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