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The Liver Meeting— 54th Annual Meeting of The American Association for the Study of Liver Diseases, October 24 - 28, Boston, MA—Day 3

Alan Franciscus
Editor-in-Chief, HCV Advocate

Poster 106: INTERNATIONAL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY FOR THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C AND PERSISTENTLY NORMAL ALT LEVELS WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®)

Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Moisés Diago, Hospital General de, Valencia, Spain; Edward Gane, Middlemore Hospital, Auckland, New Zealand; Rajender Reddy, University of Pennsylvania, Philadelphia, PA; Paul Pockros, The Scripps Clinic, La Jolla, CA; Patrizia Farci, Universita di Cagliari, Cagliari, Italy; Norman Gitlin, Emory University, Atlanta, GA; François Lamour, Pilar Lardelli, Roche, Basel, Switzerland; Mitchell Shiffman, VCU Health System, Richmond, VA.

Background
The combination of pegylated interferon alfa and ribavirin is the currently recommended treatment for patients with chronic hepatitis C (CHC) and elevated alanine aminotransferase (ALT) levels. Recent data with peginterferon alfa-2a (40 KD) 180 µg/week and ribavirin have established that the treatment duration for CHC patients with elevated ALT should be based on the HCV genotype: 48 weeks for genotype 1 and 24 weeks for genotype 2/3 patients.

However, many patients with chronic hepatitis C (CHC) have persistently normal serum ALT levels. The effectiveness of interferon alfa (IFN-a) therapy in these patients is controversial. The US and EU consensus conferences on hepatitis C recommend not to treat normal ALT CHC patients until data from controlled clinical studies become available.

Objectives
An international, multicenter, randomized, controlled study has been performed to determine the efficacy and safety of peginterferon alfa-2a (40KD) (PEG-IFN alfa-2a) in combination with ribavirin administered during 2 different treatment durations in CHC patients with normal ALT.

Methods
491 patients were randomized (ratio 3:3:1) into three arms: 212 were treated with PEG-IFN alfa-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks, 210 received the same combination for 48 wks and 69 patients received no treatment and were monitored for 72 weeks. All patients were required to have CHC infection documented by positive anti-HCV antibody test and detection of HCV RNA by PCR. Persistently normal ALT activity was defined by at least 3 ALT determinations < the upper limit of normal (ULN), a minimum of 4 weeks apart, with 1 value within the 42-day screening time and 1 value 6 to 18 months before the study onset. Patients with ALT levels > ULN during the 18 months preceding baseline were excluded from the study. Liver disease consistent with CHC was confirmed by biopsy within 36 months before the study. Cirrhotic patients and patients with other chronic liver disease or co-infected with human immunodeficiency virus were excluded from the trial. Sustained virological response (SVR) was defined as HCV RNA negativity by PCR (<50 IU/mL COBAS AMPLICOR® HCV Test v. 2.0) at the end of 24 weeks of untreated follow-up.

Results
Demographic and baseline virologic features were similar in all three groups. Male gender: 42%, 39%, 38%; median age: 44, 44, 41 years, and median weight, 74 kg, 73 kg, 70 kg, respectively. Genotype 1: 68%, 67%, 66 %; and mean viral load: 1.2, 1.1 and 1.3 x 106 IU/mL, respectively. Overall SVR was 30% and 52% for the 24 and 48 wk treatment groups, respectively, versus 0% for the untreated control group (p <0.0001). For genotype 1, SVR was 13% in the 24 wk treatment group vs 40% in the 48 wk treatment group (p<0.001). For genotypes 2 and 3, 24 weeks treatment had a SVR of 72% vs 78% in patients treated for 48 weeks (p = ns). The safety profile was typical of IFN treatment but the incidence of the commonest IFN-related adverse events was lower than in previous studies on abnormal ALT CHC patients. ALT values remained normal or near normal in the vast majority of patients from both treatment and control groups. Median ALT levels decreased from baseline in treatment responders. Mild, transient ALT elevations were observed after end of treatment in relapsers from treatment groups. Only 2 patients, one treated for 24 weeks, and one from the control group, developed ALT flares (>10x ULN).

Conclusion
The efficacy results are comparable to those obtained in previous trials in CHC patients with elevated ALT (Hadziyannis et al. J Hepatol 2002; 36(S1) pp.3A) and a duration of treatment according to genotype can be recommended following established algorithms.

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Poster 136: ANTIVIRAL EFFECT OF BILN 2061, A NOVEL HCV SERINE PROTEASE INHIBITOR, AFTER ORAL TREATMENT OVER 2 DAYS IN PATIENTS WITH CHRONIC HEPATITIS C, NON-GENOTYPE 1

Markus Reiser, Medizinische Universitätsklinik Bochum, Bochum, Germany; Holger Hinrichsen, I Medizinische Universitätsklinik Kiel, Kiel, Germany; Yves Benhamou, Goup Hospitalier Pitie-Salpetriere Paris, Paris, France; Roel Sentjens, Academisch Medisch Centrum Amsterdam, Amsterdam, Netherlands; Heiner Wedemeyer, Medizinische Hochschule Hannover, Hannover, Germany; Luis Calleja, Clinica Puerta de Hierro Madrid, Madrid, South Africa; Xavier Forns, Hospital Clinico Barcelona, Barcelona, Spain; Jens Croenlein, Boehringer Ingelheim, Biberach, Germany; Chan Yong, Boehringer Ingelheim, Ridgefield, CT; Gerhard Nehmiz, Gerhard Steinmann, Boehringer Ingelheim, Biberach, Germany.

Introduction
BILN 2061 is a potent and specific inhibitor of the HCV serine protease in-vitro and in patients infected with genotype 1 (GT 1) as recently reported. In a first exploratory trial, the effect of a 2-day oral treatment with BILN 2061 was investigated in GT 2 and GT 3 patients with minimal liver fibrosis.

Methods
In a randomized, double-blind group comparison, 10 male patients with HCV other than GT 1 (InnoLiPA) and no or minimal liver fibrosis (Ishak 0-2) were administered 500 mg BILN 2061 or placebo in an oral solution (randomized 8:2) b.i.d. over 2 days. Virus load (VL) was measured as HCV RNA by Cobas Amplicor HCV Monitor v2.0.

Results
Mean age of all 10 patients was 37 +/-7 years. HCV genotypes were GT 2 (3 patients) and GT 3 (7 patients). 9/10 patients were naive for anti-HCV therapy. All patients completed the study and were followed up for 12 +/-2 days. VL decreased by >1 LOG10 unit in 4/8 patients treated with 500mg BILN 2061 b.i.d., without detectable difference between GTs 2 and 3. A weak response was observed in 1 BILN 2061-treated patient, whereas 3/8 BILN 2061-treated patients and 2/2 patients given placebo experienced no response. The largest VL decrease was observed in the one patient with GT 2 HCV that had been previously treated with anti-HCV therapy. However HCV-RNA was still detectable. After end of treatment, VL returned to baseline levels within 1-7 days. No adverse events were reported. Liver function tests did not change during treatment. Vital signs, routine laboratory and ECG did not show relevant drug-induced changes. Tolerability was rated "good" by the investigators in 9 patients and “satisfactory” in 1 BILN 2061-treated patient.

Conclusion
BILN 2061, given p.o. over 2 days at 500 mg b.i.d., demonstrated antiviral activity in 5/8 non-GT-1 in patients. In contrast to our previous results in GT-1 patients, the antiviral activity was not uniform and less pronounced. No safety issues were identified among the 8 patients exposed to BILN 2061.

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Poster 145: ANALYSIS OF UNOS DATA SHOWS THAT THE OUTCOME OF LIVER TRANSPLANTATION IN PATIENTS WITH HEPATITIS C HAS REMAINED UNCHANGED BETWEEN 1991-2001 IN THE USA

Hwan Y. Yoo, Indiana University School of Medicine, Indianapolis, IN; Paul J. Thuluvath, The Johns Hopkins University School of Medicine, Baltimore, MD.

Introduction
It has been suggested that, for hitherto unexplained reasons, the survival of patients with HCV has declined among those who were transplanted more recently.

Objective
To compare the outcome of liver transplantation (LT) in patients with HCV at different time intervals between 1991-2001. We selected 1991 since the data on HCV status was unavailable prior to that period.

Material
UNOS (United Network for Organ Sharing) data from 1991 to 2001 was used after excluding pediatric patients, patients with multiple transplantation and those with incomplete survival data. Based on the time of transplantation, patients were arbitrarily divided into 3 groups: 1991-1993 (Period 1), 1994-1997 (Period II) and 1998-2001 (Period III). Patients with HCV were compared to those without HCV (‘Case -Controls’) to adjust for improvement in overall outcome during the same period.

Results
There were 7,455 patients with HCV (Period 1-1,173, Period II-2, 679, Period III- 3,603) and 20,734 patients in control group (Period 1-4,806, Period II- 8,419, Period III-7, 509). Survival of patient was analyzed after adjusting for age, sex, race, ABO blood type matching status, cold ischemia time, UNOS listing status, serum creatinine, body mass index and age of the donor. As expected, 3-year patient survival was lower in HCV compared to that of controls (78.5% vs. 81.4%, HR 1.12, 95% CI 1.04-1.20, p=0.003). However, there was no difference in patient survival among HCV patients who were transplanted between 1991-1993, 1994-1997 and 1998-2001 (77.4%, 79.6% and 78.5% respectively). The graft survival also showed similar results (72.8%, 71.0% and 69.8% respectively). The patient and graft survival for control patients showed significant improvement in period 2 and 3 compared to period 1.

Conclusion
The analysis of UNOS data shows that patient and graft survival in HCV patients has remained unchanged between 1991-2001.

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Poster 146: A MORE SEVERE HEPATITIS C RECURRENCE (HCVR) POST LIVER TRANSPLANTATION (OLT) OBSERVED IN RECENT YEARS MAY BE EXPLAINED BY THE USE OF LOWER-DOSE CORTICOSTEROID (CS) MAINTENANCE PROTOCOLS

Carlos G. Fasola, George J. Netto, Nicholas Onaca, Mark Thomas, Edmund Q. Sanchez, Shrina Chinnakotla, Robert M. Goldstein, Marlon F. Levy, Gary L. Davis, Goran B. Klintmalm, Baylor University Medical Center, Dallas, TX.

Purpose
To assess the effect of steroids in HCVR post OLT at two years post OLT in recent years.

Methods
Hep C 1994 -1999 OLT (n=133) outcome, at years 1 (Y1) and 2 (Y2), was analyzed in 3 groups of patients according to the steroid maintenance dose received from their immunosuppression (IS) standpoint and according to the era studied (’94-95; ’96-97 and ’98-99). IS was based on calcineurin-inhibitors (CNI:CSA [80%] or FK [20%] ) + Prednisolone (P). Patients were categorized according to total amount of Prednisolone maintained in Y1 (range: 2,958-10,113 mg) and Y2 (range: 2,958-13,763 mg) as: low (Y1: less than 5,162 mg; Y2: less than 6,500 mg), medium (Y1:5,162-6,315; Y2:6,500-8500) or high dose (Y1: more than 6,315; Y2: more than 8,500). Selection criteria was based on percentiles 33 and 66 range distribution. Laboratory data and liver histology were evaluated by protocol, in all patients, at 1 and 2 years post OLT and respectively compared. HCV recurrence was assessed by the degree of fibrosis (stages (S) 0 to 4), as defined in the past (A.J.S. Pathology 19(12):1409, 1995). Patient and graft survivals were compared among groups. Demographics, UNOS status, ICU and Hospital stay, incidences of ACR, bacterial and CMV infections were assessed. Fisher’s exact and Chi-Square tests* were used for table analyses. Kaplan-Meier for actuarial survivals. A p value < 0.05 = significant.

Results
No statistical differences were found regarding age, gender, race, UNOS status, hospital and ICU stay, infections and blood tests. The tables show the era impact in graft histology done at 2-year of follow up and in the amount of steroids used. It also show the effect of maintenance steroids in HCVR at 2 years. Graft survivals at 2 years for eras I, II and III were respectively: 92%, 96% and 97% (p=0.51) and for steroid doses: 96% (low), 91% (medium) and 100% (high, p=0.40). Patient survival was better for all groups, but statistically no different.

Conclusions
More severe HCV recurrence post OLT has been reported recently. Our data support those publications. Rather than a pure era effect, our findings of more aggressive HCV recurrence can be explained by the shorter and lesser amount of steroids used in recent years. Corticosteroids may be an important component of IS in HCV-OLT and minimize severe HCVR. The current practice of early CS withdrawal should be reconsidered and examined in prospective studies.

Hepatitis C Recurrence at 2 Years of Follow Up

  Era '94-95 Era '96-97 Era '98-99
Fibrosis Degree n (%) n (%) n (%)
Stage 0 24 (57%) 16 (33%) 5 (17%)
Stages 1-2 13 (31%) 21 (43%) 15 (52%)
Stages 3-4 5 (12%) 12 (24%) 9 (31%)
Total 42 (100%) 49 (100%) 29 (100%)
      p=0.01

Corticosteroid Maintenance Doses

  Era '94-95 Era '96-97 Era '98-99
Corticosteroid
Doses
n (%) n (%) n (%)
Low 3 (6%) 26 (49%) 18 (57%)
Medium 17 (35%) 17 (32%) 11 (34%)
High 28 (59%) 10 (19%) 3 (9%)
Total 48 (100%) 53 (100%) 32 (100%)
      p = 0.0001

Hepatitis C Recurrence at 2 Years Post OLT According to Steroid Maintenance Doses

  LOW MEDIUM HIGH
Fibrosis Degree n (%) n (%) n (%)
Stage 0 10 (22%) 15 (39%) 24 (59%)
Stages 1-2 20 (45%) 17 (45%) 12 (29%)
Stages 3-4 15 (33%) 6 (16%) 5 (12%)
Total 45 (100%) 38 (100%) 41 (100%)
      p = 0.007

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Poster 147: SHOULD WE DISCARD OLD DONORS FOR HEPATITIS C CANDIDATES ? THE IMPORTANCE OF DONOR STEATOSIS

Marta Ponce, Marina Berenguer, Martín Prieto, Victoria Aguilera, Domingo Carrasco, Miguel Rayón, Francisco Orbis, Joaquín Berenguer, La Fe Hospital, Valencia, Spain.

Introduction
Recurrent Hepatitis C following liver transplantation is a major concern in transplant units. Recent data have shown that the age of the donor is significantly associated with the outcome, with a worse histological progression in those receiving older donors. Unfortunately, the increasing imbalance between donors and potential candidates makes it impossible to discard these “so-called” marginal donors.

Aims
(1) to analyze the outcome of HCV-infected patients receiving organs from donors older than 50 years;
(2) in these patients, to determine pre and/or early post-transplant factors associated with a worse histological outcome.

Methods
91/145 HCV-infected patients transplanted between 1999 and 2001, with at least one year of follow-up, were included. Protocol biopsies were performed at yearly intervals (median/patient:1, range:1-3). An aggressive course was defined by the progression to fibrosis 3 or 4 in the first 3 years post-transplantation. Potential predictors of outcome included demographics, donor-related variables (steatosis, sex, age, anti-HBc positivity), host variables (history of alcohol consumption, Child-Pugh / HCC / nutritional status at transplantation, interferon therapy pretransplantation, HBV markers), early post-transplant variables (immunosuppression, biochemical tests, early surgical complications- vascular thrombosis and/or biliary complications-, development of recurrent histological acute hepatitis.

Results
32/ 91 patients progressed to F3-4 in the first 3 years post-transplantation. Variables predicting the negative outcome were: age of the donor (p=0.07), degree of steatosis in the organ-donor (p=0.02); AST and ALT levels at 1 and 2 months post-transplantation (p=0.05; 0.04; and 0.006; 0.009; respectively), GGT at 2 months (p=0.03); and development of acute hepatitis (p=0.02). Of the 48 (53%) patients receiving an organ from a donor older than 50, 21 (44%) developed F3-4 within 2-3 years of transplantation. In contrast, of 43 patients receiving organs from younger donors, only 11 (25%) progressed to F3-4 (p=0.07). The median donor age in those progressing to F3-4 was higher than in those with benign outcome (54 vs 48 years, p=0.07). Variables associated with an aggressive course in those receiving organs from old donors were: development of recurrent acute hepatitis (p=0.05), and AST-ALT levels at 2 months post-transplantation (p=0.04 and 0.006, respectively). In those receiving grafts from younger donors, variables associated with a negative outcome were: significant steatosis in the organ donor (p=0.01) and development of early surgical complications (p=0.03).

Conclusions
The use of organs from old donors is associated with a high risk of developing aggressive recurrent hepatitis C. If these organs are used, the development of acute hepatitis and/or significant increases in the transaminase levels in the early post-transplant period may help in predicting a negative outcome. In contrast, when using young donors, the degree of liver steatosis is probably the single most important factor in influencing clinical outcome. These findings may help implementing early antiviral therapy and/or directing some of these organs to non-C candidates.

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Poster 148: IMPACT OF PEGYLATED INTERFERON alfa-2b AND RIBAVIRIN ON LIVER FIBROSIS FOR RECURRENT HEPATITIS C IN LIVER TRANSPLANATION-A SINGLE CENTER EXPERIENCE

Sandeep Mukherjee, Richard K Gilroy, Joyce Rogge, Lynne Weaver, Timothy M McCashland, Daniel F Schafer, University of Nebraska Medical Center, Omaha, NE

Background
Recurrent hepatitis C (HCV) is universal after orthotopic liver transplantation(OLT). Patients are often treated with interferon-based therapy to eradicate the virus and prevent cirrhosis requiring retransplantation. We describe our experience with pegylated-interferon and ribavirin combination therapy on 39 patients with recurrent HCV from a single liver transplant program.

Methods
Between November 2001 and September 2002, consecutive patients with recurrent HCV were screened to determine if they were eligible for treatment. Recurrent HCV was defined as the presence of HCVRNA viremia with a liver biopsy demonstrating recurrent hepatitis, steatosis or non-specific changes in patients transplanted for HCV. This cohort was followed prospectively after starting a treatment protocol of pegylated interferon alfa-2b 1.5 µg/kg qweekly and ribavirin 800mg qd (Schering-Plough, Kenilworth, NJ, USA) with folic acid 1 mg qd. Patients with genotypes 1 and 4 were treated for 12 months, other genotypes for 6 months and doses adjusted per treatment protocol. Steroids were discontinued prior to treatment. Complete blood counts were performed weekly for the first month and monthly thereafter with liver function tests. HCVRNA was repeated at 3 months, end of treatment (EOT) and 6 months after EOT for patients HCVRNA negative at EOT. Liver biopsies were repeated at EOT and biopsies scored according to the methodology described by Batts and Ludwig.

Results
45 patients were screened and 39 eligible for treatment. There were 33 males and 6 females with a median age of 50.4 years. 31 patients were genotype 1, 2 were genotype 2 and 3 each were genotype 3 and 4. Median pre-treatment viral load was 1.7 million iu/ml and median interval between OLT and treatment initiation was 20 months. 18 patients have completed treatment, 4 remain on treatment and 17 were intolerant. Of the 18 patients who completed treatment, 17 were HCVRNA negative at 3 months and 15HCVRNA negative at EOT (this included 1 patient who was HCVRNA positive at 3 months). 6 months after EOT, 12 patients remain HCVRNA negative ( HCVRNA pending in 3). Improved fibrosis scores, defined as a downstaging of the EOT biopsy by at least 1 stage, were present in 6 patients, unchanged in 10 and worse in 2. Interestingly, of the 3 non-responders to treatment, one patient each had an improved score or unchanged score at EOT.

Conclusions
Side effects are an important limiting factor in the treatment. of recurrent HCV with only 46.1% of patients completing treatment. Sustained HCV eradication occurred in at least 66.7% of patients who completed treatment but in an intention-to-treat analysis, sustained eradication occurred in 30.8% of patients. However, improved fibrosis scores were demonstrated in responders and non-responders to treatment. This suggests that failure to eradicate the virus should not necessarily lead to treatment discontinuation as a subgroup of patients may benefit from maintenance therapy if serial liver biopsies demonstrate improved fibrosis.

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Poster 189: TREATMENT OF CHRONIC HEPATITIS C WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®): PATIENT AGE HAS A MARKED INFLUENCE ON THE INDIVIDUAL ESTIMATED PROBABILITY OF ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE

Graham R Foster, Digestive Disease Research Centre, Barts and The London, London, United Kingdom; Michael W Fried, University of North Carolina, Chapel Hill, NC; Stephanos J Hadziyannis, Henry Dunant Hospital, Athens, Greece; Monique Chaneac, Roche, Basel, Switzerland.

Introduction
Overall sustained virological response (SVR) rates to peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) ranged from 56 to 61% in pivotal trials in patients with chronic hepatitis C (CHC). The probability of achieving an SVR varied with HCV genotype, viral load, histological status and other patient factors. In patients infected with HCV genotype 1, only pretreatment viral load had a greater influence than age on the probability of achieving an SVR.

Purpose
In this analysis we investigated the influence of age and adherence on the probability of achieving an SVR with peginterferon alfa-2a (40KD) and ribavirin in an individual patient infected with HCV genotype 1.

Methods
Data from 2 international, randomized trials in which patients received peginterferon alfa-2a (40KD) 180 µg/wk plus ribavirin were combined. In 1 study (Fried et al. N Engl J Med. 2002;347:975-982), patients were treated for 48 wk with a standard dose of ribavirin (1000 or 1200 mg/day). In the second study (Hadziyannis et al. J Hepatol. 2002; 36 [suppl 1]: 3A), patients were randomized to 1 of 4 groups: all patients received peginterferon alfa-2a (40KD) combined with either a low dose (800 mg/day) or the standard dose of ribavirin, and were treated for 24 or 48 wk. SVR was defined as absence of HCV RNA in serum by qualitative PCR (<50 IU/mL, COBAS AMPLICOR® HCV Test, v2.0) on or after wk 60.

All 1737 patients who received peginterferon alfa-2a (40KD)/ribavirin were aged >18 yr, had HCV RNA levels >2000 copies/mL, elevated ALT levels, and a liver biopsy consistent with a diagnosis of CHC. Data included in this analysis were restricted to patients infected with HCV genotype 1 (n = 736) as described below.

Logistic regression models were constructed based on HCV genotype 1, baseline time point and adherence (>80% and <80%). An adherent patient was defined as one who received the assigned dosages of peginterferon alfa-2a (40KD)/ribavirin for >80% of the planned duration of treatment. Because of the low number of non-Caucasian patients, the model was restricted to Caucasian patients. The analysis was limited to patients aged <60 yr and with a BMI of <30 kg/m2. Patients with very extreme values were also excluded from the analysis.

Parameters used in the model include the following: pretreatment viral load (100,000 to 24 x 106 copies/mL); age (20 to 60 yr); duration of treatment (24 or 48 wk); pretreatment ALT quotient range (1-7); BMI (18-30); histological status (cirrhosis or noncirrhosis); and Caucasian race.

Results
Of 736 patients with HCV genotype 1 infection used to build the model, 336 (45.6%) had an SVR. In addition, 597 of 736 patients (81.1%) were adherent.

When the model was programmed for a noncirrhotic, Caucasian patient with a baseline ALT quotient of 3, HCV RNA level of 3.269 x 106 copies/ml and a BMI of 25, the probability of a 20-year-old patient achieving an SVR was 74.4% (95% confidence interval [95% CI]: 66.1 - 81.7%). In contrast, the probability of achieving an SVR in a 60-year-old with the same baseline characteristics was 44.2% (95% CI: 35.2 - 53.5%). When the model parameters include, in addition to those mentioned above, an assumption that the patient would be adherent (as defined above), the probability of achieving an SVR increased to 85.4% (95% CI: 78.0 - 90.7%) in the 20-year-old and 52.9% (95% CI: 42.6 - 63.0%) in the 60-year-old.

Conclusion
In conclusion, patient age has a profound influence on the probability of achieving an SVR with peginterferon alfa-2a (40KD) and ribavirin therapy. Clinicians and their patients should consider the influence of patient age on the timing of the decision to start treatment. With our model, it is possible to predict the probability of achieving an SVR in an individual patient, and to demonstrate the impact of adherence on treatment outcome. This tool will be useful in motivating patients to adhere to treatment.

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Poster 192: EARLY VIRAL KINETICS PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE AFTER 1 OR 4 WEEKS OF PEG-INTERFERON-ALFA-2A AND RIBAVIRIN THERAPY (DITTO-HCV PROJECT)

Avidan U Neumann, Esther Hagai, Bar-Ilan University, Ramat-Gan, Israel; Solko W Schalm, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Michael von Wagner, Saarland University Hospital, Homburg/Saar, Germany; Georgios Germanidis, Aristotle University of Thessaloniki, Thessaloniki, Greece; Yoav Lurie, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel; Gabriele Missale, Azienda Ospedaliera di Parma, Parma, Italy; Maria Martell, Hospital General Vall d’Hebron, Barcelona, Spain; Jan-Maarten Vrolijk, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Cristophe Hezode, Hopital Henri Mondor - Universite Paris XII, Creteil, France; Gunnar Norkrans, University of Goeteborg, Goetoborg, Sweden; Francesco Negro, Hospital University of Geneve, Geneve, Switzerland; Alexandre Soulier, Hopital Henri Mondor - Universite Paris XII, Creteil, France; Elke Verheij-Hart, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Giuseppe Colucci, Tegimenta AG, Rotkreuz, Switzerland; Carlo Ferrari, Azienda Ospedaliera di Parma, Parma, Italy; Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Jean-Michel Pawlotsky, Hopital Henri Mondor - Universite Paris XII, Creteil, France; for the DITTO-HCV group.

Background
Early Hepatitis C viral (HCV) kinetics was previously shown to predict sustained virological response (SVR). The current consensus stopping rule is defined at 12 weeks of treatment with peginterferon-alfa and ribavirin. Earlier prediction is needed in order to improve the cost/effect ratio. However, the predictive value of earlier viral kinetics for the current standard of care has not yet been established.

Objectives
The DITTO-HCV European funded project is for now the largest study of frequent early viral kinetics during therapy with peginterferon-alfa and ribavirin. We aim to optimize viral kinetics prediction criteria in order to enable stopping or tailoring treatment as early as possible. Our objectives: 1) negative predictive value (NPV) as close as possible to 100% (thus minimalizing stopped patients with missed SVR), 2) high specificity (thus increasing the fraction of patients that can be safely stopped). 3) a high positive predictive value (PPV) using the same criteria.

Methods
134 chronically HCV infected naïve patients received peginterferon-alfa-2a (40KD) (Pegasys ®) (180 µg qw) plus ribavirin (Copegus ®) (1000-1200 mg qd) for 48 weeks. Of those, 67%, 28%, 4% and 1% had HCV genotype 1, 2-3, 4 or 5 respectively. Viral kinetics were measured according to centralized serum HCV RNA quantifications on days 0, 1, 4, 7, 8, 15, 22 and 29 (Cobas Amplicor® HCV Monitor v2, Roche). SVR was defined as undetectable serum HCV RNA (<50 IU/ml) after 24 weeks of follow-up post treatment. The early viral response prediction criteria (EVR) and thresholds tested here (see Table) were prospectively defined.

Results
The overall SVR rate was 64%. The EVR studied, together with their NPV, PPV, specificity (SP), statistical significance and number of HCV-RNA quantifications needed (NSMP), are given in the Table.

The EVR-w12 criteria has good NPV (100%) but its specificity is low (21%), thus relatively few non-responders can be stopped. None of the simple 2nd-slope or Week-1 criteria shows NPV higher than 90%, thus not adequate for a stopping rule. A new composite criteria (DITTO-2nd-slp) gives NPV=100% and specificity=34% already after 4 weeks of treatment. Furthermore, another new composite criteria (DITTO-1st-week) also gives NPV=100% with specificity=28% already after 1 week. Although composite, these new criteria are simple to calculate and necessitate only 1 or 2 more viral quantifications compared to the current Week-12 criteria. Thus allowing to lower the mean cost by 2410 USD per patient. Note that SVR (56% for gen 1 and 87% for gen 2-3) is predicted independently of genotype. Moreover, by selecting more strict thresholds for the DITTO-1st-week (e.g. 4.5 log at day 4 and 2 log decline at day 7) and DITTO-2nd-slope (e.g, 0.6 log/week) criteria one can obtain higher PPV up to 90%.

Conclusions
Sustained viral response to treatment with peginterferon-alfa-2a (40KD) and ribavirin can be predicted, independent of genotype, as early as 1 or 4 weeks of treatment by new composite, but still simple and practical, criteria of viral kinetics. Similar NPV and PPV and better specificity was obtained here by the DITTO-1st-week or DITTO-2nd-slope prediction criteria, giving rise to significantly lower cost/effect as compared to the current stopping rule at 12 weeks. These results warrant future prospective testing in larger trials, since they can give rise to considerable saving in cost and quality of life related to over-treatment or alternatively allow early tailoring of treatment.

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Poster 971: LONG TERM FOLLOW UP OF SUSTAINED RESPONDERS TO INTERFERON ALPHA IN CHRONIC HEPATITIS C: A META-ANALYSIS ASSESSING TRUE CLINICAL ENDPOINTS

Bart J Veldt, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Giorgio Saracco, Ospedale Molinette, Torino, Italy; Bettina E. Hansen, Solko W Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; For the Eurohep* study group.

Background
Sustained virological response at six months after treatment is the key outcome for treatment efficacy in hepatitis C. However, reports about the incidence of clinical events during long term follow up of European patients with a sustained response to interferon treatment are scarce.

Aims
To determine the virological relapse rate and to assess clinical endpoints during long term follow-up in European sustained responders to interferon treatment.

Methods
Meta-analysis of individual patient data of 8 European protocolled follow-up studies.

Results
286 sustained responders were followed up for 59 months (range 12-120). Fifteen sustained responders had cirrhosis before treatment. HCV-RNA was detected in 25 (8.7%) of 286 sustained responders; the late relapse rate at five years of follow up was 10.5% (95%CI 6.5%-14.5%). The only factor predictive of late virological relapse was the total dose of interferon, acccording to multivariate analysis (Hazard Ratio=0.650; 95%CI 0.426-0.991, p=0.045); doses = 216 MU being associated with the highest late relapse rate. Two patients originally not classified as having cirrhosis, developed decompensation at 30 and 60 months of follow up (rate of decompensation at 5 year follow up: 1.0% (95 %CI 0.0-2.3), the latter died of this decompensated cirrhosis. No HCCs were detected. The outcome in cirrhotic patients did not differ from other patients with sustained response to interferon.

Conclusions
The late virological relapse rate at five years of follow up was 10.5% (95%CI 6.5%-14.5%) in sustained responders to interferon treatment. Treatment with a high total dose of interferon reduces the risk of late virological relapse. The five year occurrence of clinical events was 1.0 % (95%CI 0.0-2.3) among 286 sustained responders.

*Eurohep study group participants are U Hopf, Berlin; N Boyer, Clichy; O Weiland, Huddinge; F Nevens, Leuven; I Castillo, Madrid; A Bellobuono, Milan; C Cammà and A Craxi, Palermo; P Marcellin, Paris; S W Schalm and J T Brouwer, Rotterdam and G Saracco, Torino

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Poster 972: VX-950: THE DISCOVERY OF AN INHIBITOR OF THE HEPATITIS C NS3•4A PROTEASE AND A POTENTIAL HEPTITIS C VIRUS THERAPEUTIC

Robert B Perni, Gurudatt Chandorkar, Pravin R Chaturvedi, Lawrence F Courtney, Caroline J Decker, Cynthia A Gates, Scott L Harbeson, Ann D Kwong, Chao Lin, Yu-Ping Luong, William Markland, Govinda Rao, Roger D Tung, John A Thomson, Vertex Pharmaceuticals Inc., Cambridge, MA

INTRODUCTION
The deficiencies of current anti-HCV therapy are well known. The poor tolerability of the interferon-alpha (IFN-alpha)-ribavirin combination therapy limits its value, particularly versus Genotype 1 where even the pegylated IFN-alpha/ribavirin combinations are generally less than 50% effective in achieving sustained viral responses. The need for a direct anti-viral therapy for hepatitis C is clear. The NS3•4A protease of the hepatitis C virus represents an attractive target that should be amenable to modern drug design techniques. Designing small molecules that have high affinity for the shallow, largely hydrophobic active site of this serine protease has been a significant challenge and only recently the first HCV protease inhibitor to show anti-viral activity in humans was reported (Lamarre et al, 2002, Hepatology, 36, Pt2, 301A). Nature has designed this protein with a natural substrate recognition sequence of a lengthy 10 amino acids. Consequently, numerous hydrophobic interactions and hydrogen bonds are required to effectively bind any potential inhibitor. In addition, either a charged terminus or a covalent attachment of the inhibitor to the catalytic serine is needed to anchor the assembly. To maximize binding while simultaneously maintaining an acceptable biological profile, we have chosen to base our inhibitor scaffolds on a reversible covalent warhead motif in order to eliminate charged groups and facilitate cellular penetration. We now report the discovery of VX-950, a small molecule inhibitor of the hepatitis C NS3•4A protease. This molecule was derived through structure-based drug design methodology, evolving from the natural NS5A-NS5B substrate. VX-950 has a measured Ki of 44 nM versus the NS3•4A enzyme. Inhibition of the polyprotein processing in hepatocytes as measured by the HCV replicon assay has been demonstrated. VX-950 is orally bioavailable in several species with a favorable pharmacokinetic profile. The uptake of the drug is characterized by first pass hepatic extraction resulting in high concentrations of drug in the liver, which should be advantageous for treatment of chronic HCV. On the basis of these attributes VX-950 has been selected for clinical evaluation in humans.

Conclusion

  • HCVNS3-4A protease inhibitor VX 950 has been identified as a development candidate for the treatment of HCV
  • VX 950 has demonstrated good cellular activity in two assays. The anti viral activity can be sustained in viral clearance assays resulting in a continuing decline of HCV RNA for 9 days
  • This is possibly a function of the slow binding enzyme mechanism
  • Higher liver exposures have been achieved
  • This reversible tight slow binding was discovered suing structure based drug design
  • Clinical trials are planned to begin in early 2004

The authors wish to gratefully acknowledge the significant contributions to this research by our collaborators at Eli Lilly and Co

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Poster 974: IFN-A 2B INHIBITS INTERNAL RIBOSOME ENTRY SITE MEDIATED TRANSLATION OF GREEN FLUORESCENCE PROTEIN FROM SIX DIFFERENT HCV GENOTYPES

Alfredo Panebra, Krishna Shah, Ramesh Prabhu, Frank Bastian, Robert F Garry, Virendara Joshi, Salima Haque, Fredric G Regenstein, Tulane University Health Sciences Center, New Orleans, LA; Richard Elliott, University of Glasgow, Glasgow, United Kingdom; Srikanta Dash, Tulane University Health Sciences Center, New Orleans, LA

Introduction
Interferon alpha is the standard therapy for chronic hepatitis C, but the mechanism(s) by which this cytokine inhibits HCV replication is not understood. We reported previously that different forms of interferon inhibit replication of hepatitis C virus by directly blocking at the level of viral RNA translation.

Aim
This study was conducted to examine the regulation of internal ribosome entry site mediated translation (IRES) of different HCV genotypes by IFN-a 2b and other cytokines in Huh-7 cells.

Methods
Chimeric clones consisting of the 5’UTR-IRES sequences of different HCV genotypes (HCV1a, HCV1b, HCV2a, HCV2b, HCV 3, HCV4, HCV5 and HCV6) and the green fluorescence protein (GFP) gene were constructed. High-level expression of GFP was achieved using a replication defective adenovirus that expresses T7 RNA polymerase. Direct effects of IFN-a 2b as well as other cytokines (for example TNF-a, interleukins) on translation of GFP were determined by fluorescence microscopy and Western blot analysis.

Results
IFN-a 2b specifically inhibits translation of GFP mediated by IRES sequences from six major HCV genotypes in a concentration dependent manner. This inhibition is not due to intracellular degradation of GFP mRNA, but rather due to a block at the level of GFP mRNA translation. Other cytokines such as TNF-alpha or interleukins did not inhibit IRES mediated translation of GFP mRNA.

Conclusions
Interferon alpha directly inhibits IRES mediated translation of RNA from different HCV genotypes. This inhibition is specific to IFN-a 2b since other cytokines have no effect on IRES mediated translation of GFP.

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Poster 976: TOTAL HCV CORE ANTIGEN CORRELATES WITH HCV RNA, AND PREDICTS RESPONSE TO PEGINTERFERON ALFA 2-A (PEG-IFN) AND RIBAVIRIN (RIB) THERAPY IN CHRONIC HEPATITIS C

Eduardo Padilla, Ramon Planas, Vicky González, Hospital Germans Trias i Pujol, Badalona, Spain; Celia Perez, Hospital General de Valencia, Badalona, Spain; Dolors Gimenez, Hospital del Mar, Barcelona, Spain; Lourdes Matas, Rosa Maria Morillas, Eduard Cabre, Hospital Germans Trias i Pujol, Badalona, Spain; Ricard Sola, Hospital del Mar, Barcelona, Spain; Moises Diago, Hospital General de Valencia, Valencia, Spain; Vicens Ausina, Hospital Germans Trias i Pujol, Badalona, Spain

Background
Assessment of early virological response (EVR) may predict outcome in chronic hepatitis C patients treated with PEG-IFN and Rib. A decrease in HCV RNA to undetectable levels or by at least 2 log10 units after 12 weeks is considered the optimal definition of EVR. The core Ag of HCV may constitute an alternative direct marker for assessing the levels of viremia in chronic hepatitis C patients.

Objectives
To determine the correlation between total HCV core Ag and HCV RNA levels, as well as to assess whether total HCV core Ag quantification at baseline, 1 month, and 3 months after treatment could predict sustained virological response (SVR) to PEG-IFN and Rib combination therapy, in comparison to HCV RNA.

Methods
HCV viremia was determined using the total HCV core Ag test (trak-C, Ortho-Clinical Diagnostics, Raritan, NJ), and qualitative/quantitative HCV RNA assays (Amplicor, and Amplicor Monitor COBAS V.2.0, Roche Diagnostics, CA) in 62 patients with chronic hepatitis C infected with genotype 1 in 46 (74.2%), and genotype non-1 in 16 (25.8%) (genotype 3: 10, 4: 4, and 2:2) cases, respectively.

Results
SVR was achieved in 34 (54.8%) patients (20/46: 43.5% in genotype 1, and 14/16: 87.6% in genotype non-1). SVR was significantly associated with baseline HCV RNA (p=0.04) and total HCV core Ag (p=0.01) levels, and infecting genotype (p=0.002). There was a good correlation between total HCV core Ag and HCV RNA concentrations considering 115 samples out of 134 that tested positive for both markers (r=0.91; p<0.001), as well as at baseline (r=0.89), 1 month (r=0.83) and 3 months after therapy (r=0.76). We estimated that 1 pg/mL of total HCV core Ag is equivalent to approximately 10,000 HCV-RNA IU/mL. Viral replication was not detected by total HCV core Ag in 28 out of 38 (73.6%) samples with an HCV RNA below 23.000 IU/ml. SVR was predicted at baseline in 67.9% of cases using total HCV core Ag levels<80 pg/mL, and in 65.2% of cases using HCV RNA quantification (<800.000 UI/mL). At 1 month after therapy, the positive predictive value (PPV) of response to therapy - defined as the proportion of SVR patients among patients with HCV core Ag levels ≤2.5 pg/mL - was 65.9%, and 68.4% considering the HCV RNA drop ≥ 2 log criteria. Corresponding figures at 3 months after therapy were 56.1% and 56.4%, respectively. For HCV core Ag, the negative predictive value (NPV) at 1 and 3 months after therapy were 76.5% and 100% respectively, 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. Moreover, the prediction of response to PEG-IFN and Rib combination therapy based on HCV core Ag levels before therapy, or at 3 months, was similar to that observed with HCV RNA.

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Poster 982: PEGYLATED INTERFERON ALFA-2B IN COMBINATION WITH RIBAVIRIN FOR THE TREATMENT OF CHRONIC HEPATITISC GENOTYPE 4

Fuad Hasan, Haifa Asker, Jamila Al-Khaldi, Iqbal Siddique, Salim F Owaid, Misfer Al-Ajmi, Basil Al-Nakib, Kuwait University, Kuwait, Kuwait

Background
The hepatitis C virus (HCV) genotype is an important predictive parameter for the success of pegylated interferon plus ribavirin therapy. To date, most published therapeutic trials had enrolled patients infected mainly with HCV genotypes 1, 2 and 3. Data regarding the responsiveness of genotype 4, the predominant type of HCV in the Middle East, are very limited.

Objective
To assess the efficacy of pegylated interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis caused by HCV genotype 4.

Patients and Methods
44 treatment naive patients infected with HCV genotype 4 were enrolled in this open label, prospective study. Cohort characteristics included the following: 30 M/14F, mean age 44.4 + 8.9 yrs, mean weight 73.3 + 7 kg. All patients had raised ALT and were compensated. The median pre-treatment HCV-RNA level was 2.35 x 106 copies /ml (0.47 x 106 iu/ml), range 0.3 x 106 - 30 x 106 copies/ml. 13 patients (30%) exhibited cirrhosis and 2 (4%) had bridging fibrosis on pretreatment liver biopsy specimens. All patients were to receive pegylated interferon alfa-2b 1.5 mcg/kg/wk plus ribavirin 1000-1200 mg/day for 48 weeks. Patients were followed up for 24 weeks after completing therapy. End of treatment viral response (ETR) and sustained viral response (SVR) were defined as absence of HCV-RNA from serum (<100 copies/ml) at 48 weeks of treatment and at the end of follow-up, respectively. Data were analyzed on an intention - to- treat basis.

Results
ETR and SVR were 68% and 61% respectively. Among patients with pre-treatment HCV-RNA > 2 x 106, SVR was 50% compared with SVR of 81% among patients with HCV-RNA < 2 x 106 (P=0.05). Patients with cirrhosis or severe fibrosis had significantly lower SVR rate compared to those with mild or no fibrosis (33% vs 76%; P<0.05).

Two patients (4.5%) discontinued therapy because of severe flu-like symptoms. One patient developed hypothyroidism. Dose reduction of ribavirin and pegylated interferon alfa-2b were necessary in 27% and 2% of patients respectively.

Conclusion
Pegylated interferon alfa-2b in combination with ribavirin is effective in the treatment of HCV genotype 4. Treatment was well tolerated by most patients.

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COMBINATION THERAPY OF PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) SIGNIFICANTLY ENHANCE SUSTAINED VIROLOGICAL AND BIOCHEMICAL RESPONSE RATE IN CHRONIC HEPATITIS C GENOTYPE 4 PATIENTS IN SAUDI ARABIA

O A Shobokshi, F E Serebour, L Skakni, N Al-Jasser, A O Tantawi, A Sabah, T Dinish, M Al-Quaiz, K Qahtani, A Sandokji, A Al-Blowi, M Al-Karawi, B Al-Kayyal, S Al-Momen, H Akbar, A Ayoola, M El-Hazmi, A Humaida, I El-Hazmi, H Eissa, F Khawajah, M Al-Khalifa.

BACKGROUND
Hepatitis C genotype 4 accounts for 60 to 90% of HCV chronic infections in the Eastern Mediterranean region but this is rare in other parts of the world. Earlier studies have reported poor treatment response rates for conventional interferons with HCV genotype 4. The advent of pegylated IFN and its success with other genotypes was our motivation for this study.

OBJECTIVE
To determine and compare the efficacy and safety of peginterferon alfa-2a plus ribavirin with peginterferon alfa-2a monotherapy and IFN alfa-2a (Roferon® A) plus ribavirin combination therapy in the treatment of chronic hepatitis C genotype 4 patients in Saudi Arabia.

STUDY DESIGN
Open label multicenter clinical trial in which 180 patients infected with chronic hepatitis C genotype 4 were randomized into treatment groups (1:1:1) as follows:

GROUP A: Peginterferon alfa-2a (40KD) 180µg qw plus ribavirin (400mg) bid.
GROUP B: Peginterferon alfa-2a (40KD) 180µg qw.
GROUP C: IFN alfa-2a (Roferon® A)(4.5MIU) tiw plus ribavirin (400mg) bid.

Treatment duration was for 48 weeks and follow up period of 24 weeks was observed.

RESULTS
Early virological response (>2-log drop or HCV-RNA clearance) at week 12 was 77%, 60% and 43% in groups A, B and C, respectively. End of treatment response (week 48) for the groups were 67%, 59% and 37%. Sustained virological responses (week 72) were 50%, 28% and 30% respectively. Among week 12 early responders the sustained virological responses were 65.2% and 47.2% in the two pegylated IFN groups and the sustained biochemical response was 69.6% and 69.4%.

Twelve patients (6.7%) dropped out of the study as follows: group A, 7 patients (11.7%), group B, 4 (6.7%) and group C, 1 (1.7%). These were various adverse events ranging from alopecia, thyroiditis, oesophageal varices, tonic convulsion, encephalopathy and depression. Interestingly 5 of the 12 patients had early virological response.

CONCLUSIONS
a) A 100% negative predictive value among non-responders was observed for all treatment groups at early virological response at week 12.
b) Despite the use of a low dose ribavirin of 400mg bid, an enhanced sustained virological response of 50% (65% in early responders) was determined for the combination of peginterferon alfa-2a plus ribavirin.
c) A comparatively low relapse rate was observed in patients treated with peginterferon alfa-2a plus ribavirin.
d) Patients infected with HCV genotype 4 can be safely and effectively treated with peginterferon alfa-2a (PEGASYS®) plus ribavirin (COPEGUS®).

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Poster1013: A DYNAMIC MODEL TO PREDICT SUSTAINED VIROLOGICAL RESPONSE TO COMBINATION PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C

Peter Ferenci, University of Vienna, Vienna, Austria; Michael W. Fried, University of North Carolina, Chapel Hill, NC; Monique Chaneac, Roche, Basel, Switzerland.

Background
Overall, 56% of patients achieved sustained virological responses (SVR) after 48 weeks of treatment with the combination of peginterferon alfa-2a (40KD) (PEGASYS®) 180 µg/week and ribavirin (COPEGUS®) 1000 or 1200 mg/day in a large international, randomized, phase 3 trial.(Fried et al. N Engl J Med. 2002;347:975-982). In this study, 97% of patients without an early virological response (EVR), defined as either a ≥2-log10 drop in viral load or complete disappearance of HCV RNA in serum by 12 weeks of therapy, failed to achieve an SVR. This information is useful because it allows for the early termination of treatment in those unlikely to respond to a full course of treatment.

Purpose
To refine the ability to predict the likelihood of achieving a sustained virological response after treatment with peginterferon alfa-2a (40KD) and ribavirin, based on virological response data obtained at week 4 and week 12 of therapy

Methods
The dynamic model is based on data from patients treated with peginterferon alfa-2a (40KD) 180 µg/week and ribavirin 1000 or 1200 mg/day for 48 weeks in a large, international, randomized trial (Fried et al. N Engl J Med. 2002;347:975-982). For the purpose of this analysis, an early virological response (EVR) was defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL; COBAS AMPLICOR® HCV Test, v2.0; Roche Diagnostics) or a decrease of ≥2-log10 in HCV RNA levels as determined by quantitative PCR (COBAS AMPLICOR HCV MONITOR® Test, v2.0; Roche Diagnostics) after 12 weeks of treatment. For this analysis SVR was defined as a single undetectable HCV RNA level by qualitative PCR on or after week 60. Treatment was to be stopped in patients with detectable HCV RNA after 24 weeks.

Results
A total of 453 patients were randomized to treatment with peginterferon alfa-2a (40KD) and ribavirin and received study medication. The disposition of patients who were HCV RNA negative after 24 weeks of treatment is shown in the Table and grouped according to their HCV RNA status at week 4, 12 and 24. Patients with missing data at any of these time points were not included in the analysis. Patients with ≥2-log10 drop in HCV RNA levels at a given time point, and who were negative at the previous and following time point, were grouped with patients assessed as HCV RNA negative at that time point (n = 8). The probability of achieving an SVR increased in inverse proportion to the time taken to achieve undetectable HCV RNA levels. Thus, the highest SVR rate (89%) and, correspondingly, the lowest relapse rate during follow-up (8%), was obtained in patients who were consistently HCV RNA negative at weeks 4, 12 and 24.

Conclusions
The outcome of combination therapy with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) is highly dependent on the rapidity of the virological response. Patients who become HCV RNA negative after 4 weeks have the best chance for achieving an SVR. It may be hypothesized that to decrease the frequency of relapse in the remaining patients, treatment longer than 48 weeks may be required. This approach should be tested in a prospective trial.

HCV RNA Status

wk 4 wk 12 wk 24 N EOT
Resp n
SVR N (%) Relapse during follow-up n (%)
Neg Neg Neg 112 96 100 (89%) 7 (7%)
≥2-log drop Neg Neg 132 116 99 (75%) 24 (21%)
<2-log drop Neg Neg 24 21 18 (75%) 6 (29%)
≥2-log drop ≥2-log drop Neg 26 21 13 (50%) 9 (43%)
<2-log drop ≥2-log drop Neg 33 30 15 (45%) 15 (50%)

End of treatment response (EOT) = HCV RNA negative at week 48

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