STUDY

M. Curry, A. Cardenas, N.H. Afdhal  

 

Introduction

The COPILOT clinical trial is evaluating maintenance therapy with PEG-Intron 0.5mcg/kg weekly versus colchicine (COLC) 0.6mg twice daily in 600 patients with HCV and advanced fibrosis who have failed prior interferon treatment. Clinical endpoints include death, liver failure, transplantation, variceal bleeding and liver cancer. The 2 year evaluation suggested an improved event free survival in patients on PEG compared to colchicine (Hepatology 2004;40;239A). We evaluated the role of portal hypertension (PHTN) on the clinical outcomes of maintenance therapy and the role of maintenance PEG-Intron on portal pressure. 

 

Patients/Methods

537 patients are enrolled in the trial to date; 267 COLC and 270 PEG. 83% of patients in each group have cirrhosis and 40% have PHTN defined by varices or gastropathy. Endoscopy is performed every 2 years for development of new varices. A substudy evaluated portal pressure using HVPG measurements prior to PEG and after 24 weeks of PEG in 5 patients with varices who were not on B blockers. Clinical endpoints were evaluated in patients with and without PHTN.

 

Results

132 patients have had repeat endoscopy at 2 years and new varices were seen in 11 of 66 patients on COLC versus 5 of 66 patients on PEG (p =ns). All 5 patients had baseline elevated HVPG ( Mean 15mmHg) and all had a reduction in HVPG after 24 weeks on PEG ( Mean 6 mmHg; overall HVPG reduction 41%,mean reduction in HVPG 7mmHg). Primary event rate for patients with PHTN was 13.5% per year on COLC and 5.5% per year on PEG (p < 0.004). Primary event rate without PHTN was 3% in each treatment group.Variceal bleeding over 2 years occurred in 11 patients on COLC (9%) and 1 patient on PEG (1%). Ascites and liver failure was also more common in COLC (n = 20) compared to the group on PEG (n=13).

 

Conclusion

Maintenance PEG therapy may retard varices development, reduces portal pressure and prevents variceal bleeding and complications of PHTN compared to COLC. Clinical endpoints are more common in patients with PHTN. PEG should be considered in patients with cirrhosis who fail interferon and ribavirin therapy

 


SUSTAINED VIROLOGIC RESPONSE (SVR) IN THE EPIC3 TRIAL: WEEK TWELVE VIROLOGY PREDICTS SVR IN PREVIOUS INTERFERON/RIBAVIRIN TREATMENT FAILURES RECEIVING PEG-INTRON/REBETOL (PR) WEIGHT BASED DOSING (WBD)

T. Poynard, E. Schiff, R. Terg, F. Goncales, M. Diago, J. Reichen, R. Moreno, P. Bedossa, M. Burroughs, J. Albrecht

Introduction

EPIC3 is a large, prospective, controlled trial designed to understand 1) the efficacy of treatment with PR for 48 weeks in previous treatment failures to interferon-alfa and ribavirin therapy (I/R) and 2) for non-responders (NR) to PR, to determine the efficacy of PEG-Intron 0.5 microgram/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 PR in the first 575 patients in EPIC3. Additionally, we evaluated the ability of 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] week 12 or 24).

 

Methods

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

 

Results

Of the first 575 patients enrolled in the combination therapy trial, 21% achieved SVR. Of those who attained EVR, 38% achieved SVR: 61% of those 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-Intron plus weight based Rebetol achieves SVR in a substantial proportion of I/R treatment failures who are HCV-RNA (-) at treatment week 12.


 

EFFICACY AND SAFETY OF ANTIVIRAL THERAPY IN LIVER TRANSPLANT RECIPIENTS WITH CHRONIC HEPATITIS C

J.A. Carrion, M. García-Retortillo, M. Navasa, A. Rimola, J.C. García-Valdecasas, X. Forns1

 

Introduction

Recurrence of hepatitis C after liver transplantation (LT) is a major problem in transplant programs. 

 

Aim

The aim of this prospective study was to assess the efficacy and safety of antiviral therapy in liver transplant recipients with chronic hepatitis C.

 

Methods/patients

Fifty-two patients with chronic hepatitis C (diagnosed by liver biopsy after a minimum of 6 months following LT) were randomized to receive:

 

Group A- pegylated interferon alfa-2b (1,5 µg/Kg/w) and ribavirin (800-1000 mg/d) for 48 weeks;

 

Group B- no treatment. Patients with severe HCV recurrence (Group C: bridging fibrosis or necrosis, cholestatic hepatitis) were treated as group A.

 

Efficacy was evaluated 6 months after treatment discontinuation and was defined as persistent HCV-RNA negativization (SVR). All patients underwent a liver biopsy 6 months after treatment discontinuation. The baseline characteristics of the 52 patients were: age 57 years, 36 (69%) males, 45 (87 %) infected with genotype 1b, viral load (VL) 3.5x106 IU/ml, significant liver fibrosis (F≥2) 15 (29%).

 

Results

From the 37 patients with complete follow-up, 5/12 (42%) of group A, 0/10 of group B and 4/15 (27%) of group C achieved SVR (p < 0.05).  An early virological response  (EVR: decrease in VL > 2 log10 at week 4 of treatment) occurred in 7 (78%) of 9 patients with SVR versus 3 (17%) of 18 non-responders (p=0.004). Although preliminary data do not demonstrate significant histological improvement in patients achieving SVR, disease progression leading to graft loss occurred only in non-responders from group C (6 of 11, 55%). Severe adverse events were frequent in treated patients: neutropenia and anemia requiring stimulating factors in 11 (41%) and 22 (81%), respectively, depression in 2 (7%) and rejection in 2 (7%). Interferon or ribavirin dose reductions were necessary in 10 (37%) and 21(78%) cases, respectively and definitive treatment interruption in 11 (41%).

 

Conclusion

In conclusion, in liver transplant recipients with chronic hepatitis C antiviral treatment  is effective in one third of patients. However, tolerance is poor and severe adverse events are very frequent. Therefore, treatment should be recommended only in patients with severe HCV recurrence or in those with histological evidence of disease progression.


 

RECURRENCE OF HEPATITIS C VIRUS IS MORE SEVERE IN LIVER TRANSPLANTED HIV-HCV CO-INFECTED PATIENTS THAN IN HCV MONO-INFECTED PATIENTS

J.C. Duclos Vallee, C. Feray, E. Teicher, D. Vittecoq, A.M. Roque Afonso, M. Gigou, E. Dussaix,M. Sebagh, C. Guettier, D. Azoulay, R. Adam, P. Ichai, F. Saliba, B. Roche, D. Castaing, H. Bismuth, D. Samuel  

 

Background.

The recurrence of HCV infection after liver transplantation (LT) in HIV-HCV co-infected patients could be more severe and may affect the prognosis after LT.

 

Aim

We compare in a single center, the survival and the severity  after LT- recurrence of HCV in co-infected and mono-infected consecutive patients.

 

Patients

9 patients (76 males) receiving a first liver graft for HCV-related liver disease (37 for hepatocellular carcinoma) between June 1998 and October 2004 were included. Among them, 23 were HIV positive, had HAART-controlled HIV and more than 150 cells/mm3 of CD4 before LT. Post LT liver biopsies were available in all patients with more than 6-months of survival and during the second year in 55 patients. Sex and age of donor and recipient, hepatocellular carcinoma, HCV genotypes, type of transplantation, (living donor, domino) were studied variables.

 

Results

Co-infected patients were younger than mono-infected patients (41y± 11 vs 55 ± 8; p<0.001) and received more dominos (10/23 (43%) vs 9/76 (12%)) or livers from living donors (5/23 vs 11/76). 5/23 (27%) co-infected patients died: severe HCV recurrence and mitochondrial toxicity (n=2), acute pancreatitis (n=1), cerebral hemorrhage (n=1) and pancreatic adenocarcinoma (n=1). 10/76 (13%) mono-infected patients died of different causes: recurrent cirrhosis (n=3), recurrent hepatocellular carcinoma (n=1), sepsis (n=4) and cardiovascular causes (n=2). One- and 2-year survivals were 82% and 68% in co-infected patients and 95% and 87% in mono-infected patients (log-rank=0.10). Pegylated interferon alpha 2-b and ribavirin was administrated in 14/23 co-infected and in 16/76 mono-infected patients with a virological response in 4/14 and 10/16. In co-infected patients, the 6-month, HCV viral load was higher (6.8±0.4 log vs 6.0 ±1; p=0.03) and the score of fibrosis more severe (F ? 3 in 4/13 (31%) vs 4/42 (9%); p=0.02). Conclusions. LT in HIV-HCV co-infected patients is a legitimate indication. However, recurrence of hepatitis C is more severe and combined interferon and ribavirin-based therapies possibly less efficient in co-infected than in mono-infected patients. While waiting for new drugs against HCV, avoidance of drug toxicity, intensive and prolonged anti-HCV therapies are mandatory to improve the long-term result of this new and challenging indication of LT.


 

PEGYLATED INTERFERON AND RIBAVIRIN THERAPY DOES NOT INCREASE ACUTE REJECTION RISK POST LIVER TRANSPLANTATION – A RETROSPECTIVE CASE CONTROL STUDY

N. Elhajj, N. Kontorinis, C. Stanca, K. Agarwal, I. Fiel, E. Eggleton, C. Barton, T. Schiano 

 

Background/Aim

Due to the immunomodulatory effects of interferon, there is concern that treatment of recurrent HCV post liver transplantation (LT) may precipitate acute cellular rejection (ACR), as with kidney transplantation. The aim of this study was to assess ACR risk with Peg-IFN and RBV.

 

Methods

Patients with recurrent HCV post LT treated with either Peg-IFNalfa 2a or 2b, in combination with RBV (Peg-RBV) for > 6 months were compared to untreated HCV patients for development of moderate or severe ACR. Subjects were matched for age, sex, year of LT and immunosuppression. ACR episodes were treated with solumedrol bolus and augmentation of primary immunosuppression. Liver biopsies were graded (Banff criteria) by a blinded pathologist.

 

Results

65 post LT HCV patients treated with Peg-RBV were matched with 65 HCV untreated controls. Age, follow up and immunosuppression between 2 groups were equal. In each group immunosuppression was tacrolimus (52), cyclosporin (12) and rapamycin (1). 8 were also on mycophenolate or azathioprine. Overall, including the pre-treatment period, there were 37 episodes of ACR in 26 patients in the Peg-RBV group vs 31 episodes in 24 patients in the controls (p = 0.38). During Peg-RBV therapy there were 13 episodes of ACR in the Peg-RBV group vs 9 in the controls (p = 0.48). 33% with rejection on Peg-RBV had a prior history of rejection. Highest risk of rejection occurred in the early post LT period with 33 episodes of ACR in 30 patients in the first 6 months. ACR did not influence virological response (OTR); 3 patients with ACR achieved OTR vs 6 patients without an episode of ACR (p = 0.49). 3 had recurrent ACR on therapy and required OKT3; of these 2/3 developed chronic rejection and graft loss.

 

Conclusions

Peg-RBV does not increase the risk of ACR post LT. The early post-transplant period has the highest risk of ACR and patients undergoing therapy during this period should be closely monitored. ACR treatment does not influence virological response. Following a single episode of ACR it appears safe to continue PEG-RBV therapy, however recurrent bouts of ACR may be a risk for graft failure. 


PEGYLATED INTERFERON (PEG-IFN) ALFA 2B + RIBAVIRIN (RB) IN THE TREATMENT OF POST-LIVER TRANSPLANT (LT) RECURRENT HEPATITIS C

S. Martini, B. Lavezzo, S. Saettone, A. Franchello, A. Smedile, D. Cocchis, V. Ghisetti, E. David, M. Salizzoni, M. Rizzetto

Introduction

After LT recurrent chronic hepatitis C develops in many patients (pts).

Aim

We evaluated effectiveness, safety and tolerance of combination therapy (CT: Peg-IFN alfa2b + Rb) in LT with recurrent hepatitis C.

Methods

86 pts after LT, mean age 53 ys, M/F 68/18, genotype 1-4 82,6%, with histological recurrence HCV chronic hepatitis, mean grading 6/18 (2-16), mean staging 2/6 (1-4), were treated  with  Peg-IFN alfa2b 1 mcg/kg/week plus Rb 800 mg/die for 12 months (mo). 45 pts were naďves, 41 pts were relapser or non responder (NR) to previous conventional IFN + Rb therapy. The median delay between  LT and first antiviral therapy was 12 mo (2-114). We evaluated virological response (qualitative HCV-RNA negative) at the end of  treatment (ETVR) and at 24 weeks of follow-up (SVR).

Results

Table 1 shows results.

Conclusions

49% of naive pts achieved ETVR and 33% SVR with CT. 17% of retreated pts maintained  SVR. Response  was satisfactory in genotype 2-3 and still disappointing in genotype 1-4. In these difficult to treat pts, full dosage maintainement and duration of therapy are important. Tolerance is poor and severe side effects are frequent.

 

 


PEGYLATED-INTERFERON ALPHA-2B PLUS RIBAVIRIN IN THE TREATMENT OF HCV REINFECTION AFTER LIVER TRANSPLANTATION EXPERIENCE OF A SINGLE CENTRE

F.P. Picciotto, A. Galeota Lanza, M. De Luca, G. Tritto, F. Lampasi, G.G. Di Costanzo, M.T. Tartaglione, L. Addario, W. Utech, M. Macrě, G. Marino Marsilia, A. Ascione  

 

Background

HCV reinfection is almost universal in patients receiving liver transplantation (LT) for end stage liver disease due to HCV. In about one third of cases, progressive liver damage, rapid decompensation and death develop. To date, peg-interferon + ribavirin is considered the treatment of choice in this setting, even if results are disappointing.

 

Aim

To analyze in a prospective study the efficacy of PEG-Interferon alpha-2b + ribavirin (PEG-IFN+RBV) in HCV-reinfected patients (pts) after LT.

 

Methods

On 123 cases of HCV reinfection after LT consecutively observed in our centre during the last 4 years, 61 pts (M/F = 48/13; mean age 47±6 ys, range 41-65) were eligible for treatment and received PEG-IFN-alpha2b (1 µg/Kg/bw) and ribavirin (10 mg/Kg/bw) for 6 or 12 months, according to genotype. Genotype was 1b in 53 pts and 2 in 8. All but 3 underwent liver biopsy; the grade of fibrosis was F3-F4 (Metavir score) in 28 pts. Immunosuppression: cyclosporine (23 pts), tacrolimus (29) as single drug; plus micophenolate in 9.

 

Results

Fiftytwo/61 pts completed the scheduled treatment, although doses had to be reduced in almost all pts, and 9/61 pts dropped out for side effects. According to intention-to-treat (ITT) analysis, 40 pts were considered as non responders (NR). End of treatment response (ETR) was obtained in 21/61 pts (34%). 17/61 pts (28%) achieved a SVR while 4 relapsed. Genotype 2 was the only statistically significant predictor of SVR (p<.001). A two-fold risk of non-response (not statistically significant) was observed in pts with viral load >2M IU/ml. Neither fibrosis nor immunosuppressive regimen correlated with SVR. Four pts (all non responders) died because of end stage liver disease, one because of HCC recurrence. All of them were off antiviral therapy.

 

Conclusion

Only 28% of HCV-reinfected patients after LT, treated with PEG-IFN+RBV, achieved a SVR. Genotype 2 was the only predictive factor of SVR, while fibrosis and viral load did not play a significant role. Therefore, in this setting, antiviral therapy is less effective compared to non-LT patients, but relapse rate is similar to that observed in immunocompetent pts.

 

PEGYLATED INTERFERON ALPHA PLUS TAURINE TREATMENT IN EXPERIMENTAL LIVER FIBROSIS

M.R. Mas, I. Tasci, N. Mas, S.A. Vural, S. Deveci, B. Comert, C. Akay, A.T. Isik, E. Ozkomur, E. Cinar, Y. Ates, G. Alcigir, M. Bozdayi  

Introuction

Liver fibrosis is characterized by overproduction and diminished degradation of matrix proteins in the sinusoids. Hepatic stellate cells (HSCs) are the main source of excessive collagen synthesis. Oxidative stress (OS) has an important role in fibrogenesis. HSC apoptosis has been proposed to be involved in spontaneous recovery (SR) of liver fibrosis.

 

Aim/Methods/Patients

We studied individual and combined effects of peginterferonα2b (PegIFNα2b), and a potent antioxidant taurine on experimental liver fibrosis. Sixty male Sprague-Dawley rats were injected SC with CCl4 for 12 weeks to induce liver fibrosis. After induction of fibrosis the rats were divided into four groups. Group I (n=15) was left for SR. Group II was treated with PegIFNα2b 1.5mg/kg/week, Group III with taurine 1200 mg/kg/day, and Group IV with the combination of these two regimens. All the rats were killed after four weeks of treatment and histopathological fibrosis scores, αSMA(+) HSC counts, apoptotic HSCs and hepatocytes, and OS parameters were determined.

 

Results

PegIFNα2b and taurine equally improved fibrosis. Fibrosis scores were reduced significantly in Groups II, III and IV when compared to Group I (p<0.05). αSMA(+) cell counts were reduced in Groups II, III and IV when compared to Group I (p<0.001). Number of αSMA(+) cells in Groups II and III were similar. Group IV αSMA(+) cell counts were lower than Group III (p<0.03). PegIFNα2b did not affect hepatocyte apoptosis. Taurine alone and in combination induced hepatocyte apoptosis significantly (p<0.03, p<0.001, respectively). Effects of PegIFNα2b and taurine on hepatocyte apoptosis were similar. HSC apoptosis increased significantly in Groups II, III and IV when compared to Group I (p<0.002, p<0.03, p<0.001, respectively). HSC apoptosis significantly increased in Group IV in comparison with PegIFNα2b and taurine treatments (p<0.02, p<0.001, respectively). There was no difference between apoptotic HSC counts in Groups II and III (p>0.05). Tissue SOD, MDA, and GSHPx levels improved significantly only in Group III. In conclusion, PegIFNα2b and taurine both improved experimental liver fibrosis.

 

Conclusion

Induction of HSC apoptosis and thereby accelerating SR may be potential approaches in treatment of liver fibrosis. Although the mechanisms of action are different, combination of the two agents seems to have no significant benefit.


 

ANALYSIS OF CCR5 RECEPTOR EXPRESSION ON CD8 T CELLS DURING CHRONIC HEPATITIS C VIRUS (HCV) INFECTION ROLE OF PEGYLATED-INTERFERON A2B PLUS RIBAVIRIN

M. Calvino, J.R. Larrubia1,, T. Parra, E. Sanz de Villalobos, F. González, C. Perna, J. Pérez de Hornedo, A. Bienvenido

 

Background

CCR5 receptor plays an important role in Tc1 cells migration into inflamatory sites. During HCV infection is essential a right HCV specific CD8 T cells migration into the infected liver to control the virus. So, a possible way of viral escape could be to impair CCR5 receptor expression on CD8 T cells.

 

Objectives

1) To quantify CD8+/CCR5+ T cells frequency from peripheral blood and liver in chronic hepatitis C (CHC+), other chronic hepatitis (CHC-) and healthy controls (HC).

2) To analyse the role of anti-viral treatment (PEG-interferon a2b and ribavirin) in CCR5 expression on CD8 T cells from peripheral blood.

 

Also it has been analysed, as internal control, CCR3 and CXCR3 expression in the different groups.

 

Methods

Peripheral blood (PBMC) and intrahepatic (IHMC) mononuclear cells from 18 CHC+ patients and 4 CHC- patients and PBMC from 5 HC were obtained. Moreover, in ten CHC+ patients PBMC at different time-points during treatment were analysed. Mononuclear cells were marked with anti-CD8, anti-CCR5, anti-CCR3 and anti-CXCR3 antibodies and analysed by flow-cytometry. Data are presented as the median frequency of CD8+/CCR5+ T cells out of total CD8+ T cells plus the interquartile range (IQR). Comparison among groups were done by Mann-Whitney U, Kruskall Wallis and Wilcoxon tests.

 

Results

Frequency of CD8+/CCR5+ T cells in CHC+ was higher in liver (60.5%: IQR 46) than in peripheral blood (12.5%: IQR 7) (p<0.01). CCR5 expression on CD8 T cells was higher in PBMC from CHC+ than in HC (5.2%: IQR 4.8) but lower than in CHC- (24%: IQR 7) (P<0.05). CD8+/CXCR3+ T cells frequency was higher in CHC+ (50%: IQR 24) than in HC (32%: IQR 14) (p<0.05). CD8+/CCR3+ T cells were not detected in any group. Mean frequency of CD8+/CCR5+ T cells increased in 80% of CHC+ patients during anti-viral treatment (17%: IQR 11) (p<0.01), but neither CCR3 nor CXCR3 were modified.

 

Conclusions

1) CCR5 expression by T cells allows its intrahepatic sequestration in CHC+.

2) HCV infection reduces CCR5 expression on CD8 T cells in comparison to other chronic hepatitis. 3) Anti-viral treatment could improve CCR5 expression on CD8 T cells in CHC+.


 

INTRAHEPATIC HEPATITIS C VIRUS-SPECIFIC CD4+ AND CD8+ T CELL RESPONSES IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS TREATED WITH PEGINTERFERON ALPHA-2B: RELATION TO LIVER HISTOLOGY

S. Kamal, Q. He, C. Graham, W. Saleh, A. Al Tawil, S. Hakam, K. El Sayed, J. Rasenack, M. Koziel

 

Background

Pegylated interferon alfa (PEG IFN alpfa) improves sustained virological response rates in chronic hepatitis C and is associated with histological improvement but the biologic basis for this effect on the liver not been defined. The (HCV)-specific CD4+  and CD8+T cell responses are critical to achieving a sustained virologic response to in interferon therapy however the patterns and kinetics of intrahepatic T-cell responses in during PEG IFN alpha therapy have not been described. This prospective study assessed the intrahepatic (HCV)-specific CD4+  and CD8+T cell responses before and after PEG IFN alpha treatment and correlated the pattern of these responses to changes in liver histology. 

 

Methods

This prospective longitudinal study compared the HCV specific intrahepatic and peripheral CD4+ and CD8+ T cell responses and cytokines (ELISpot) before and after treatment with peginterferon alpha-2b/ribavirin therapy in 40 subjects. The findings were correlated to the liver histology (Ishak score) and fibrosis progression rate/year. 

 

Results

The sustained virological response (SVR) was achieved in 26/40 subjects (65%) treated with PEG IFNalpha/ribavirin combination therapy. Histological improvement was detected in all sustained virologic responders, relapsers (n=5) and 3/9 non-responders. At baseline, week narrowly focused intrahepatic HCV-specific CD4+ Th1 responses were detected in 13/40 while Cd8+ responses could be detected in 9/40 subjects. At the end of follow-up, multispecifc CD4+ Th1 responses were detected in all sustained responders, relapsers and 2 non-reponders. CD8+ T-cell response was detected in the livers of 18/40 patients. The intrahepatic HCV-specific CD4+ and CD8+ T cell responses were significantly related to a histological improvment. 

 

Conclusion

This prospective analysis indicates that peginterferon alpa-2b therapy induces  histological improvement which is associated with development of multispecific, HCV-specific CD4+ Th1 responses and detection of HCV specific CD8+ T cells in the liver that could be related to several parameters of a favorable outcome of chronic C hepatitis. 

 

GENOME-WIDE ANALYSIS OF THE TRANSCRIPTIONAL IFN-α RESPONSE IN PATIENTS TREATED FOR HEPATITIS C - IDENTIFICATION OF GENES THAT ARE ASSOCIATED WITH A STRONG ANTIVIRAL ACTIVITY

M. Trippler, S. Bein, K. Koop, G. Gerken, J.F. Schlaak  

Aims and background

The mechanism of action of interferon-alpha (IFN-α) which is used therapeutically to suppress replication of the Hepatitis C Virus (HCV) in chronically infected patients is still unclear.

 

Methods

To identify target genes that mediate the anti-HCV effect of IFN-α in vivo 24 HCV patients were treated with a standard therapy (PEG-IFNα-2b + ribavirin). 12h before and 12h after the first injection of IFN peripheral blood cells were assayed for the expression of IFN-inducible genes (ISGs) using DNA microarrays and quantitative real-time RT-PCR. HCV-RNA levels were determined 12h before and 36h after IFN injection to assess the immediate antiviral effect of IFN. The gene expression profiles were correlated with clinical and virological parameters.

 

Results

A total of approximately 770 ISGs could be identified in this cohort of patients of which 175 genes were consistently induced in all patients. 25 candidate genes could be identified that were significantly lower induced in patients with low (<1,5 log) antiviral response compared to patients with good (>1,5 log) antiviral response. 8 of those could be confirmed using real-time RT-PCR. No gene could be identified with significantly higher induction in patients with low antiviral response.

 

Conclusions

In conclusion, we could identify candidate genes that may mediate the immediate antiviral effects of IFN-α in patients treated for chronic hepatitis C. 


FLARES IN CHRONIC HEPATITIS B PATIENTS INDUCED BY THE HOST OR THE VIRUS? RELATION TO TREATMENT RESPONSE DURING PEG-INTERFERON ALPHA-2B THERAPY

H.J. Flink, D. Sprengers, B.E. Hansen, E. Verhey, M. van Zonneveld, R.A. de Man, S.W. Schalm, H.L.A Janssen  

 

Background and aims

Flares of liver inflammation are a well-known phenomenon during treatment with interferon and after stopping lamivudine given for chronic hepatitis B. Although flares are thought to represent immune-mediated clearance, little is known about the effect of flares on response to antiviral treatment.

 

Aim

In this study we investigated the timing and characteristics of flares, and assessed the relation to treatment response (i.e. serum HBeAg loss at end of follow-up).

 

Methods

A total of 266 patients, participating in a global randomized controlled study were assigned to 52 weeks of 100μg Peg-interferon alpha-2b weekly combined with, either daily 100mg lamivudine (combination therapy) or placebo (mono-therapy). The follow-up lasted 26 weeks. Flare was defined as 3-fold increase in alanine aminotransaminase (ALT) compared to baseline.

 

Results

Sixty-seven patients (25%) exhibited a total of 75 flares, with 38 (51%) flares in the combination-therapy and 37 (49%) in the mono-therapy group. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease of HBV DNA of at least 1 log, referred to as host-induced flare. In 25 (38%) patients the flare was preceded by an increase of at least 1 log HBV DNA, referred to as virus-induced flare. In 17 (26%) patients the flare did not meet one of these criteria, and was classified as indeterminate. Of patients with host-induced flare 58% responded, whereas only 20% of patients with virus-induced flares responded, p = 0.008. Multivariate logistic analysis showed that host-induced flares was the only independent predictor for response to therapy (p = 0.003, RR 3.5 CI 95% 0.9 to 13.9)

 

Conclusions

Flares are not more common in responders than in non-responders to Peg-interferon alpha-2b therapy. Virus-induced flares, which occur after an increase in HBV DNA level, and most probably indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host-induced flares which were followed by an HBV DNA decrease were highly associated with treatment response.

 


SAFETY AND EFFICACY OF COMBINATION THERAPY WITH 12KD PEGYLATED INTERFERON AND RIBAVIRIN FOR CHRONIC HEPATITIS C VIRUS INFECTION IN DECOMPENSATED CIRRHOTICS

B.E. Annicchiarico, M. Siciliano, A. Milani, A. Franceschelli, G. Bombardieri  

Istituto di Patologia Speciale Medica e Semeiotica Medica - Universitŕ Cattolica Del Sacro Cuore, Rome, Italy 

 

Introduction

The poor prognosis of decompensated HCV cirrhosis strongly recommends effective antiviral therapy. A sustained virological response could slow further clinical deterioration and could reduce the risk of hepatocellular carcinoma. Moreover, sustained response could avoid HCV reinfection in patients submitted to liver transplantation. However, some concern exists about the safety of pegylated interferon and ribavirin combination therapy in decompensated cirrhotics, expecially in front of a reduced virological response. As a result, randomized controlled trials evaluating this treatment in chronic HCV infection have excluded, until now, patients with decompensated cirrhosis.

 

Aim/Methods

Aim of our study was to evaluate safety and efficacy of combination therapy in decompensated cirrhosis. Thirty-one cirrhotics (aged from 37 to 73, 16 males, 19 with genotype 1a/1b) who have experienced ascites, encephalopathy (HE), varices, spontaneous bacterial peritonitis (SBP), jaundice or coagulopathy, were studied. Main laboratory and clinical features at the beginning of the treatment are reported in the table.

 

Results

All patients started pegylated interferon 12KD 1.5 mcg/Kg of body weight/week and ribavirin ≥10.6 mg/Kg of body weight/day. Twenty-four or 48 weeks of treatment were planned, according to genotype and early virological response. Eleven patients reduced pegylated interferon dose for neutrophils < 0.75X109/L and 4 for platelets < 45X109/L. Two patients reduced ribavirin dose for hemoglobin < 10.0 g/dL. No patient discontinuated pegylated interferon for neutrophils < 0.5X109/L or platelets < 25X109/L. One patient discontinued ribavirin for hemoglobin < 8.0 g/dL. Two patients discontinued therapy respectively at the fourth and at the12th week for neurological deterioration. Fifteen patients (48.4%) obtained early virological response, 12 (38.7%) end-of-treatment response, and 10 (32.3%) sustained virological response. The means of end-of-therapy MELD and Child-Pugh scores in the 15 patients who obtained at least early virological response were respectively 8.5 (range 6 to14) and 7.2 (range 7 to 8).

 

Conclusion

Even in decompensated HCV cirrhosis, combination therapy with pegylated interferon and ribavirin is safe and efficacious.


 

MITOCHONDRIAL EFFECTS OF A 24-WEEK COURSE OF PEGYLATED-INTERFERON (PEG-IFN) PLUS RIBAVIRIN (RBV) IN ASYMPTOMATIC HCV/HIV CO-INFECTED PATIENTS ON LONG-TERM TREATMENT WITH DIDANOSINE, STAVUDINE OR BOTH

A.L. Ballesteros, O. Miró, S. López, D. Fuster, S. Videla1, E. Martínez, G. Garrabou, A. Salas, H. Côté, J. Tor, C. Rey-Joly, R. Planas, B. Clotet, C. Tural  

 

Background

It has been suggested that the addition of RBV as a part of treatment for chronic hepatitis C virus (HCV) in human immunodeficiency virus (HIV) co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function.

 

Design

Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HIV/HCV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their same antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus Peg-IFN alfa-2b therapy (HCV-treated group).

 

Methods

We assessed peripheral blood mononuclear cells (PBMCs) mitochondrial DNA (mtDNA) content (quantitative real-time polymerase chain reaction), and mitochondrial respiratory chain (MRC) function of complexes II, III and IV (spectrophotometry), at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy

 

Results

Times on ddI or d4T exposure were 194±54.9 and 131±66.5 weeks in the HCV-treated and control groups, respectively. There were no differences between both groups at baseline, either in mtDNA content (0.9±0.1 and 1.2±0.6; p=0’02), the enzyme activity of MRC complex II (22±2 y 24±9; p=0.86), III (82±41 y 55±24; p=0.08) and IV (41±13 y 41±10; p=1) or clinical parameters. Throughout the study, mitochondrial measurements remained stable in the HCV-treated group (figure) and without differences when we compared HCV-treated and control groups at 24 weeks: [mtDNA (1.1±0.6 and 1.2±0.6; p=0.68), the enzyme activity of MRC complex II (31±14 y 25±11; p=0.23), III (63±14 y 69±34; p=0.54) y IV (54±20 y 44±19; p=0.21)].

 

Conclusions

In our study, the addition of RBV and Peg-IFN during a 24-week period in HIV/HCV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop 

 

 


 

EFFICACY OF PEG-INTERFERON ALPHA-2B (PEG-IFN) PLUS RIBAVIRIN IN RESPONDER-RELAPSERS TO A PREVIOUS COURSE OF INTERFERON ALPHA PLUS RIBAVIRIN

M. Basso, F. Torre,A. Grasso, G.F. Percario, E. Azzola, S. Artioli, N. Pelli, A. Picciotto  

Aim

Our aims were to evaluate the rate of SVR in patients relapser to a previous course of standard IFN combination therapy when retreated with PegIntron alfa 2b (1 mcg/kg/week) and ribavirin (800-1200 mg daily) for 24 (genotypes 2-3) or 48 weeks (genotypes 1-4) and to assess if very early HCV-RNA detection could have a role in predicting sustained virological response.

 

Patients and methods

Seventy-eight patients were enrolled. HCV-RNA was assessed at 2, 12, 24 or 48 weeks and at the end of follow-up (24 weeks). 50 patients were genotypes 1 or 4; 28 genotypes 2 or 3. We had 29 females and 49 males. Patients’ age was (value expressed as median & range) 48 yrs (22-65).

 

Results

We had 32 sustained responders (41%; 22 genotype not 1), 11 relapsers (14%; 9 genotype 1) and 25 non responders (32%; 23 genotype 1). 10 patients dropped out of therapy (13%; 7 genotype 1). In an intention to treat evaluation, the total rate of non responders was 45%. HCV-RNA at week 2 was available in 59 patients. It was negative in 10 patients (17%, all with favourable genotypes) and remained negative at week 12, at the end of treatment and patients became sustained virological responders. Of the 49 positive patients at week 2, 20 turned out HCV-RNA negative at 12 weeks (40%) and another 8 at the end of treatment (for a total of 28 out of 49; 57%). Of these 28 patients only 17 became sustained virological responders (35%). Conclusions: Therapy with PEG-IFN alfa 2b plus ribavirin is effective in responder-relapsers (41% SVR overall rate). A 24 weeks course is sufficient in favourable genotypes, while genotype 1and 4 patients probably require PEG-IFN higher dose.

 

Conclusion

Early HCV-RNA clearance can’t identify sustained responder patients, but its positive predictive value could have a role in addressing expensive pharmacological support, such as erythropoietin and granulocyte growth factors, to patients who have a high likelihood of achieving a SVR.


 

EFFICACY OF INTERFERON (STANDARD OR PEGYLATED) PLUS RIBAVIRIN IN NAĎVE PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 5. A FRENCH NATIONAL STUDY

C. Bonny, C. Roche, H. Fontaine, T. Poynard, C. Hézode, D. Larrey, P. Marcellin, M. Bourličre, J.P. Bronowicki, P. Merle, J.P. Zarski, C. Nicolas, K. Randl, G. Bommelaer, A. Aberge

 

Introuction

Prevalence of HCV genotype 5 in France is 2%. Little is known about virological response in this population. HCV genotype 5 are considered as bad responders and usually treated 48 weeks as genotype 1 or 4.

 

Aim

The aim of our study was to assess the antiviral response in naďve patients treated by Interferon (or Peg-Interferon) with Ribavirin for 48 weeks.

 

Patients and methods

We performed a retrospective study in order to estimate the virological response after a treatment of 48 weeks in naďve HCV genotype 5 patients. A total of 82 patients were included. Twenty eight patients received standard Interferon (3 MU*3/week) (G1) and 54 were treated by Peg-Interferon (1.5 mcg/kg/week or 180 mcg/week) (G2), associated with Ribavirin (800-1200 mg/day). Sustained virological response (SVR) was defined as an undetectable HCV RNA at week 72. Patients were considered as adherent if they received ≥ 80% of both their total Interferon and Ribavirin doses for ≥ 80% of the expected duration of therapy (AASLD 2004).

 

Results

Baseline characteristics were: mean age 58 years, sex ratio 1.4 (M/W), fibrosis score (Metavir): 63% ≥ F2, 22% F4 and pre-therapeutic viral load > 800000 UI/mL: 52%. Transmission routes were: transfusions (54%), intravenous drug use (2%), others (18%) and unknown (39%). SVR rate in intend-to-treat analysis was achieved in 61% (64% in G1 and 60% in G2, p: NS). In univariate analysis, the rate of SVR did not depend on age (<vs.≥ 45 years), sex, fibrosis score (<vs.≥ F2) and viral load (<vs.≥ 800000 UI/mL). SVR was 84% (16/19) in adherent and 54% (32/59) in non adherent patients (p<0.05). In our study, 35 patients received a Ribavirin dose ≤ 800 mg/day. SVR rate depended only on Ribavirin adherence. SVR rate was statistically superior (p<0.01) in Ribavirin adherent patients 86% (18/21) versus non adherent patients 53% (30/57).

 

Conclusion

Combination therapy (standard or Peg-Interferon plus Ribavirin) is efficient in 61% of HCV-type 5 infected patients. Ribavirin adherence strongly improves SVR (86%). This is the first study realized in a large cohort of HCV genotype 5 patients showing that these patients are good responders to combination therapy.


 

IMPACT OF OBESITY ON DEGREE OF LIVER DISEASE AND RESPONSE TO THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION

K. Cesario, F. Khandwala, K. Edwards, W. Carey, D. Barnes, N. Zein  

 

Background/Aims

It has been suggested that obese hepatitis C virus (HCV) patients have a more rapid progression of liver disease and lower rates of response to antiviral therapy. Aims were to assess the association between obesity and histological stage of liver disease, and to determine if weight-based dosing with pegylated interferon alfa-2b (PEG2b) is more likely to result in a sustained virological response (SVR) than standard dosing with pegylated interferon alfa-2a (PEG2a) in obese HCV patients.

 

Methods

All treatment-naďve, Caucasian patients with chronic HCV genotype 1 at Cleveland Clinic Foundation between 2001 and 2004 were identified. Those who received at least one dose of PEG with ribavirin at the recommended doses were included. Patients were classified by body mass index (BMI): obese (>30kg/m2) or nonobese (<30kg/m2). Demographic features and presence of steatosis, fibrosis or inflammation on pretreatment liver biopsy were compared. SVR, defined as negative HCV-RNA 6 months after discontinuation of therapy, was determined both overall and based on the type of therapy received.

 

Results

Mean BMI of obese group (n=42) was 35kg/m2, and 25kg/m2 in the nonobese group (n=91) (p<0.001). Obese patients had higher baseline HCV-RNA levels (850 vs 350 x103IU/mL, p<0.0001) and higher likelihood of steatosis on pretreatment liver biopsy (40% vs 16%, p=0.02). Frequency of advanced fibrosis (60% obese vs 44% nonobese) or marked inflammation (11% in both groups) was not significantly different. SVR data were available in 35 obese and 61 nonobese patients. Multivariate logistical analysis showed that mild hepatic fibrosis (OR 2.70, p=0.063), lower pretreatment HCV-RNA (OR 0.93, p=0.052) and weight-based dosing (OR 4.76, p=0.003) were independently associated with overall SVR. SVR in patients who received weight-based doses of PEG2b (n=46) was similar in obese (9/17, 52%) and nonobese (14/29, 48%) patients. However, SVR in those treated with standard-dosed PEG2a was lower in obese (2/11, 11%) than nonobese (8/29, 28%) patients.

 

Conclusions

Obese and nonobese HCV patients have different virological and histological profiles. Obese and nonobese patients have equal SVR when treated with weight-based doses of PEG2b. However, when treated with standard-dosed PEG2a, obese patients are less likely to attain SVR. Prospective studies are required.


 

COST EFFECTIVE PREDICTION OF SUSTAINED RESPONSE TO IFN ALPHA-2B OR PEG-IFN ALPHA-2B PLUS RIBAVIRIN COMPUTING INFECTED CELLS DYNAMICS BY EARLY ALT AND HCV-RNA DECLINE

P. Colombatto, P. Ciccorossi, F. Oliveri, A.M. Maina, L. Civitano, B. Coco, D. Flichman, R. Sacco, F. Bonino, M.R. Brunetto  

 

Introuction

The lack of 2 Log10 viral load decline after 3 months of therapy has a high NPV (97%) but a low PPV (65%) in identifying sustained responders (SR). We developed a bio-mathematical model where the dynamics of viral load and infected cells are simulated by fitting 1st month HCV-RNA and ALT decline in order to evaluate whether SR can be predicted by computing the residual number of infected hepatocyte at the end of therapy (Ieot).

 

Methods

Sixty six consecutive patients (49 males and 17 females, mean age 50.2 years, range: 26-70) treated with IFNa2b (18) or PegIFNa2b (48) plus Ribavirin in 2 clinical trials with different duration of therapy (180 or 360 days according to HCV genotype for IFNa2b and 270 days regardless to HCV genotype for PegIFNa2b treated patients). ALT and HCV-RNA (Cobas Amplicor HCV Monitor®, Roche) were measured at 0, 2, 4, 7, 14, 21, 28 days, at 3 and 6 months during therapy.

 

Results

The model fit 60 patients and failed in 3 SR with ALT increase after IFN and in 3 patients with viremia breakthrough during therapy. In the 54 patients who completed the original treatment schedule, Ieot  correlated with treatment outcome showing a mean value of 1.15∙10^2cells/ml (range: 2.0-7.26∙10^2) in 30 (12 gt 1a/b and 18 gt 2-3) SR; 2.26∙10^4 cells/ml (range: 4.08∙10^4 -8.32∙10^4) in 8 (5 gt 1a/b and 3 gt 2-3) relapsers and 1.65∙10^6 cells/ml (range: 3.07∙10^3 -1.017∙10^7) in 16 (15 gt 1-4 and 1 gt 3a) non responders (HCV-RNA >50 IU at the end of therapy), (ANOVA, P = 0.002). A value of Ieot < 1000 cells/ml identified all SR pts with 100% sensitivity, 95.8% specificity, 96.8% PPV, 100% NPV and 98.1% diagnostic accuracy. A stopping rule based on Ieot > 1000 cells/ml (assessed at 1 month) would have reduced by 91 months the duration of non effective treatments overcoming by far the cost of the additional HCV-RNA determinations.

 

Conclusion

Ieot computed by our bio-mathematical model is an accurate and cost effective tool to avoid ineffective therapy in patients with chronic hepatitis C and may be used to tailor individual treatment duration.


 

HIGH EARLY VIROLOGIC RESPONSE IN PATIENTS WITH CHRONIC HEPATITIS C, GENOTYPE 1 TREATED WITH PEGINTERFERON AND RIBAVIRIN; THE IMPACT OF GROWTH FACTORS

M. Kugelmas, W.J. Semon, G. Spiegelman, R. Reindollar

Background

Hematologic toxicity is one of the most common reasons for dose reduction or discontinuation when treating chronic hepatitis C. In turn, these dose reductions negatively affect chance of achieving early virologic response (EVR) during therapy of patients with genotype 1 chronic hepatitis C (HCV-1) (Davis, Hepatology 2003). Aims and

 

Methods

We are comparing standard of therapy (ST) with pegylated interferon alfa 2b (IFN) plus weight-based ribavirin (RBV) in patients with HCV-1 to an adjuvant therapy (AT) regimen where anemia is supported with darbepoetin alfa (starting with hemoglobin <12 or <75% of baseline), neutropenia is supported with filgrastim (ANC <900 mm3), and more lenient cut-off levels for thrombocytopenia are allowed in order to try to prevent dose reductions due to hematologic toxicity. The study is powered to show a 22% difference in SVR in favor of the adjuvant therapy arm.

 

Results

To date 58 patients with HCV-1 have received at least 12 weeks of therapy. Thirty-eight are men, 59% have high viral load (HVL >800,000 IU), age is 45±7 years old, fibrosis score (Sheuer scale) is 1.7±1.0, average weight is 79±13 kg, 7% are African American and 9% are Hispanic. Of 26 patients receiving ST 73% have achieved an EVR, and of 32 receiving AT regimen 78% have EVR. Eleven patients in the AT arm received growth factors (9 darbepoetin and 2 filgrastim) for management of hematologic side effects, but only one required dose reduction (RBV for hemoglobin <10 gm/dL). One other patient in the AT arm had a RBV dose reduction for nausea. Nine patients in the ST arm had dose reductions (34.6% in the ST arm vs. 6% in the AT arm, p= 0.03). Baseline hemoglobin fell from 15.2±1.2 gm/dL to 11.7±1.2 gm/dL in the ST arm and from 15.9±1.4 gm/dL to 12.3±1.2 gm/dL in the AT arm.

 

Conclusions

Use of growth factors prevent dose reductions of  pegylated IFN and RBV in patients receiving anti HCV-1 therapy and  maintain more physiologic hemoglobin levels. Continuation of the study will show whether use of growth factors may allow for higher antiviral efficacy.


 

DEVELOPMENT AND VALIDATION OF A SIMPLE MODEL TO PREDICT RESPONSE TO PEGINTERFERON PLUS RIBAVIRIN COMBINATION THERAPY IN GENOTYPE 1 CHRONIC HEPATITIS C

E.M. Martínez-Bauer, F.J. Crespo, M. Romero-Gómez, R. Moreno-Otero, R. Sola, N. Tesey, X. Forns, J.M. Sanchez-Tapias

 

Aim

The aim of this study was to develop simple scoring indexes to predict virological response prior to or early during pegylated interferon plus ribavirin combination therapy in naďve, HCV genotype 1 infected patients with chronic hepatitis C.

 

Methods

Two indexes, a baseline predictive index (BPI) and a week 4 of therapy predictive index (W4PI) were constructed using data from a cohort of 104 patients consecutively treated with pegylated interferon alfa-2b and ribavirin at a single hospital. The validity of BPI and W4PI was assessed in an external cohort of 141 comparable patients recruited and identically treated at four independent hospitals. Virological response was defined by negative HCV-RNA at the end of therapy and 24 weeks after treatment withdrawal. No response was defined by persistence of HCV-RNA after 24 weeks of therapy or by relapse.

 

Results

Serum HCV-RNA concentration, AST:ALT ratio, serum cholesterol, and a calculated non-invasive score aimed to estimate liver fibrosis were independently associated to response by uni and multivariate analysis of baseline data in the estimation cohort. At week four of therapy, BPI and clearance of HCV-RNA were independently associated to response. BPI and W4PI were formulated using these variables and the power of these indexes to predict response was explored by receiving operator (ROC) curves. The area under the ROC curve in the estimation group and in the validation group were, respectively, 0.856 and 0.847 for BPI, and 0.908 and 0.907 for W4PI. In the estimation cohort, a BPI score lower than 6.60 had 97% sensitivity and 92% negative predictive value and a score higher than 9.70 had 96% specifity and 91% positive predictive value. A W4PI score lower than 1.35 had 97% sensitivity and 93% negative predictive value and a score higher than 6.02 had 98% specifity and 96% positive predictive value. The predictive values of BPI and W4PI in the validation group were closely similar.

 

Conclusion

In conclusion, BPI and W4PI may be valuable for therapeutic decision and to design studies for evaluation of alternative therapeutic strategies in genotype 1-infected patients with chronic hepatitis


 

PEGINTERFERON ALFA-2A VERSUS PEGINTERFERON ALFA-2B IN THE TREATMENT OF CHRONIC HEPATITIS C

S. Mauss1, F. Berger1, G. Felten2, D. Hueppe2, G. Schmutz1  

1Center For HIV and Hepatogastroenterology, Duesseldorf, Germany 
2Practice for Gastroenterology, Herne, Germany 

Background

Recent studies in HCV-monoinfected patients may suggest differences in the efficacy or tolerance of the two currently approved pegylated interferons. Prospective, controlled studies are ongoing, but data will not be available before 2006.

 

Methods

To gain controlled, comparative data we conducted a matched pair analysis for patients treated with peginterferon alfa-2a or peginterferon alfa-2b from our data base (n=427). Eligible were all patients with first interferon-based therapy and follow-up since initiation of therapy for at least 18 months for hcv-genotype 1 (n=90) or 4 (n=4) and 12 months for genotype 2 (n=18) or 3 (n=54). Patients were matched within each center for hcv-genotype and hcv-rna (< vs. >800.000 IU/mL). Therapy consisted of peginterferon alfa-2a (180 µg qw) or peginterferon alfa-2b (1.5 µg/kg qw) plus ribavirin 800-1200 mg bid based on weight. Primary endpoint is hcv-rna <100 IU/ml 24 weeks post treatment (SVR). For statistical analysis Mann Whitney and Fisher test was used. At baseline patients treated with peginterferon alfa-2a had a median age of 39 years, and median hcv-rna of 453000 IU/mL, not statistically different from peginterferon alfa-2b 40 years and hcv-rna 489000 IU/mL. Body mass index tended to be lower in the peginterferon alfa-2a group, 23.5 kg/m2 vs. 24.9 kg/m2 (p=0.06).

 

Results

Sustained virologic response (SVR) and relapse after end of treatment response (EOTR) are shown in the table. Premature discontinuation due to adverse events or patient request was identical with 27/83 patients (32%) each.

 

Conclusion

In this matched pair analysis no statistical significant differences in efficacy and tolerance were observed between peginterferon alfa-2a and peginterferon alfa-2b.



 

PEGYLATED INTERFERON ALFA-2B PLUS RIBAVIRIN IN THE RE-TREATMENT OF PATIENTS NON RESPONSIVE TO IFN/RIBAVIRIN

G. Taliani1, A. Aceti2, M. Capanni3, F. Esperti4, C. Ferrari5, P. Forte6, L. Framarin7, V. Guadagnino8, F. Leoncini1, S. Luchi9, N. Marino10, F. Mazzotta10, S. Milani2, C. Pasquazzi2, F. Rosina7, D. Tacconi11, T. Stroffolini12, A.L. Zignego13  

1Department of Infectious Diseases, University of Florence and Careggi Hospital, Florence, Italy  2Department of Infectious Diseases, La Sapienza University, Rome, Italy 3Department of Gastroenterology,University of Florence, Florence, Italy 4Department of Infectious Diseases, Hospital of Pistoia, Pistoia, Italy 5Department of Infectious Diseases, University of Parma, Parma, Italy  6Department of Gastroenterology, Careggi Hospital, Florence, Italy  7Department of Gastroenterology, Gradenico Hospital, Turin, Italy  8Department of Infectious Diseases, University of Catanzaro, Catanzaro, Italy  9Department of Infectious Diseases, Hospital of Lucca, Lucca, Italy  10Department of Infectious Diseases, S Maria Annunaizta Hospital, Florence, Italy

Background

Currently, no recommended re-treatment exists for patients non responsive to interferon (IFN) plus ribavirin (RBV).

 

Aim

The aim of this study was to evaluate efficacy and safety of re-treatment with pegylated interferon (PEG-IFN) alfa-2b 1.5 mcg/kg once-weekly plus RBV 1000-1200 mg/day for 48 weeks in patients who did not respond to a standard 6-month IFN/RBV treatment.

 

Patients

141 patients (77% males, mean age 49.3 +/-11.3 years) from 14 italian centers were enrolled. 85 % of patients had genotype 1 or 4; 51.9% had high viral load (>800.000 IU/mL); 21% were cirrhotics; 47.5% had received 2 or more IFN courses. Mean number of previous IFN courses was 1.9 +/-1.1 and the mean duration of the last IFN/RBV course was 7.2 +/- 2.4 months.

 

Results

Drop out rate was 19%, with a great variability among Centers (0-80%). Dose reduction of IFN was 20%, and of RBV was 21% but no correlation between dose reduction and response was found. By intent-to-treat analysis virological response was observed in 22.7% of patients at week 24, in 30% at week 48 and in 20% at the end of follow-up. By multiple logistic regression analysis low baseline gammaGT (p=0.017) and HCV-RNA levels (p=0.02) and absence of exposure to HBV (p=0.04) were independent predictors of SVR. Among patients with all predictors of response an SVR of 42% was observed. Among patients who at week 24 were HCV-RNA positive, extending the retreatment until 48 weeks induced 20.3% of end of treatment VR and 6% of SVR. Relapse rate was 19% in early responders (within week 24) compared to 58% in late responders (after week 24; p=0.01).

 

Conclusions

Re-treatment with PEG-IFN alfa-2b plus RBV of IFN/RBV non-responder patients induced 20% of SVR. Selection of patients based on pre-treatment predictors of response and continuation of therapy for 48 weeks may significantly improve the rate of sustained virological response. Extending the therapy in late virological responders might prove useful to reduce the rate of relapse.


 

RELEVANCE OF RIBAVIRIN PLASMA CONCENTRATION FOR THE PREDICTION OF TREATMENT RESPONSE

M. Maynard1, P. Pradat1, M.C. Gagnieu2, F. Bailly1, C. Trepo1  

1Department of Hepatology, Hôtel-Dieu, Lyon, France  2Department of Biochemistry, Hôpital Edouard-Herriot, Lyon, France 

Background and Aim

Combination therapy with ribavirin and pegylated interferon is the standard treatment for chronic hepatitis C virus (HCV) infection. Approved ribavirin dosages vary from 800 to 1200mg/d on the basis of body weight. Pharmacokinetics studies indicate that there is no relation between ribavirin ingested dose and plasma concentration. However, a relationship between sustained virological response and ribavirin concentration has been previously reported, a high plasma concentration being associated with a decrease of HCV RNA levels.  The aim of this study was to define the target ribavirin concentration associated with optimal HCV clearance at W12 of treatment.

 

Methods

22 patients with HCV infection treated with pegylated interferon 1.5µg/kg/week and ribavirin at a dose of 800-1200mg/day were assessed for trough ribavirin plasma concentration at W4 under therapy using a high-performance liquid chromatography method. Virological response was defined as undetectable HCV-RNA (or HCV-RNA drop>=2log from baseline) at W12.

 

Results

Among 22 patients, 14 achieved a virological response at W12 whereas 8 were non-responders. The median ribavirin plasma concentration at W4 was 1.90mg/L but varied from 1.55mg/L in non-responders to 2.13mg/L in responders (p=0.02). A ROC curve analysis indicated that the threshold of 2mg/L gave the best sensitivity/specificity ratio with a sensitivity of 57% and a specificity of 100% (AUC=0.804;p=0.02). Using this threshold, the ribavirin plasma concentration had a positive predictive value of 100% meaning that all patients with a concentration above 2mg/L achieved a virological response at W12. Conversely, only 43% of patients with a concentration below 2mg/L at W4 achieved a virological response (negative predictive value 57%).

 

Conclusions

Although conducted on a small number of cases, this study provided the following significant results: 1.A clear-cut difference in ribavirin plasma concentration appeared between responders and non-responders with significantly higher levels in virological responders. 2.The observed median ribavirin plasma concentration at W4 of treatment was similar to those previously reported. 3.All patients reaching a concentration higher than 2mg/L at W4 were virological responders at W12 which confirms the relevance of plasma ribavirin levels for monitoring therapy. 4.The threshold of 2mg/L could  therefore be used as the target concentration for ribavirin dose adjustment.


 

INFLUENCE OF APOLIPOPROTEIN E4 ALLELE (APO E4)ON VIRAL DYNAMICS AND EARLY RESPONSE RATE IN HCV TYPE 1-INFECTED PATIENTS TREATED WITH PEG-IFNA AND RIBAVIRIN

V. Weich1, G. Teuber2, C. Sarrazin3, H. Klinker4, P. Buggisch5, E. Schott1, A. Bergk1, H. Witt1, T. Berg1  

1Charité, Campus Virchow Klinikum, Berlin, Germany, 2Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt, Germany, 3Universitätsklinikum des Saarlandes, Homburg/Saar, Germany 
4Klinikum der Universität, Würzburg, Germany, 5Universitätsklinik Eppendorf, Hamburg, Germany 

 

Background

Lipoproteins have been reported to be involved in the infection cycle of hepatitis C virus. A protective role of the apolipoprotein E4 allele regarding the development of severe liver fibrosis was recently described in HCV-infected patients.  Furthermore, reduced sustained response rates (SVR) after standard interferon alpha (IFNa) plus ribavirin combination therapy were found in HCV type 1-infected patients carrying the E4 allele.

 

Aim

The aim of the present study was to assess  whether carriage of an Apo-E4 allele influences viral dynamics (and  early virologic response rates) in a homogeneous group of HCV type 1-infected patients treated with pegylated IFNa and ribavirin.

 

Patients and Methods

296 treatment-naive patients with histologic proven chronic HCV type 1 infection (56% male, mean age  44 y) were  analyzed. All patients received 1.5 µg/kg Peg-IFNa-2b plus 800- 1400 mg ribavirin/day. HCV RNA was measured quantitatively and qualitatively after 1, 4, 8 and 12 weeks of treatment. The Apo-E polymorphism was determined by PCR amplification and melting curve analysis with FRET probes.

 

Results

Early viral decline (from baseline until treatment week 1 (TW1) as well as from TW1 until TW12) was not significantly different between Apo-E4 and non-Apo-E4 allele carriers. The frequency of a complete virologic on-treatment-response (i.e HCV RNA negative) in Apo-E4 allele positive and negative carriers was  5% vs. 10% at TW1, 30% vs. 31% at TW4, 48% vs. 52% at TW8 and 67% vs. 78% at TW12. No single Apo-E genotype (E2/2, E2/3, E2/4,E3/3, E3/4, E4/4) could be associated with the degree of HCV RNA suppression during the first 12 weeks of treatment.

 

Conclusion

Early viral kinetics during combination therapy with Peg-IFNa-2b plus ribavirin are not influenced by the Apo-E genotype. The previously postulated disadvantage of treatment response in Apo-E4-allele carriers after standard combination therapy could not be confirmed. The more effective antiviral regimen given to our patients (i.e. Peg-IFNa plus ribavirin) which may have overcome the unfavourable genetic background might be an explanation for this discrepancy. However, data on SVR as well as on end of treatment response remain to be seen.

 


COST-EFFECTIVENESS OF PEGINTERFERON ALFA-2B PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C IN HIV-HCV CO-INFECTED PATIENTS

J.B. Wong1, M. Buti2, M.A. Casado3, L. Fosbrook4, V. Soriano5, R. Esteban2  

1Clinical Decision Making, Tufts-New England Medical Center, Boston MA, USA 2Hepatology Department, Hospital Vall D'Hebron, Barcelona, Spain  3Pharmacoeconomics & Outcomes Research Iberia, Madrid, Spain  4Schering-Plough, Madrid, Spain  5Instituto Carlos III, Madrid, Spain 

Background

Since the introduction of highly active anti-retroviral therapy (HAART), hepatitis C (HCV) has emerged as the leading cause of non-AIDS mortality. HCV treatment in HIV co-infection may be able to reduce future liver deaths.

 

Aim

To estimate the cost-effectiveness of peginterferon alfa-2b+ribavirin for HIV-HCV co-infected patients with various CD4 levels.

 

Methods

Lifelong clinical and economic outcomes were based on Cox proportional hazard models estimating the likelihood of developing Metavir fibrosis stages F1, F2, F3 or F4 over time (using 2313 liver biopsies), a meta-analysis of fibrosis progression in HIV-HCV infection, and recent UNOS, SEER and NIH data (Wong, AASLD 2003). AIDS-related mortality was based on a Weibull proportional hazards survival model developed from 12,574 HIV-infected patients starting HAART (Egger Lancet 2002). For 40-year olds with F2 fibrosis and CD4 200-350 or >350, we compared no HCV therapy to peginterferon alfa-2b+ribavirin. Viral response was based on 5 Spanish studies. Drug and disease costs were based previously on published Spanish data updated to current costs (Buti J Hep 2000) assuming a 12-week stopping rule. Cost-effectiveness results are presented as incremental cost per discounted (3%) quality-adjusted life year gained.

 

Results

HCV therapy should increase life expectancy by 1.5 years and 1.2 quality-adjusted life years (a 16% increase) for CD4 200-350 and by 4.1 years and 3.2 quality-adjusted life years (a 31% increase) for CD4>350. For sustained viral response=35.6% (n=272), cost-effectiveness ratios were €10,400 for CD4 200-350 and €8,900 for CD4>350. Varying the sustained viral response over the 95% CI from 29.9% to 41.7% yielded cost-effectiveness ratios of €11,900-€9,300 for CD4 200-350 and €9,600-€8,400 for CD4>350. If fibrosis progression rates did not increase with co-infection, cost-effectiveness ratios were €12,500 for CD4 200-350 and €9,200 for CD4>350. Among 30-year olds, cost-effectiveness ratios were €12,100 for CD4 200-350 and €8,700 for CD4>350 and, and among 50-year olds, they were €15,200 for CD4 200-350 and €9,000 for CD4>350.

 

Conclusion

Peginterferon alfa-2b+ribavirin should be cost-effective for co-infected patients with F2 fibrosis and CD4>200, but especially for those with CD4>350 because of their longer life expectancy and hence higher likelihood of developing hepatic complications during their lifetime.


EFFICACY OF 6 MONTHS TREATMENT WITH PEG-INTERFERON ALFA-2B PLUS RIBAVIRIN (P/R) IN PATIENTS INFECTED WITH HEPATITIS C WITH GENOTYPE 1 OF LOW VIRAL LOAD (G1LVL)

S. Zeuzem1, R. Esteban-Mur2, P. Ferenci3, J. Sperl4, Y. Horsmans5, J. Cianciara6, E. Ibranyi7, O. Weiland8, S. Noviello9, C. Brass9  

1Saarland University Hospital, Homburg/Saar, Germany  2Hospital Vall D'Hebron, Barcelona, Spain 3University Clinic of Vienna, Vienna, Austria  4Ikem, Prague, Czech Republic  5Hopital Saint LUC - UCL, Bruxelles, Belgium 
6Warsaw Medical University, Warsaw, Poland  7St. Laszlo Hospital, Budapest, Hungary  8Huddinge University Hospital, Stockholm, Sweden  9Schering-Plough Research Institute, Kenilworth NJ, USA 

Background

Previous 48 week treatment studies suggest that G1LVL patients have high sustained virologic response rates (SVR) similar to genotype 2/3 patients. Recent data demonstrated that genotype 2/3 patients respond similarly with 24 weeks of therapy as historical 48-week treated controls.  No similar data exist for G1LVL patients.

 

Aim

To compare the efficacy of 24 weeks of P/R with a historical control treated for 48 weeks with PEG-Intron plus a similar ribavirin dose (>10.6 mg/kg) (Manns, Lancet 2002).

 

Methods

Treatment-naďve G1LVL patients (≤2 million copies/mL) were treated for 24 weeks with PEG-Intron 1.5 µg/kg/week subcutaneously plus oral ribavirin 800-1400 mg/day based on body weight. Plasma HCV RNA was determined at treatment weeks 4, 12, 24 and follow-up weeks 12 and 24 using quantitative PCR assay (Taq-Man/sensitivity 29 IU/ml). Genotype was determined by sequencing the PCR product.

 

Results

A total of 235 G1LVL patients were treated (237 enrolled).  End of treatment (EOT) virologic response was 81% and SVR was 50% with 24 weeks treatment.  The 48 week historical control had similar EOT of 74% but higher SVR of 71%. This difference was due to high virologic relapse rate after 24 weeks of therapy (37%) compared to historical control (4%).  A subset of patients treated for 24 weeks, those who became HCV RNA negative at treatment week 4, had a similarly high SVR (89%) compared to the historical control (85%).  In contrast, SVR was low (25%) and relapse high (75%) in those patients who first had an undetectable HCV RNA at week 12.  Discontinuation (3%) and dose reductions (25%) for adverse events were lower than in the historical control (14%, 49%, respectively).

 

Conclusion

Overall, 24 week treatment with P/R in G1LVL patients achieves similar EOT response, but lower SVR compared to a 48-week treated historical control.  However, for patients who become HCV RNA negative at week 4, treatment for 24 weeks has similar high efficacy with superior safety compared to 48 week therapy.

 

 


HEPATIC CYCLOOXYGENASE (COX)-2 AND RESPONSE TO COMBINED INTERFERON & RIBAVIRIN THERAPY IN CHRONIC HEPATITIS C

A. Yosry1, Y. El-Sharif1, A. Hendawi2, G. Esmat1, M. Salah1, S. Zakaria1  

1Tropical Medicine Department & Liver Unit, Cairo University, Cairo, Egypt  2Pathology Department, Cairo University, Cairo, Egypt 

Introduction

There is ongoing recognition of the role of COX-2 in hepatic regeneration, liver matrix remodeling, portal hypertension and fibrosis progression.

 

Aim

To determine the degree of expression of COX-2 in the liver tissue of patients of chronic hepatitis C and whether it is related to the response of these patients to antiviral therapy with Interferon and Ribavirin.

 

Methods

This is a prospective study of 30 patients with chronic hepatitis C  . COX-2 expression was detected by imunohistochemical analysis of pretreatment liver biopsies using CHEMICON  ready to use kits. All patients received pegylated Interferon Alpha-2b at a fixed dose of 100ug s.c once weekly and Ribavirin 1000-1200mg orally daily for 48 weeks. COX-2 expression was also detected in 10 normal liver biopsies from donors of living donor liver transplantation.

 

Results

The 30 patients were 83% males and 17% females, 21-57 years old (40.3±8.6ys). HCV genotype was 4a in 70%, 4b in 10%, 1b in 17%   and was untypable in 3% of patients. The histological activity grade was A1 in 53%, A2 in 17%, and A3 in 30% of patients. The fibrosis stage was S1 in 53%, S2 in 7%, and S3 in 40% of patients (modified Scheuer classification). COX-2 expression was detected in liver biopsy of 47% of patients. The intensity of expression was weak in 33%  and moderate in 14% of patients.  The presence and intensity of COX-2 expression did not correlate with the age and sex of the patients, the genotype of the HCV, the viral load, and the histologic activity grade and fibrosis stage. Sustained virological response (SVR) to combined Interferon and Ribavirin therapy occurred in 50% of patients. SVR correlated inversely with the intensity of COX-2 expression in liver tissue (p=0.045).None of the 4 patients with moderate intensity of COX-2 expression in liver tissue showed a SVR to treatment.

 

Conclusion

COX-2 expression is upregulated in liver tissue of patients with chronic hepatitis C. Patients with more intense expression of COX-2 in their liver tissue seem to be poor responders to combined Interferon and Ribavirin therapy.


HEPATOCYTES ACTIVATE HSC VIA MMP-9. ROLE OF IFN-ALPHA2B IN MODULATING LIVER FIBROSIS IN HCV PATIENTS

F. Marinosci1, C. Bergamini1, E. Fransvea1, N. Napoli1, P. Maurel2, S. Antonaci1, G. Giannelli1  

1Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy 2INSERM U632: Physiopathologie Hepatique 1919 Route de La Mende, Montpellier, France 

Hepatic stellate cells (HSCs) play a key role in liver fibrosis, since they live in a quiescent phenotype in Disse’s space, but become active and deposit abundant levels of extracellular matrix (ECM) proteins, responsible for liver fibrosis, when in contact with proteolytic ECM fragments. In chronic hepatitis C, liver fibrosis occurs as consequence of viral replication and of immuno-mediated tissue injury, leading to cirrhosis development. The molecular mechanisms responsible for HSCs activation are not yet known, however inflammatory cytokines are believed to play a role. The goal of antiviral therapies is to block viral replication, to slow down the inflammation  allowing a tissue repair. These events avoid the development of fibrosis and consequently of cirrhosis. In this study we show that human hepatocytes primary cultures express matrix metalloproteases (MMP)-2, MMP-9, and tissue inhibitors of MMPs, TIMP-2 and TIMP-1, respectively. After stimulation with inflammatory cytokines such as IL-1beta, TNF-alpha, IL-6 and IL-8 commonly elevated in chronic C hepatitis, MMP-9 strongly increases but  MMP-2 does not. The addition of recombinant interferon alpha-2b (rIFNalpha-2b) hampers cytokine-stimulated MMP-9 increase. No modifications were observed regarding TIMP-1 and TIMP-2. Furthermore, the conditioned media of hepatocytes stimulated with inflammatory cytokines, but not also with rIFNalpha-2b, activate HSCs in vitro. The addition of MMP-9 inhibitor, batimastat, inhibits HSCs activation. Similarly, in HCV chronic patients, a decrease of MMP-9 but not of MMP-2 was observed in the plasma at the end of the follow-up period after ribavirin plus pegylated IFNalpha-2b treatment in sustained virological responders but not in non responders.  Consistently in tissue specimens, collected before and after therapy from the same patients, MMP-9 levels, measured by immunohistochemistry and real-time PCR, decreased in responders but not in non responder patients. In conclusion, our results suggest an additional mechanism whereby human hepatocytes could participate in  liver fibrogenesis as  result  of MMP-9 production, in particular after inflammatory cytokine stimulation. Whether or not this is direct consequence of the reduced inflammation or rather an IFN effect onto hepatocytes it is not yet known, however, this provides new  insight into the use of IFNalpha-2b as an anti-fibrogenic therapeutic agent.


ENHANCED ANTIVIRAL ACTIVITY OF NM107, ALONE OR IN COMBINATION WITH INTERFERON ALFA

V. Bichko1, M. Tausek1, L. Qu1, M. LaColla1, S. Bergelson1, C. Pierra2, S. Benzaria2, D. Storer2, G. Gosselin2, J.P. Sommadossi1, D. Standring1  

1Idenix Pharmaceuticals Inc., Cambridge MA, USA  2Idenix SARL, Montpellier, France 

Background

NM107 is 2’-C-methylcytosine, a ribonucleoside analogue that inhibits flavi- and pestivirus replication in vitro. NM283, an orally bioavailable prodrug of NM107, is currently in phase II clinical development for the treatment of chronic hepatitis C and was shown to reduce serum hepatitis C virus (HCV) RNA levels in both chronically infected chimpanzees and in patients with chronic hepatitis C. 

 

Objective

The objective of this study was to evaluate the antiviral activity of NM107 in vitro in combination with recombinant human interferons alfa-2b (Intron A) or beta (Avonex).

 

Methods

The antiviral activities of NM107, interferon alfa-2b, interferon beta and combinations thereof were studied in vitro using infection with bovine viral diarrhea virus (BVDV), a pestivirus related to HCV.  Several virus strains from both cytopathic (cp) and noncytopathic (ncp) biotypes were used in de novo and/or persistently infected Madin-Darby bovine kidney (MDBK) cells.

 

Results

In vitro studies on BVDV NS5B polymerase indicate that NM107 triphosphate is a specific chain terminator of BVDV RNA synthesis.  In cell-based assays, NM107 is a potent inhibitor of BVDV propagation (EC90 0.87 ± 0.18 microM) and could eradicate a persistent BVDV infection after 28 days of treatment.  Interferon alfa-2b inhibited BVDV modestly in vitro (EC90 32.5 ± 18.2 IU/mL).  Combination of 4 microM NM107 and 2000 IU/mL interferon alfa-2b exhibited synergistic antiviral activity.  The reduction in virus titer was 4.56 log10, 2.4 log10 higher than the calculated logarithmic additive effect (2.16 log10).  Enhancements of antiviral activity of over 4 log10 were seen for combinations of interferon alfa-2b and NM107 with the NY1 strain of BVDV. However interferon beta did not inhibit BVDV and had no effect on the antiviral potency of NM107.

 

Conclusions

NM107 is a promising antiviral agent that acts synergistically with interferon alfa-2b in vitro.  Clinical studies of NM283 in combination with interferon alfa are ongoing.


INTERFERON-α INDUCED ALTERNATIVE SPLICING IN THE THROMBOPOIETIN (TPO) -5'UTR INTERFERES WITH TPO-RESPONSE TO THROMBOCYTOPENIA

G. Prohaska, A. Gangl, M. Peck-Radosavljevic  

Department of Gastroenterology and Hepatology, Medizinische Universität Wien, Vienna, Austria 

Introduction

Interferon-α (IFN) therapy, the current treatment of choice for chronic hepatitis C, causes thrombocytopenia induced partly by inadequate thrombopoietin production without decreased TPO-mRNA expression (Peck-Radosavljevic, Hepatology 1998). Hepatocytes produce different TPO-transcripts through alternatively spliced 5’-UTR’s (untranslated region) with highly variable translation efficiencies (Ghilardi, Blood 1998).

 

Aim

The purpose of this investigation was to identify the molecular mechanisms of altered TPO expression.

 

Methods

Experiments were carried out in the PLC/PRF/5 hepatoma cell line (Interferon alpha2b; IntronA®, AESCA Schering-Plough, Kenilworth, NJ). Initially, run-on transcriptions were carried out. Ribonuclease protection assays were performed using 10 µg of total RNA and flourescein labelled riboprobes, detecting TPO (P1WT) and TPO (P1deltaE2) splice variants. cDNA synthesis and Real Time PCR were carried out (Applied Biosystems; TaqMan Reverse Transcription Reagents Kit and TaqMan Universial PCR Master Mix) using primers and probes positioned in exons 1-2 TPO (P1WT) or exons 1-3 TPO (P1deltaE2). Metabolic labelling (35S-methionin) and immunoprecipitation were conducted. TPO concentrations in the supernatants were measured by TPO-ELISA.

 

Results

In PLC/PRF/5 cells, IFN-α does not influence mRNA synthesis at the transcriptional level as shown by run-on-transcription, but leads to alternative splicing, regulating TPO protein expression posttranscriptionally. The results of Real Time PCR and Ribonuclease protection assay show that IFN-treatment increases the TPO-P1WT-splice variant (producing TPO without detectable bioactivity) up to 140.9 % of untreated controls. In contrast, the rare (2 % of total mRNA) but translationally efficient TPO-P1deltaE2-variant declined to 70.2 %. Consistently, immunoprecipitation of 35S-methionin labelled TPO proteins revealed a lower translation rate of 85.5 % compared to untreated controls. Accordingly, a reduced level of secreted TPO protein (60.2 % of control) was observed in supernatants of the hepatoma cells used.

 

Conclusion

Reduction of the most efficiently translated TPO (P1deltaE2) mRNA by IFN induced differential splicing facilitates posttranscriptional regulation of TPO expression and explains the blunted TPO-response to IFN-induced thrombocytopenia. Preferential usage of different splice variants in response to IFN might constitute a more general principal of gene regulation.


QRT-PCR ANALYSIS OF TELOMERASE MRNA EXPRESSION IN LIVER BIOPSY SPECIMENS IN PATIENTS WITH HEPATITIS B AND C UNDERGOING ANTIVIRAL THERAPY

B. Marek1, D. Kajdaniuk1, U. Mazurek2, E. Janczewska-Kazek3, B. Strzalka2, Z. Ostrowska4, B. Kos-Kudla5, A. Fila2, H. Borgiel-Marek6, J. Kajdaniuk1, J. Glogowska-Szelag1, W. Foltyn5, M. Beniowski3, T Wilczok2, N. Ciesielska-Kopacz7, I. Banas1  

1Division of Pathophysiology, Department of Pathophysiology And Endocrinology, Medical University of Silesia, Zabrze, Poland 2Department of Molecular Biology And Medical Genetics, Medical University of Silesia, Sosnowiec, Poland 3Department of Infectious Diseases, Medical University of Silesia\, Chorzow, Poland 4Department of Clinical Biochemistry, Medical University of Silesia, Zabrze, Poland  5Clinic of Endocrinology, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Zabrze, Poland  6Department of Maxillofacial Surgery, Medical University of Silesia, Katowice, Poland  7Department of Internal Diseases, Allergology and Immunology, Medical University of Silesia, Zabrze, Poland 

Background

Telomere shortening limits the regenerative capacity of hepatocytes in chronic liver disease, eventually resulting in exhaustion of regenerative capacity and cirrhosis formation. Telomerase is an enzyme, which is responsible for the protection of telomeres and play key role in stabilization of chromosomes.

 

Aim

The aim of the study was to investigate the expression of telomerase subunits mRNA in liver biopsy specimens. Our study group consisted of 35 patients with histologicaly confirmed chronic hepatitis B (HB) and 40 patients with chronic hepatitis C (HC).

 

Methods

The control group consisted of 20 patients with minimal necroinflammatory activity, without fibrosis. Treatment of patients with HB included sc/im injections of interferon α 2a taken 6 MU three times a week for 24 weeks. Treatment of patients with HC included s/im injections of interferon α 2b taken 3 MU three times a week for 48 weeks + ribavirin 1000-1200 mg per day according to body mass. The levels of the RNAs of telomerase reverse transcriptase (TERT), telomerase RNA (TR) and telomerase-associated protein (TP1) were evaluated by reverse transcriptase quantitative polymerase chain reaction (QRT-PCR). After treatment the patients were divided into responders and nonresponders patients.

 

Conclusions

We concluded that the appearance of viral hepatitis is associated with the mRNA expression of TERT and TR in liver. We observed the overexpression of TERT and TR mRNA telomerase subunits in liver of patients with HB and HC in comparison to control group. It can be a result of infiltrating lymphocytes in diseased liver or improve liver regeneration. In patients with HB and HC before antiviral therapy, expression levels of TERT and TR mRNA in liver biopsy specimens can not be predictive markers of response to the therapy. All three telomerase components were consistently expressed in higher levels in responders HB patients after antiviral therapy in comparison to the patients before the therapy. It seems that observed simultaneous increase of mRNA TERT, TR, TP1 expression levels in liver biopsy specimens can be prognostic markers of good response to antiviral therapy in patients with HB.


SEQUENTIAL COMBINATION OF PREDNISONE, LAMIVUDINE AND INTERFERON ALPHA 2B FOR HBEAG POSITIVE CHRONIC HEPATITIS B: A RAMDOMIZED AND CONTROLLED PILOT STUDY

E. Vilar, E. Arús, B. Grá, R. Llanio, M. Castellano, C. Ruenes, L. Tamayo, N. Turcaz  

Department of Hepatology, National Institute of Gastroenterology, Vedado, Cuba 

Background

Interferon alfa 2b, Lamivudine and Adefovir are the only FDA approved antivirals for chronic hepatitis B treatment, resulting in very low percentages of effective virological response (VR) which do not surpass 30%. The antivirals combination has been recently investigated with contradictory results related to its efficacy.

 

Objective

Objective. To evaluate the efficacy and safety of the combination of Interferon alfa 2b plus Lamivudine with previous Prednisone immunosuppression in patients with CHB.

 

Methods

Methods. A randomized and controlled study was conduced, in which the sample was 44 patients with HBeAG-positive CHB and ALT persistently elevated. The patients were distributed into two groups; PLI (n=22), Prednisone 40 mg daily for four weeks, followed by: two weeks without treatment, Lamivudine 150 mg daily for four weeks; Lamivudine plus Interferon alfa 2b (10 MIU every other day) for 24 weeks followed by continuos Lamivudine 150 mg daily to complete 52 weeks. LI (n=22), the same scheme and duration, but without using Prednisone.  Virological response was measured 24 weeks after concluding the treatment and was defined by HBeAg seroconversion (loss of HbeAg and appearance of anti-Hbe) plus decrease of serum HBV DNA (Roche Amplicor PCR assay) under 105 copies/ml. Normalisation of ALT and histologic improvement was defined as secondary endpoint. For the comparative analysis of antiviral efficacy, Fisher’s Exact Probability Test was used with a significance level of alfa=0.05.

 

Results

In PLI group, the VR was seen in 68% while in  LI group, 54% did (p=0.26).  The VR was clinically, but not statistically superior in naive patients (76% vs 53%, p=0.15) and patients with ALT < 2x ULN (77% vs 50%, p=0.16) in PLI and LI groups, respectively. Not significant differences were seen in normalisation of ALT. Histological improvement was observed in 45% (both groups) for inflammation and 41% (PLI) and 23% (LI) for fibrosis. Both treatments were well tolerated.

 

Conclusions

The virological response was clinically, but not statistically superior in the group with prednisone priming. This effect was more marked in naďve and patients with ALT< 2 ULN. The fibrosis score improvement was clinically more evident in PLI group.