Safety and Efficacy of Viramidine in Combination with Pegylated Interferon Alfa-2A for Treatment of Hepatitis C in Therapy-Naïve Patients

R. Gish 1, S. Arora 2, D. Nelson 3, H. Fernandez 4, K. Lamon 4

1 Department Of Hepatology, California Pacific Medical Center, San Francisco CA, USA; 2 Department Of Internal Medicine, University Of New Mexico, Albuquerque NM, USA; 3 Department Of Medicine, University Of Florida, Gainesville FL, USA; 4 Valeant Pharmaceuticals International, Costa Mesa FL, USA

 

Introduction

Ribavirin combined with pegylated interferon alfa is effective in achieving sustained viral responses in some hepatitis C patients, but is associated with dose-limiting hemolytic anemia. An on-going dose-ranging study will examine whether viramidine, a liver-targeting prodrug of ribavirin, is a safer substitute for ribavirin.

Methods

180 patients were randomized to receive pegylated interferon alpha-2a 180 µg/wk SQ in combination with viramidine 400 (N=47), 600 (N=43), 800 (N=45) mg PO BID or ribavirin 1000/1200 mg/daily (N=45).

 

Patients were predominately male (64%), Caucasian (76%), genotype 1 (73%), with a median age of 49 years (23 to 68), and median HCV RNA 6.5 log10 copies/mL (range 4.0 to 7.5).

 

A 24-week interim analysis assessed HCV RNA levels and the occurrence of anemia (hemoglobin < 10 g/dL).

Results

Following 24 weeks of treatment, there was no significant difference between viramidine (800-1600 mg/day) versus ribavirin in the proportion of patients with undetectable HCV RNA or a log decrease in viral load of 2 or more (83% versus 83%, respectively).

 

There were significantly fewer patients in the viramidine groups with anemia when compared with the ribavirin arm (2% versus 24%; p< 0.001). Among patients receiving the 400 mg BID and 600 mg BID doses of viramidine, there were no cases of defined anemia. Other adverse events were similar among treatment groups.

Conclusions

Viramidine demonstrated antiviral activity comparable to that of ribavirin when used in combination with peginterferon alfa-2a but with a significantly lower incidence of hemolytic anemia.

 

Total HCV Core Antigen Correlates with HCV RNA, and Predicts Sustained Virological Response (SVR) to Peginterferon Alfa 2-A (PEG-IFN) and Ribavirin (RIB) Therapy in Chronic Hepatitis C (CHC)

V. Gonzalez 2, R. Planas 1, E. Padilla 2, C. Perez 3, D. Gimoz 4, L. Matas 1, R.M. Morillas 2, E. Cabrosup 2, R. Solosup 4, M. Diago 3

1 Liver Unit. Hospital Universitari Germans Trias I PujolSpain; 2 Microbiology Department. Hospital Germans Trias  Pujo Spain; 3 Liver Section. Hospital General De Valencia, Valencia, Spain; 4 Liver Section. Hospital Del Mar, Barcelona, Spain

 

Introduction

Early virological response (EVR) may predict outcome in chronic hepatitis C patients treated with PEG-IFN and Rib. The core Ag of HCV may constitute an alternative marker for assessing the levels of viremia in CHC C patients.

 

Objections

To assess whether total HCV core Ag at baseline, 1 and 3 months after treatment could predict SVR to PEG-IFN and Rib therapy, in comparison to HCV RNA.

 

Methods

HCV viremia was determined using the total HCV core Ag test, and qualitative/quantitative HCV RNA assays in 62 patients with CHC (genotype 1: 46; genotype non-1: 16).

 

Results

SVR was achieved in 34 (54.8%) patients (43.5% in genotype 1, and 87.6% in genotype non-1). There was a good correlation between HCV core Ag and HCV RNA concentrations (115/134 samples positive for both markers; r=0.91). We estimated that 1 pg/mL of total HCV core Ag is equivalent to approximately 10,000 HCV-RNA IU/mL. SVR was predicted at baseline in 67.9% of cases using HCV core Ag levels<80 pg/mL, and in 65.2% of cases using HCV RNA quantification (<800.000 UI/mL). For HCV core Ag, the negative predictive value (NPV) at 1 and 3 months after therapy were 76.5% and 100%, whereas for HCV RNA the NPV were 69.6% and 80% respectively.

 

Conclusions

Total HCV core Ag is a quick, reproducible, and easy to perform alternative to HCV RNA methods. The prediction of response to combination therapy based on HCV core Ag levels before therapy, or at 3 months, was similar to that observed with HCV RNA.

 

The Burden of Chronic Hepatitis C (CHC) from the Perspective pf the UK National Health System (NHS)

J. Green 1, K. Patel 1, G. Lewis 2

1 Hoffmann-La Roche, Nutley NJ, USA; 2 Roche Products Ltd., Welwyn Garden City

 

Introduction

The failure to diagnose and successfully treat CHC patients can generate substantial future costs to the UK NHS. This work attempts to estimate the total costs of failing to treat the current cirrhosis-free CHC population in the UK. Consequently, the following cost estimates exclude the cost burden of patients already at more advanced stages of CHC.

 

Methods

We constructed a Markov model in which a hypothetical cohort of CHC patients may be followed over their expected lifetime. The CHC patients could progress through a total of 6 health states (including death) with the probability of transition derived from published literature. NHS resource utilisation and unit costs were derived from an expert panel of hepatologists and the Pharmaceutical Information Cost Assessment System, respectively. Based on published estimates of the prevalence of CHC in the UK, the clinical progression of 235,157 CHC patients was followed and associated NHS costs estimated.

 

Results

The total lifetime discounted costs (6%) of the CHC cohort if untreated were estimated as £4.3bn. By year 3 in the model, 21 patients had already progressed to liver transplantation, with a maximum of 566 patients in need of a liver transplantation 19 years into the model.

 

Conclusion

If HCV is not diagnosed or treated, the progression of CHC patients not only reduces life expectancy, but also generates a considerable cost burden to NHS. Due to the asymptomatic nature of the disease and its slow progression, such long term costs of CHC are often underestimated by NHS decision makers.

 

The Impact of Sustained Virological Response (SVR) on Health-Related Quality of Life (HRQL) in Patients with Chronic Hepatitis C (CHC) and Persistently Normal ALT Levels (PNALT) Treated with Peginteron Alfa-2A (Pegasys) and Ribavirin (Copegus)

C. O’Brien 1, N. Wintfeld 2, K.K. Patel 2, S. Zeuzem 3, M.L. Shiffman 4, M. Diago 5, A. Tran 6, P. Pockros 7, J. Green 2

1 University Of Miami, School Of Medicine, Miami FL, USA; 2 Roche, Nutley NJ, USA; 3 Saarland University Hospital, Homburg, Germany; 4 VCU Health System USA; 5 Hospital General De Valencia, Valencia, Spain; 6 Hopital De LArchet, Nice, France; 7 The Scripps Clinic, La Jolla CA, USA

 

Background

Previous studies have found that SVR improves HRQL in patients with CHC and elevated ALT levels. However, the effect of SVR on HRQL in patients with CHC and PNALT has not been described.

 

Methods

514 patients with CHC and PNALT (at least three normal levels within the previous 6 to 18 months) were randomized to receive either peginterferon alfa-2a (PEGASYS) 180 mcg/week plus ribavirin 800 mg/day (COPEGUS) for 24 or 48 weeks or no treatment. Patients completed the Short Form 36 (SF-36), and the Fatigue Severity Scale (FSS). Analysis of covariance was used to compare SF-36 and FSS scores between responders and non-responders and between responders and untreated controls at end of follow-up.

 

Results

SVR rates were 30%, 52%, and 0% in the 24-week, 48-week and no treatment groups, respectively. Responders had better SF-36 and FSS scores than non-responders and untreated controls. The differences between responders and non-responders were significant in the SF-36 general health (p<.001), pain index (p<.001), role physical (p<.01), social function (p<.05), vitality, (p <.05), and physical component scores (p<.001), and the FSS (p<0.01). The differences between responders and untreated controls were significant in general health (p<.001) and vitality (p<.001).

 

Conclusion

SVR in patients with CHC and PNALT after therapy with peginterferon alfa-2a (PEGASYS) plus ribavirin (COPEGUS) is associated with improved HRQL and less fatigue compared with non-responders or untreated patients. When considering treatment for patients with CHC and PNALT, the possibility of improving HRQL should be considered.

 

An Open-Label, Multicenter Study of the Efficacy and Safety of Peginterferon Alfa-2A (40KD) (Pegasys), Alone or in Combination with Ribavirin (Copegus), in Patients with HIV/HCV Coinfection

E. Ortega 1, A. Martín1, C. Barros 2, K. Aguirrebengoa 3, J. González4, A. García5, R. Rubio 6, F. Pulido 6

1 Hospital General Universitario, Valencia, Spain; 2 Hospital De Mles, Madrid, Spain; 3 Hospital De Cruces, Bilbao, Spain; 4 Hospital La Paz, Madrid, Spain; 5 Hospital Santa María Del Rosell, Cartagena, Spain; 6 Hospital 12 De Octubre, Madrid, Spain

 

Background
Liver disease has emerged as a major cause of morbidity and mortality in patients with HIV/HVC coinfection, mainly as a result of coinfection or hepatotoxicity induced by antiretroviral drugs.

Objective

To evaluate the efficacy and safety of peginterferon alfa-2a treatment alone or with ribavirin.

Methods

Patients initially received peginterferon alfa-2a 180 mcg/week alone. HCV-RNA levels were monitored to assess virological response (VR). At week 4, patients with VR (<50 IU/mL HCV RNA) remained on peginterferon alfa-2a alone while those with continual viremia 50 IU/mL HCV RNA) had ribavirin 800 mg/day + peginterferon alfa-2a. This study is ongoing.

Results

311 patients have been recruited (227 males/82 females, mean age 38 years, 47% HCV genotype 1, mean ALT 118 U/L, 30% have bridging fibrosis or cirrhosis, mean CD4+ cells counts are 647/mm3, 82% are on HAART). 298 patients completed 4 weeks of therapy, of which 24% have had an early VR. 49% (129/260) and 65% (141/216) of patients had a VR at weeks 12 and 24, respectively. At the moment, data of week 48 is available for 104 patients and 94 of them have VR. Complete data of EOT and EOF will be available for March 2004.

Both treatment regimens were generally well tolerated. Discontinuation was observed in 76 patients (25,5%), 38 of these withdrawals were due to adverse events (related o not to treatment), among those, 13 were laboratory abnormalities.

Conclusion

Peginterferon alfa-2a alone or in combination with ribavirin seems to be an effective and safe treatment in patients coinfected.

 

Early Prediction of Sustained Virological Response (SVR) During Treatment with Peginterferon Alfa-2A (40KD) (Pegasys) Plus Ribavirin (Copegus) in Patients with HIV/HCV Coinfection:  Results From the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) Study

M. Rodriguez-Torres 1, F.J. Torriani 2, E. Lissen 3, N. Brau 4, M. Sulkowski 5, R. Sola 6, B. Clotet 7, N. Clumeck 8, D. Cooper 9, D. Dieterich 10

1 Fundacoin de Investigacion de Diego, Santurce, Puerto Rico; 2 Department Of Medicine, University Of California, San Diego CA, USA; 3 Virgen Del Rocio University Hospital, Sevile, Spain; 4 Bronx VA Medical Center, Bronx NY, USA; 5 Johns Hopkins University School Of Medicine, Baltimore MD, USA; 6 Rovira  Virgili University, Reus, Spain; 7 Germans Trias  Pujol University Hospital, Barcelona, Spain; 8 CHU Saint-Pierre, Brussels, Belgium; 9 University Of New South Wales, Sydney, Australia; 10 Mt. Sinai School Of Medicine, New York NY, USA

 

Introduction

The absence of an early virological response (EVR) at week 12 of combination peginterferon alfa-2a (40KD) (PEGASYS)/RBV (COPEGUS) therapy has a high negative predictive value (NPV, 97%) for the probability of achieving an SVR in HCV monoinfected patients (Fried et al. NEJM 2002;347:975). We determined whether this also applies to HCV/HIV coinfected patients.

 

Methods

We analysed data from 289 HCV/HIV-co-infected patients randomized to 48 weeks of peginterferon alfa-2a (40KD) 180 µg/wk + RBV 800 mg/d in the APRICOT study. Patients had compensated liver disease, a CD4+ count >100 cells/mL, and stable HIV disease. SVR was defined as undetectable HCV RNA (<50 IU/mL) after 24 weeks of treatment-free follow-up (COBAS AMPLICOR HCV Test, v2.0). EVR was defined as undetectable HCV RNA or a ≥2-log10 decline in HCV RNA by week 12 or 24.

 

Results

Overall, 204 patients (71%) had an EVR, of whom 114 (56%) achieved an SVR. 45% of the 110 genotype 1 patients who had an EVR also achieved an SVR.

 

Conclusions

The results are consistent with those in patients with HCV mono-infection. Treatment with PEGASYS/COPEGUS may be discontinued at week 12 in co-infected patients without an EVR because they are highly unlikely to develop an SVR. This will decrease adverse events and save healthcare resources. Patients with an EVR have a good chance of achieving an SVR.

 

Final Week-72 Results of the AIDS Pegasys Ribavirin International Co-Infection Trial (APRICOT): A Randomized, Partially Blinded, Multinational Comparative Trials of Peginterferon Alfa-2A (40KD) (Pegasys) Plus Ribavirin (RBV) (Copegus) vs. Interferon Alfa-2A (IFN) Plus Ribavirin in the Treatment of HCV in HIV/HCV CO-INFECTION

F.J. Torriani 1, J. Rockstroh 2, M. Rodriguez-Torres 3, E. Lissen 4, J. Gonzoz 5, A. Lazzarin 6, G. Carosi 7, J. Sasadeusz 8, C. Katlama 9, D. Dieterich 10

1 University Of California, San Diego CA, USA; 2 University Of Bonn, Bonn, Germany; 3 Fundacion De Investigacion De Diego, Santurce, Puerto Rico; 4 Virgen Del del Rocío University Hospital, Seville, Spain; 5 Hospital La Paz, Madrid, Spain; 6 San Raffaele Vita-Salute University, Milan, Italy; 7 University Of Brescia, Brescia, Italy; 8 Royal Melbourne Hospital, Melbourne, Australia; 9 Groupe Hospitalier De La Pitie Salpetriere, Paris, France; 10 Mt Sinai School Of Medicine, New York NY, USA

 

Introduction

PEGASYS/RBV combination therapy produced sustained virological responses (SVR) in 56-63% of HCV-monoinfected patients in phase 3 trials (Fried NEJM 2002; Hadziyannis J Hepatol 2002).

 

Aim

APRICOT was designed to evaluate the safety and efficacy of this combination in patients with HIV/HCV co-infection.

 

Methods

868 co-infected subjects were randomized to 48 weeks of treatment with IFN 3 MIU tiw plus RBV 800mg/d, PEGASYS 180 mcg/wk plus placebo, or PEGASYS 180 mcg/wk plus RBV. Eligible subjects were HCV RNA and HCV antibody positive, had compensated liver disease, a CD4+ count >=100 cells/mL, and stable HIV disease, with or without antiretroviral therapy (ART). SVR was defined as HCV RNA <50 IU/mL after 24 weeks of treatment-free follow-up (COBAS AMPLICOR HCV Test v 2.0).

 

Results (ITT)

The groups were well matched at baseline. Overall SVR rates were 40%, 20% and 12% in patients treated with PEGASYS/RBV, PEGASYS/placebo and IFN/RBV, respectively (P<0.0001 for PEGASYS/COPEGUS vs either comparator; P=0.0078 for PEGASYS/placebo vs IFN/RBV). Data from patients with undetectable HCV RNA at both end-of-treatment (EOT) and end-of-follow-up (EOF), underscores the importance of adding RBV to IFN-based regimens to prevent relapse in co-infected patients as well (Table).

 

Conclusions

Based on an SVR of 40%, PEGASYS/COPEGUS is the preferred treatment for HCV in co-infected patients.

Peginterferon Alpha-2A (40KD) Monotherapy vs. Peginterferon Alpha 2A and Ribavirin in Naïve Patients with Chronic Hepatitis C:  Preliminary Results of the SMIEC II Trial in Patients with Early Viral Clearance of Peginterferon Monotherapy

P. Piccolo 1,2, B. Koehler Horst 1, F. Angelico 1, S. Gentile 1,2, S. Francioso 1, P. Tarquini 1, R. Della Vecchia 1, L. Ponti 1, A. Barlattani 1, A. Grieco 1, F. Soccorsi 1, P. Guarascio 1, L. Demelia 1, O. Sorbello 1, G. Forlini 1, F. Bandiera 1, S. Zaru 1, M. Angelico 1,2

1 SMIEC-2 Study Group, Gastroenterology Unit ,Tor Vergata University, Rome, Italy; 2 Gastroenterology Unit, Fatebenefratelli Hospital - Isola Tiberina, Rome, Italy


Introduction

Early virological response to antiviral treatment is a strong predictor of sustained response, yet it is not used to stratify patients in clinical trials.

 

Aims/Methods

This study was to compare efficacy and safety of mono- versus combination therapy in patients who achieved early viral clearance (EVC) on peginterferon alpha-2a 40kD (PEG-IFN) monotherapy.

 

Two-hundred-eight naive patients (159 males; median age, 42 years) with chronic hepatitis C (genotype 1,4: 62%) completed 12 weeks of PEG-IFN treatment, 180 mg qw. One-hundred-twenty-one (58%) achieved EVC, defined as undetectable HCV RNA (<50 IU/ml) by qualitative PCR (Amplicor, Roche) and were randomized to continue PEG-IFN monotherapy or to add ribavirin (RBV) 800 mg/day, for 12 additional weeks: 64 patients received PEG-IFN monotherapy, while 57 patients received combination therapy (PEG-IFN + RBV).

 

Results

Qualitative HCV RNA at 24 weeks is available in 83 patients (44 and 39, respectively): 39 (88.6%) in the monotherapy group vs. 37 (94.8%) in the combination therapy group remained HCV RNA negative (ns). Between weeks 12 and 24 there were 2 drop-outs in the monotherapy and 5 in the combination group and a similar number of dose reductions. HCV RNA negative patients at week 24 are continuing treatment for a total of 48 weeks.

 

Conclusion

In patients who achieve early viral clearance, continuing PEG-IFN monotherapy results in similar rates of viral clearance at 24 weeks compared to PEG-IFN plus ribavirin. These preliminary data suggest that, in this subgroup of easy-to-treat naïve patients, monotherapy may be as effective as combination therapy.

 

Early Prediction of Sustained Virological Response (SVR) During Treatment with Peginterferon Alfa-2A (40KD) (Pegasys) Plus Ribavirin (RBV) (Copegus) in Patients with Persistently Normal Alanine Aminotransferase (ALT) Levels:  Results of a Multinational Trial

P.J. Pockros 1, M. Diago 2, E. Gane 3, K.R. Reddy 4, D. Prati 5, M.L. Shiffman 6, P. Farci 7, C. OBrien 8, P. Lardelli 9, F. Lamour 9, S. Zeuzem 10

1 Scripps Clinic, La Jolla CA, USA; 2 Hospital General Universitario, Valencia, Spain; 3 Middlemore Hospital, Auckland, New Zealand; 4 University Of Pennsylvania, Philadelphia PA, USA; 5 IRCCS Ospedale Maggiore, Milan, Italy; 6 VCU Health System, Richmond VA, USA; 7 Università Cagliari, Cagliari, Italy; 8 University Of Miami, Miami FL, USA; 9 Roche, Basel, Switzerland; 10 Saarland University Hospital, Homburg, Saar, Germany

 

Introduction

The absence of an early virological response (EVR) at week 12 of combination peginterferon alfa-2a (40KD) (PEGASYS)/RBV (COPEGUS) therapy has high negative predictive value (NPV,97%) for the probability of achieving an SVR in patients with CHC and elevated ALT levels (Fried. NEJM 2002;347:975).

 

Aim:

We aimed to determine whether this rule applies to patients with persistently normal ALT levels.

 

Methods

422 patients with persistently normal ALT levels (≤upper limit of normal, 30IU/L, on ≥3 occasions over 18-months) were randomized to 24 or 48wks of treatment with peginterferon alfa-2a (40KD) 180µg/wk/RBV 800mg/d. The study was conceived before phase 3 studies revealed that RBV 1000/1200mg/day is optimal for genotype 1. SVR was defined as undetectable HCV RNA (<50IU/mL) after 24wks of follow-up (COBAS AMPLICOR HCV Test,v2.0). EVR was defined as undetectable HCV RNA or a ≥2-log10 decline in HCV RNA at week 12.

 

Results

SVR rates of 30% (n=212) and 52% (n=210) were obtained in patients treated for 24 and 48wks.

 

Conclusions

The results are consistent with those obtained in patients with CHC and elevated ALT levels. Treatment with PEGASYS/COPEGUS may be discontinued at week 12 in patients without an EVR because they are highly unlikely to develop an SVR. This will prevent unnecessary adverse events and save healthcare resources. Patients with an EVR have a high likelihood of achieving an SVR.

 

The Influence of Cumulative Exposure to Combination Peginterferon Alfa-2A (40KD) (Pegasys) and Ribavirin on Sustained Virological Response (SVR) Rates in Patients with Genotype 1 Chronic Hepatitis C

K.R. Reddy 1, M.W. Fried 2, ML. Shiffman 3, S.J. Hadziyannis 4, H. Sette 5, T.R. Morgan 6, S. Schaefer 7, M. Popescu 8

1 University Of Pennsylvania, Philadelphia PA, USA; 2 University Of North Carolina, Chapel Hill NC, USA; 3 VCU Health System, Richmond VA, USA; 4 Department Of Medicine And Hepatology, Henry Dunant Hospital, Athens, Greece; 5 Instituto De Infectologia Em�o Ribas, San Paulo, Brazil; 6 VA Medical Center, Long Beach, USA; 7 IST GmbH, G��urg, Germany; 8 Roche, Basel, Switzerland

 

Introduction

Patients who receive full doses and durations of peginterferon/ribavirin combination therapy have higher SVR rates. It is, however, unclear if one drug is more important than the other. We investigated the relationship between cumulative drug exposure to Pegasys and ribavirin, and SVR rates.

 

Methods

Pooled data from 569 patients randomized to 48wks of Pegasys 180mcg/wk+ribavirin 1000/1200mg/day in two phase III trials were analyzed.

 

 

The following exposure categories were used: 100%, 90-99.9%, 80-89.9% and <80%.

 

Results

63% and 20% of patients had 100% Pegasys and ribavirin exposure, respectively. 81% and 71% had cumulative Pegasys and ribavirin exposure of >=90%, respectively. The overall SVR rate was 49.2%; 61.9% in patients treated for >=80% and 11.8% in those treated for <80% of the prescribed duration. Patients receiving treatment for >=80% of the prescribed duration who were exposed to >=80% of both Pegasys plus ribavirin had an SVR of 65%.

 

Conclusions

  1. Dose reductions occurred more frequently with ribavirin,
  2. Exposure to Pegasys was greater than ribavirin;
  3. Treatment success correlated with exposure. Ribavirin exposure and SVR rates were significantly correlated. 4) Decreasing exposure to Pegasys had less impact on SVR rates compared with ribavirin.

 

Sustained Virological Response After Prolonged Treatment with Peginterferon Alfa-2A (40KD) (Pegasys) and Ribavirin (Copegus) in Treatment Naïve Patients with Chronic Hepatitis C and Detectable HCV RNA After Week 4 of Therapy:  TERAVIC-4 Study

J.M. Sánchez -Tapias 1, M. Diago 2, P. Escartín3, J. Enríquez 4, R. Moreno 5, M. Romero-Gómez 6, R. BᲣena 7, J. Crespo 8, R. Andrade 9, The TeraViC-4 Study Group, Spain 10

1 H. Clinic I Provincial, Barcelona, Spain; 2 H. General, Valencia, Spain; 3 H. Puerta Hierro, Madrid, Spain; 4 H. Sant Pau, Barcelona, Spain; 5 H. La Princesa, Madrid, Spain; 6 H. U. Valme, Sevilla, Spain; 7 H. Ramón y Cajal, Madrid, Spain; 8 H. Marqués Valdecilla, Santander, Spain; 9 H. Virgen Victoria, Málaga, Spain; 10 Roche, Madrid, Spain

 

Introduction

TeraViC-4 targets patients with chronic hepatitis C who do not have very early virological responses after week 4 of therapy (noVR4 = detectable serum HCV RNA >50 IU/ml PCR).

 

Methods

Patients received PEGASYS 180 mcg/week and COPEGUS 800 mg/day. At week 4, PCR(+) patients were randomized to continue either 44 (A, N=165) or 68 (B, N=161) weeks’ treatment. The protocol has been published (Sanchez-Tapias. Methods Find Exp Clin Pharmacol. 2002;24:579-584). SVR was defined as undetectable HCV RNA by the end of the follow-up period in those patients with EOT viral response.

 

Results

Baseline characteristics of the randomized groups were similar. Withdrawal rates (17% (A) vs 36% (B)) and the reasons given differed between No-VR4 groups after week 24.

 

Therapy was well-tolerated and no unexpected adverse events were observed. Longer treatment did not increase the frequency of neutropenia or thrombocytopenia.

 

Conclusions

PEGASYS 180 mcg/week plus COPEGUS 800 mg/day for 72 weeks could offer a better clinical approach for patients with No-VR4, but it obliges the clinician to monitor treatment adherence. The 800 mg/day dose of ribavirin used in the trial has been proven to be optimal in patients infected with HCV genotype 2 or 3, but not in those with genotype 1 who require 1000/1200 mg. This evidence was not established when the trial was initiated.

 

Combination Therapy with Peginterferon Alfa-2A (40KD) (Pegasys) Plus Ribavirin (Copegus) in Treatment-Naïve Patients with Chronic Hepatitis C and Genotype 1 Infection:  Individual Estimated Probability of Sustained Virological Response (SVR)

O. Weiland 1, M.W. Fried 2, S.J. Hadziyannis 3, G.R. Foster 4, D. Messinger 5, K. Freivogel 6, M. Chaneac 7

1 Karolinska Institutet, Stockholm, Sweden; 2 University Of North Carolina, Chapel Hill NC, USA; 3 Henry Dunant Hospital, Athens, Greece; 4 Barts And The London, London; 5 IST GmbH, Mannheim, Germany; 6 IMOR GmbH, Loerrach, Germany; 7 Roche, Basel, Switzerland

 

Introduction

We constructed an “SVR Calculator” for estimating the probability that an individual patient will achieve an SVR after treatment with PEGASYS/COPEGUS. The probability can be calculated at baseline, or after 12 weeks’ treatment, and can include assumptions about adherence.

 

Methods

Data included were from patients treated with PEGASYS 180mcg/week and COPEGUS 800 or 1000/1200mg/day in two phase III trials (Fried NEJM 2002; Hadziyannis 2002).

 

The influence of pretreatment factors (gender, age, race, BMI/weight, viral load, ALT quotient, histology, adherence) on SVR rates was examined by a logistic regression model. Data falling outside the 5th-95th percentiles were excluded; thus, data from 736 of 1037 genotype 1 patients with these characteristics were used in the model: Caucasian men and women, aged 18-65yrs, BMI 18-32 kg/m2, ALT quotient 1-8, HCV RNA 0.1-24 million copies/mL.

Results

Factors that significantly modified the probability of an SVR included: age, viral load, ALT quotient, histology, BMI. The effect of age on the probability of achieving an SVR in a patient treated according to current recommendations is tabulated.

 

Conclusion

By varying the input parameters the individual probability of achieving an SVR with PEGASYS/COPEGUS can be calculated. This tool can be used to make treatment decisions and to motivate patients to stay on therapy.

 

Sustained Virological Response (SVR) to Peginterferon Alfa-2A (40KD) (Pegasys) Plus Ribavirin (RBV) and Amantadine (AMA) vs. Induction Therapy with Interferon Alfa-2A (Roferon-A) Plus RBV and AMA in IFN/RBV Non Responders (NR)with Chronic Hepatitis C (CHC)

S. Fargion 1, M. Borzio 2, A. Maraschi 1, A. Cargnel 3, Gel Gruppo Epatologico Lombardo 3

1 Dipartimento Medicina Interna, Università Milano, Ospedale Maggiore IRCCS, Milano, Italy; 2 Divisione Medicina Generale, Ospedale Civile Melegnano, Melegnano, Italy; 3 II Divisione Malattie Infettive, Ospedale Sacco, Milano, Italy

 

Introduction

Despite the use of combination therapy (IFN+RBV), still a large proportion of CHC patients does not respond to therapy.

 

Aim

To determine the benefit of a triple combination regimen (PEG-IFN or daily IFN, plus RBV and AMA) in NR to IFN/RBV.

 

Patients

185 patients who failed to respond to a prior course of 12-week of IFN/RBV therapy, have been randomized to receive 180 mcg once-weekly of PEG-IFN alfa-2a (40KD) plus RBV (800-1000mg/day) and AMA (200mg daily) (group A) for 48 weeks or IFN alfa-2a (6 MIU daily for 4 weeks, 3 MIU daily for 20 weeks, and then 3 MIU tiw for 24 weeks) plus RBV (800-1000mg/day) and AMA (200mg/day) (group B) for 24 weeks. Patients with detectable HCV-RNA after 24 weeks of treatment were considered non responders, and therapy discontinued.

 

Results

Baseline patient characteristics did not differ in the two groups. Nineteen percent of patients discontinued therapy. End of treatment was 47 and 25 % (p=0.06) and SVR 24 and 19 %, in group A and B, respectively, with an overall SVR of 22%. SVR was 39% and 18% in genotype non-1 and 1 (p=0.05). Patients of age < 40 years (p=0.05) and viral load > 2MU (p=0.01) responded significantly better PEG-IFN.

 

Conclusions

A proportion of patients with chronic hepatitis C not responders to IFN/RBV can eradicate HCV-RNA infection with triple therapy, especially if they have non-1 genotypes. Younger subjects (< 40 years) and those with higher viral load seem to benefit more from treatment with PEG-IFN.

 

Prospective Evaluation of the 24 Hour Interferon (INF) Induced Decline in Hepatitis C Virus Genotype 1 Load to Predict Sustained Virologic Response (SVR) to Peginterferon-Alfa-2A/Ribavirin Combination Therapy With or Without Amantadine

P. Ferenci 1, E. Formann 1, M. Gschwantler 2, H. Laferl 3, H. Brunner 4, F. Hackl 5, R. Hubmann 6, R. Stauber 7, A. Gangl 1

1 University Of Vienna, Dept. Internal Med. IV, Vienna, Austria; 2 Rankenanstalt Rudolfsstiftung, Vienna, Austria; 3 Kaiser Franz Josef Hospital, Vienna, Austria; 4 Krankenhaus Lainz, Vienna, Austria; 5 Elisabethinenhospital, Linz, Austria; 6 General Hospital, Linz, Austria; 7 Karl Franzens University, Graz, Austria

 

Introduction

Response to antiviral therapy in chronic hepatitis C (CHC) can be measured at various time points. The 24h response to a single IFN dose (24hVR) identifies unresponsiveness to standard IFN/ribavirin therapy.

 

Aim

This study was to investigate prospectively the 24hVR to predict outcome of PEGIFN/ribavirin combination therapy in interferon naïve CHC patients (genotype 1).

 

Methods

At randomization, 210 patients participating in a prospective trial comparing amantadine and placebo in addition to standard treatment (180 μg PEGASYS® /week + 1-1.2g COPEGUS®/d [both Roche, Basel, CH]) were stratified according to the 24hVR (stratum A: >1.4 log decrease in viral load within 24 hrs; stratum B: 0.8-1.39; stratum C: < 0.8).

 

The 24hVR was performed 2 weeks prior randomization. Viral load was determined by the Cobas Amplicor Monitor HCV Test®, v2.0 (Roche Diagnostic Systems, USA). At writing, 154 and 126 patients completed 48 weeks of treatment and 6 months follow up, respectively. In these patients the 24hVR was compared with the end of treatment response (EOTR) and SVR (each defined as HCV-RNA neg). Analysis was done without knowing to which treatment group a patient was assigned.

 

Results

EOTR (ITT analysis; Stratum A:83%; B:78%; C:33%; A/B vs. C p<0.05) and SVR (A:68%; B:50%; C:17%; p<0.05) were different among the 3 groups. The best outcome was observed in stratum A.

 

Conclusion

The 24hVR is a useful predictor of the outcome of PEGASYS/COPEGUS therapy and may be helpful to identify patients who may benefit from longer treatment.