EFFICACY OF INTERFERON (STANDARD OR PEGYLATED) PLUS RIBAVIRIN IN NAÏVE 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. Bourlière, J.P. Bronowicki, P. Merle, J.P. Zarski, C. Nicolas, K. Randl, G. Bommelaer, A. Abergel

Introduction

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 naïve 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 naïve 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.

EVALUATION OF DIFFERENT MORPHOLOGICAL CHARACTERISTICS OF LIVER FIBROSIS BY BLOOD MARKERS

P. Calès¹, F. Oberti¹, I. Fouchard-Hubert¹, S. Michalak², I. Valo², Y. Gallois³, Y. Tourmen³, G. Soulard¹, M.C. Rousselet², F. Lunel⁴, A. Chevailler⁵

¹Hepatology Unit, CHU, Angers, France
²Pathology Unit, CHU, Angers, France
³Biochemical Unit, CHU, Angers, France
⁴Virological Unit, CHU, Angers, France
⁵Immunological Unit, CHU, Angers, France

Introduction

The non-invasive diagnosis of liver fibrosis is an emerging issue. We have described a blood score for clinically significant fibrosis (CSF) (Gastro 1997;113:1609-16).

Aim

Our aim was to develop blood scores for the evaluation of different characteristics of fibrosis in viral and alcoholic chronic liver diseases (CLD).

Methods

598 consecutive patients with CLD and liver specimen (LS) were included whose. 478 patients with viral (n=383, CSF: 54.8%) or alcohol (n=95, CSF: 69.5%) CLD were evaluated in an exploratory phase. 120 patients with HCV CLD and LS>14mm (CSF: 47.5%) were selected in a validating phase. Blood measurements included either indirect markers: platelets (PLT), prothrombin index (PI), alkaline phosphatases (AP), bilirubin (BIL), apoA1 (APO) and albumine (ALB), or direct markers: alpha2macroglobulin (A2M), hyaluronic acid (HA). LS were evaluated with the Metavir score (consensus scoring by 2 pathologists), validated in alcoholic CLD (J Pathol 2003;201:55-62), and the area of fibrosis (J Hepatol 1998;28:439-46) and fractal dimension (an objective measure of architecture (Hepatology 2002;36:840-9), by image analysis. Scores were determined by binary logistic and linear regressions and their performances were expressed by the AUROC or adjusted R2 (aR2). Results. 1) The diagnosis of CSF was predicted in viral CLD by 7 variables (PLT, PI, AST, A2M, HA, urea, age) with AUROC: 0.883 vs 0.820 for Fibrotest (p=0.02). In validating phase, AUROC were 0.907 vs 0.857 for Fibrotest. In alcoholic CLD, the AUROC for CSF was 0.962 with 4 variables (PI, A2M, HA, age). 2) The area of fibrosis was estimated in viral CLD by 5 variables (HA, GGT, BIL, PTL, APO) with aR2: 0.645, and in alcoholic CLD by 4 variables (HA, PI, A2M, PTL) with aR2: 0.836. 3) The fractal dimension was predicted in viral and alcoholic CLD by 4 variables (HA, PI, A2M, ALB) with aR2: 0.662.

Conclusions

The 3 main morphological characteristics of liver fibrosis (pathological scoring, area of fibrosis, fractal dimension) can be estimated with a high accuracy by a combination of a few simple blood markers both in viral and alcoholic CLD. Our score is significantly superior to the reference test for pathological scoring in viral CLD.

DOES THE CLINICAL OUTCOME OF HEPATITIS C INFECTION VARY WITH THE INFECTING HEPATITIS C VIRUS TYPE?

H.E. Harris¹, K.P. Eldridge¹, C-G. Teo², S. Harbour², M.E.B. Ramsay¹

¹Immunisation Department, Centre for Infections, Health Protection Agency, London, UK
²Sexually Transmitted And Blood-Borne Virus Laboratory, Centre for Infections, Health Protection Agency, London, UK

Introduction

It is not known whether differences in the natural history of hepatitis C virus (HCV) can be explained by differences in the infecting genotype.

Aim

The aim of this study was to describe the prevalent genotypes in a national cohort of patients who acquired HCV infection at a known date and to investigate whether there was any evidence to suggest that the natural history of their infections might vary with the infecting type.

Methods

Data on clinical outcomes were extracted from the HCV National Register and mortality data were taken from death certification. Sera were available for 749 cases who had been enrolled in the UK HCV National Register. HCV RNA-positive specimens were genotyped and HCV RNA-negative specimens were serotyped. Logistic regression analysis was used to investigate the effect of HCV type on viral clearance and histological stage of liver disease. 444 of the sera were found to carry HCV RNA. The most prevalent HCV types were 1 (52%), 3 (29%) and 2 (16%). Of the 305 specimens found to be HCV RNA-negative, it was possible to serotype 160 of them; serotypes 1 (58%), 3 (24%) and 2 (13%) were the most common. There was no evidence of any association between viral type and: mortality, signs and symptoms of liver disease or histological grade of liver disease. A significant association was observed between viral type and response to treatment, with type 1 infections being associated with poor response to treatment when compared to types 2 or 3 (P=0.003). Viral type was independently associated with spontaneous viral clearance, with type 1 being more likely to clear spontaneously than non-1 types (OR 0.50, 95% CI 0.30–0.84, P= 0.009). Viral type was also independently associated with histological stage of liver disease, with type 1 being associated with stage scores above the median when compared to non-1 types (OR 2.03; 95% CI 1.07-3.83; P=0.03).

Results

The results of this study suggest that HCV type 1 infection is more likely to be associated with spontaneous clearance but is clinically more aggressive than type non-1 infection when it persists.

DOSE OPTIMIZATION AND SAFETY OF THE THERAPEUTIC HEPATITIS C VIRUS (HCV) PEPTIDE VACCINE IC41 IN HEALTHY SUBJECTS

C. Klade¹, E. Tauber¹, V. Buerger¹, S. Jelovcan¹, M. Buschle¹, J. Frisch¹, C. Firbas², B. Jilma²

¹Intercell AG, Vienna, Austria
²Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

Introduction

Induction of HCV-specific T-cells holds promise for therapy of patients not responding to or relapsing from standard therapy. Therapeutic vaccination with synthetic peptides and the novel synthetic T-cell adjuvant Poly-L-Arginine has been shown to induce interferon (IFN)-gamma secreting cytotoxic and helper T-cells. IC41 is a novel fully synthetic vaccine containing 5 peptides harbouring several cytotoxic (human lymphocytic antigen (HLA)-A*0201) and promiscuous T-helper epitopes of HCV.

Aim

The aim of this study was to compare the safety and efficacy of different doses of the vaccine and of different ratios of peptide to Poly-L-Arginine.

Methods

Healthy volunteers (n=128) were enrolled into a randomized, placebo controlled, single-blind, parallel group phase 1 study to determine the optimal dose for immunological T-cell response. Cryo-preserved peripheral blood mononuclear cells were used in IFN-gamma enzyme-linked immunospot (ELIspot), T-cell proliferation and HLA-tetramer assays. Safety assessments were local and systemic tolerability and routine laboratory parameters. IC41 was well tolerated and the local reactions were of transient nature and of mild to moderate degree. In terms of T-cell induction, IC41 induced significant responses in all peptide/Poly-L-Arginine groups, with higher responder rates (up to 75%) and more robust responses in higher dose groups. Poly-L-Arginine was required for induction of IFN-gamma secreting T-cells. With increasing number of vaccinations higher responder rates and more robust responses were found.

Conclusion

In conclusion, IC41 is a safe, well-tolerated fully synthetic therapeutic peptide vaccine capable of inducing both HCV specific IFN-gamma secreting cytotoxic and helper T-cells in humans.

SUCCESSFUL RETREATMENT OF INTERFERON / RIBAVIRIN NONRESPONDERS WITH DAILY DOSING OF CONSENSUS INTERFERON

S. Kaiser, H.G. Hass, M. Gregor

Department of Medicine I, University Hospital of Tuebingen, Tuebingen, Germany

Introduction

Retreatment of nonresponders with conventional interferon alfa and ribavirin leads to very low sustained response rates of only about 7%. These rates are not significantly changed with the use of pegylated interferons.

Aim

In the present study, the efficacy of CIFN daily dosing and induction therapy followed by ribavirin combination treatment in combination therapy nonresponders was evaluated. 182 patients (92% Genotype 1) were included.

Methods

Patients were either treated with CIFN at a dosage of 27, 18 or 9 ug for 4 weeks, followed by a reduced CIFN dosage by 9 ug in the two higher dosed arms for 8 weeks. The CIFN 9 ug arm remained unchanged. Thereafter, treatment was continued in all groups with CIFN at 9 ug QD with ribavirin at 10 - 15 mg/kg/d for another 36 weeks. Data show that after the initial 24 weeks of CIFN / ribavirin therapy a primary response was observed in 43 - 71%. The sustained virological response rates (SVR) were 38 – 45% for standard interferon / ribavirin nonresponders (n=121) and 27 – 31% for peginterferon / ribavirin (n=61) nonresponders. The CIFN dose had to be dose reduced in 16 - 21% of patients and discontinued in 7 - 9% of patients. The most common cause were reductions in WBC and platelet counts, especially in the 27 ug CIFN group, while no growth factors were used in this study. The overall tolerability of the CIFN 9 and 18 ug regimen were of comparable tolerability to a standard therapy with pegylated interferon and ribavirin, while the CIFN 27/18/9 ug regimen was less tolerable during the high dose induction period. However, drop out rates were not different between the dosing regimen.

Conclusion

It is concluded, that CIFN daily dosing / induction therapy together with subsequent ribavirin combination therapy shows promising response rates in previous combination therapy non-responders including nonreponders to standard as well as peginterferons. Although a significant proportion of patients experienced a relapse after cessation of therapy, the overall sustained response rates are nevertheless promising. It is concluded that CIFN may be an effective treatment modality for this difficult-to-treat patient group.

ARE CURRENT FIBROSIS SERUM MARKERS REALLY AN ALTERNATIVE TO LIVER BIOPSY IN CHRONIC HEPATITIS C?

V. Leroy^1,2, M.N. Hilleret¹, N. Sturm³, C. Trocme⁴, J.C. Renversez⁵, P. Faure⁵, F. Morel⁴, J.P. Zarski^1,2

¹Département D'hépato-Gastroentérologie, CHU Grenoble, Grenoble, France
²Inserm U548, CEA, Grenoble, France
³Département D'anatomie-Pathologie et Histologie, Grenoble, France
⁴Laboratoire D'enzymologie, DBPC, GREPI EA 2938, Grenoble, France
⁵Laboratoire de Biochimie, DBI, Grenoble, France

Introduction

We recently described a score of fibrosis combining PIIINP and MMP-1, which are involved in fibrogenesis and fibrolysis respectively.

Aim

The aim of this study was to evaluate its diagnostic accuracy compared to that of a panel of other markers including prothrombin time (PT), hyaluronate (HA), Fibrotest (FT), APRI and Forns’ score in chronic hepatitis C (CHC) patients Methods:

Methods

One hundred and eighty CHC patients seen in our centre for a pre-therapeutic liver biopsy were prospectively included. Liver fibrosis was assessed using the METAVIR index. Sinusoidal fibrosis, steatosis and iron load were quantified. Biochemical measurements were performed on serums collected the day of the biopsy.

Results

Median length of liver biopsies was 22 mm. Patients were classified as F0:n=15, F1:n=74, F2:n=40, F3:n=26, F4:n=24. Overall diagnostic accuracy of the 4 combined scores was better than that observed with PT and HA alone. AUROC ranged from 0.79 to 0.84 for discriminating F0/F1 vs F2/F3/F4 and from 0.81 to 0.88 for discriminating F0/F1/F2 vs F3/F4 (NS). Accuracy was not altered by the length of biopsies or by the presence of sinusoidal fibrosis, steatosis or iron in liver. Applying the lower cut-off described for each score, METAVIR fibrosis greater than F1 could be ruled out in about one third of patients with NPV ranging from 82 to 84%. The higher cut-off selected about 20% of patients whom extensive fibrosis (F3F4) was confirmed with a PPV ranging from 89 to 93%. Simultaneous use of at least 2 scores improved NPV up to 100% for the diagnosis of F0F1, but decreased the number of selected patients. Commercial application of FT proposes an estimated fibrosis METAVIR. Discordances of at least 1 point were observed in 52% and of 2 points in 22% of patients. The only parameter associated with discordance was FT between 0.20 and 0.80.

Conclusion

Our results confirm that PIIINP/MMP-1 provides relevant information on liver fibrosis with a good accuracy, comparable to that observed with FT, APRI and Forns’ score. However none of these scores can reliably give and estimated METAVIR index in each patient. Combination of several scores could improve their accuracy.

SAFETY AND EFFICACY OF ANTIVIRAL THERAPY IN PATIENTS WITH DECOMPENSATED CIRRHOSIS ASSOCIATED WITH CHRONIC HEPATITIS C INFECTION

J.K. Lim¹, J.C. Imperial^1,2

¹Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford CA, USA
²Department of Medicine, San Mateo Medical Center, San Mateo CA, USA

BACKGROUND/AIMS

Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the U.S. Although interferon-based regimens are frequently used in compensated cirrhosis, the role of antiviral therapy in the treatment of patients with decompensated cirrhosis remains poorly defined.

METHODS

We evaluated the safety and efficacy of antiviral therapy in 32 patients with decompensated HCV cirrhosis. At the time of inclusion, 25.0% of patients were Child-Pugh A, 59.4% were Child-Pugh B, and 15.6% were Child-Pugh C, with a mean Child-Pugh score of 8.03 +/- 1.75 (95% CI 7.40-8.66). Most patients were white (87.5%) and male (74.2%), with a mean age of 54.9 +/- 7.2 years (95% CI 52.28-57.47) and mean weight of 92.2 +/- 24.4 kg (95% CI 83.41-101.0). Thrombocytopenia (90.6%), fluid retention (62.5%), esophageal varices (46.9%), and hepatic encephalopathy (21.9%) were the most common decompensation events. All patients underwent an intensive pretreatment regimen to optimize hepatic function prior to antiviral therapy (e.g. eradication of varices, resolution of ascites), and were monitored closely throughout therapy within a major university transplant program. Patients were treated with pegylated interferon/ribavirin (78.1%), pegylated interferon monotherapy (12.5%), or interferon/ribavirin (9.4%), for a mean of 37.8 +/- 17.1 weeks (95% CI 31.55-44.13).

RESULTS

Sustained virologic response (SVR) was achieved in 10/32 patients (31.3%), including 21.1% in genotype 1 and 53.8% in non-genotype 1 patients. Normalization of ALT was achieved in 40.6% of patients. The mean CTP score following end-of-treatment was 6.06 +/- 1.22 (95% CI 5.62-6.50). Most patients (84.4%) experienced adverse events; six (18.8%) required withdrawal of antiviral therapy, and one (3.1%) experienced liver decompensation. Anemia requiring erythropoietin support (50.0%), neutropenia requiring G-CSF support (15.6%), depression (18.8%), and infections (9.4%) were the most common adverse events. Five patients (15.6%) were removed from transplant listing due to clinical improvement. No patients died during treatment.

CONCLUSION

Antiviral therapy appears to be safe and effective in carefully selected patients with decompensated cirrhosis associated with chronic HCV infection. Treatment may result in SVR in nearly one-third of patients, and lead to improvements in biochemical markers and liver synthetic function.

ABSORPTION, METABOLISM AND EXCRETION OF [14C]VIRAMIDINE IN HUMAN

C-C. Lin, C. Xu, N. Zhu, L-T. Yeh

Drug Development, Valeant Pharmaceuticals International, Costa Mesa CA, USA

Background:

The combination of ribavirin and pegylated interferon-alfa is the standard treatment for chronic hepatitis C. However ribavirin may cause hemolytic anemia. Viramidine is a prodrug of ribavirin with excellent liver-targeting properties in monkeys. Improved safety has also been shown with viramidine in a one-month toxicity study in monkeys. Aim: To evaluate absorption, metabolism and excretion of [14C]viramidine in humans following a single oral administration.

Methods Six healthy adult male subjects >= 50 years of age participated in the study. Following an overnight fast, each volunteer received a single oral dose of [14C]viramidine given as three 200 mg capsules with a total radioactivity of 52.2 microcuries. Plasma, red blood cell (RBC), urine and fecal samples were collected and analyzed for radioactivity. Plasma levels of viramidine and ribavirin were determined by a validated LC-MS/MS method. A HPLC procedure was used to evaluate the metabolic profile in urine.

Results

Viramidine was rapidly absorbed and extensively converted to ribavirin with a Tmax of 1.5, 2 and 3.5 hours for viramidine in plasma, ribavirin in plasma and total radioactivity in plasma, respectively. Viramidine and ribavirin accounted for only 5.5% and 59% of plasma AUC radioactivity, respectively, indicating extensive conversion of viramidine to ribavirin, followed by further metabolism of ribavirin. The drug was largely trapped in RBCs with a RBC to plasma radioactivity AUC ratio of 82.5. Viramidine and ribavirin accounted for 1.0% and 99% of RBC AUC radioactivity, respectively. Excretion of total radioactivity in urine and feces accounted for 50.9% and 26.1% of the dose, respectively. The amount of unchanged viramidine (3.4% of dose) and ribavirin (10% of dose) in urine was small after oral administration of viramidine (0-336h). Urine metabolic profile (0-24h) indicated viramidine was excreted in urine, primarily as TCONH2 (64.1%), TCOOH (17.0%) and ribavirin (15.7%) with a small amount of unchanged viramidine (3.2%).

Conclusions

In humans, following oral dosing, viramidine was rapidly absorbed and extensively converted to ribavirin, followed by further metabolism. Ribavirin was largely trapped in RBC and excreted primarily into urine as TCONH2 with smaller amounts as TCOOH, ribavirin and viramidine.

ASSOCIATION BETWEEN DIABETES, OVERWEIGHT, OBESITY AND DYSLIPIDEMIA WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS C PATIENTS

A. Loaeza-del Castillo¹, F. Vargas-Vorácková²

¹Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición,
²Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición,

Introduction

Fibrosis progression in chronic hepatitis C (CHC) patients is variable, factors associated with an accelerated progression have been identified, but they do not account for the heterogeneity seen between individuals.

Aim

To determine the prevalence of diabetes, overweight, obesity and dyslipidemia in CHC patients and the association of these metabolic factors with liver fibrosis progression.

Method

Patients with CHC seen in our institution between 1993 and 2003 were retrospectively studied (n=1618). Patients with a known duration of infection acquired by transfusion with a liver biopsy performed before any antiviral treatment were included. Patients with overt hepatic insufficiency were excluded. The diagnoses of diabetes, overweight, obesity and dyslipidemia were investigated and liver fibrosis stage (METAVIR). Variables were tested for their association with significant fibrosis (F2, F3, F4).

Results

108 patients were included, 71 (66%) female and 37 (34%) male, mean age was 48.7 + 12.2 years. Age at infection was 24.7 +/- 13 years, acquired between 1944-2000. 78% were HCV-genotype 1. Fibrosis stage was: F0=15 (14%), F1=38 (35%), F2=9 (8%), F3=8 (8%) and F4=38 (35%). Mean fibrosis progression rate was 0.106 +/- 0.101 (0 – 0.44). 26 patients (24%) had diabetes, 10 (9%) glucose intolerance, 24 (22%) obesity (body mass index (BMI) >/= 30 kg/m2) and 49 (45%) overweight (BMI >/= 25 < 30 kg/m2). Dyslipidemia was investigated in 75 patients and confirmed in 25 (33.3%). Association between these variables and fibrosis is depicted in the table.

Conclusions

Diabetes is a factor strongly associated with advanced fibrosis and cirrhosis. In populations with a high prevalence of diabetes, such as Hispanics, this association must be taken into account. Lipid metabolism has a specific role in the pathogenesis of CHC and the possible protector role of dyslipidemia for significant liver fibrosis should be investigated in further studies.

IS DELIVERY MODE RELATED TO PERINATAL TRANSMISSION OF HEPATITIS C VIRUS (HCV)

E. Mariné- Barjoan¹, A. Bongain², A. Berrébi³, C. Laffont⁴, V. Triolo⁵, H. Haas⁵, F. Monpoux⁵, J. Izopet⁶, J. Tricoire⁷, E. Mazurier⁸, J. Ducos⁹, C. Pradier¹⁰, A. Tran¹

¹Hépatogastroentérologie, CHU, Nice, France, ²Gynécologie Obstétrique, CHU, Nice, France, ³Gynécologie Obstétrique, CHU, Toulouse, France,⁴Virologie, CHU, Nice, France,⁵ Pédiatrie.CHU, Nice, France, ⁶Virologie. CHU Toulouse. France, ⁷Pédiatrie, CHU, Toulouse, France ⁸Pédiatrie, CHU, Montpellier, France ⁹Virologie, CHU, Montpellier, France ¹⁰Santé Publique, CHU, Nice, France

Objective

To analyse factors related to perinatal HCV transmission.

Methods

Multi-centre prospective study conducted in HCV-positive mothers in Southern France (Alpes-Maritimes, Haute-Garonne, Hérault) between October 1998 and September 2002. Mothers´and children´s clinical, HCV/HIV virological characteristics and mode of delivery were recorded. All babies were controlled at M3 by PCR-RNA. They were considered infected if the HCV-RNA was positive with the same genotype as the mother’s.

Results

The analysis was conducted in 240 children. HCV-RNA was positive in 136 mothers and 26% were HIV-positive. Eighty children were delivered by caesarian section, 80% before onset of labour. In 63% of cases membranes were intact. Fifty-six percent of these were elective caesarian sections. Twelve children were HCV-infected (5.6%) at 12 months’ follow-up, among whom 3 HCV-RNA became negative at 18 months. Their mothers all had positive HCV-RNA at the time of delivery. Rate of transmission was significantly higher among HIV/HCV co-infected mothers compared with HCV-infected mothers (11.0% versus 3.8 %; p=0.05). None of the children were HIV-infected. There was no statistically significant association between HCV transmission and mode of delivery (5 contaminated children among 45 deliveries by elective caesarian (11%) versus 7 contaminated children born by vaginal delivery (4%), timing of caesarian section and condition of the membranes. Among HCV-RNA positive mothers, the risk of HCV transmission was significantly higher for women with a high viral load (median 5.99 log copies/ml versus 5.68 log copies/ml, p< 0,008). After adjusting for study centre, the risk was higher among HIV-positive women (OR aj: 4.6 95%CI 1.006-21.734).

Conclusions

A high HCV viral load at the time of delivery and HIV co-infection are the main risk factors for perinatal transmission of HCV. Caesarian section, whether elective or not, is not associated with a lower risk of HCV transmission. Spontaneous resolution of viral RNA is possible in children. . We are grateful to Nice University Hospital, the French National Agency for AIDS Research, and the Fondation de France

ACCURATE MODELS PREDICTING RESPONSE TO PEGYLATED INTERFERON WITH RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C AS EARLY AS WEEK 4

M. Martinot-Peignoux¹, L. Comanor², J.M. Minor³, M.P. Ripault¹, N. Boyer¹, C. Castelnau¹, N. Giuily¹, P. Marcellin¹

¹INSERM U-481 and Service D'Hépatologie, Clichy, France, ²Independent Research Consultant, Palo Alto CA, USA ,³Agilent Technologies, Inc., Santa Clara CA, USA

Background

Current models used to predict response to peginterferon plus ribavirin treatment, based on viral decline during the first 12 weeks of therapy, have focused on creating an early stopping rule to avoid unnecessary prolongation of therapy.

Methods

We developed a multivariate model that predicted sustained virological response (SVR) and non-response (NR) at baseline, and during the first 12 weeks of therapy using collected data from 186 unselected patients with chronic hepatitis C treated with peginterferon plus ribavirin. These models employed ordinal regression with similarity least squares technology to assign the probability of a given outcome. Model variables included sex, age, prior treatment status, genotype, baseline serum alanine aminotransferase levels, histologic necroinflammation and fibrosis scores and serum hepatitis C virus RNA concentration at baseline, weeks, 4, 8, and 12.

Results

Multivariate models demonstrated high performance values at all time points. The multivariate baseline model demonstrated negative predictive value (NPV) and positive predictive value (PPV) of 91% and 95%, respectively and for the week 4 model these values had improved to 97% and 100%, respectively with 95% sensitivity, 89% specificity and 93% accuracy. The week 4 model was equally efficient for naive or previously treated patients. Its internal validation demonstrated 90% PPV, 94% NPV, 95% sensitivity, 88% specificity and 92% accuracy.

Conclusion

A week 4 stopping rule for patients with chronic hepatitis C treated with Pegylated Interferon with Ribavirin might be proposed by using the model developed in our study.

INSULIN RESISTANCE IS ASSOCIATED WITH HEPATIC STEATOSIS, BODY MASS INDEX AND OXIDATIVE STRESS SERUM MARKERS IN NON-3 GENOTYPE CHRONIC HEPATITIS C INFECTION

A.C. Oliveira¹, A.L. Salgado¹, M.M.B. Leite-Mor¹, R.M. Catarino¹, K. Giavarotti², V.B. Junqueira², E.R. Parise¹

¹Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, Brazil
²Disciplina de Geriatria, Universidade Federal de São Paulo, São Paulo, Brazil

Background

Recent evidences suggest that insulin resistance (IR) is associated with fatty liver and fibrosis progression in patients with chronic hepatitis C (CHC). The exact mechanisms by wich IR can contribute to this fibrotic response remains to be elucitated.

Aim

To correlate insulin resistance (IR) with demographic, biochemical, and hystological findings and serum parameters of oxidative stress in non 3 genotype CHC.

Patients and Methods

150 subjects with detectable HCV-RNA were submitted to liver biopsy. Fibrotic and inflammatory findings were scored according to Knodell et al. The genotype of the HCV-RNA was identified through restriction analysis of the amplified sequences of the non-coding 5’ region. Insulin and C-peptide concentrations were assayed by immunofluorimetry (Perkin Elmer BR-CS). IR index were calculated by the homeostasis model assesment (HOMA-IR). Patients with concurrent HBV/HIV infections and alcohol intake>20g/day were excluded from the study. In 60 CHC patients, with non 3 genotype, blood samples were also tested for determination of serum ferritin, glutathione and malondialdehyde (MDA) by enzymatic and colorimetric methods, serum vitamin E, licopen and b-caroten by HPLC, leptin serum levels by an immunofluorimetric assay.

Results

HOMA-IR values were significantly higher in CHC patients with non 3 genotypes (n=105) than those with genotype 3 (n=45), (3.57+0.27 x 2.35+0.20, mean+SEM, respectively, p=0,001) and in non 3 genotype patients with (n= 59) than without (46) hepatic steatosis (4.30+0.39 x 2.44+0.27, p<0,001). Among the 60 non 3 genotype patients, there was a significative correlation (p<0.05) of HOMA-IR values with BMI (rs=0.511), hepatic staging (rs= 0.463) and inflammatory Knodell index (rs=0.331), with C-peptide (rs=0.783), serum MDA (rs=0.416) and glutathione (rs=-0.387). No significant correlation were found for HOMA and serum leptin levels even when leptin was corrected by BMI. Multiple regression analysis identified BMI and MDA as independent predictors for insulin resistance in this population.

Conclusion

In these patients with CHC with non-3 genotype, insulin resistance is related to liver steatosis and independently associated with BMI and serum markers of oxidative stress. Acknowledgment: Research supported by FAPESP (02/05260-6)

NO CORRELATION BETWEEN FAT LIVER ACCUMULATION AND LIVER FIBROSIS IN GENOTYPE 1B HCV RELATED CHRONIC LIVER DISEASE

M. Persico¹, B. Palmentieri¹, I. de Sio³, G.B. Gaeta², V. La Mura¹, E. Persico¹, F. Carrino¹, C. Marzocchella¹, R. Torella¹

¹Internal Medicine and Hepatology Unit, Naples, Italy,²Unit of Infectious Disease,³ Gastroenterology Unit

Introduction

It is general belief to consider liver steatosis as a risk factor of chronic liver disease. Moreover steatosis is considered in HCV related chronic active hepatitis (CAH) an adjunctive factor of progression and evolution of liver disease. In particular, steatosis seems specifically related to the course of the disease in genotype 3a patients with CAH.

Aim

The aim of this study was to test the role of steatosis on liver damage (fibrosis) in a consecutive case-study of genotype 1b patients undergone to liver biopsy because of increase of serum ALT.

Patients and Result:

180 patients ( sex: M98/F82; median age: 51 range 17 - 68) underwent to ultrasound examination and liver biopsy. Based on liver histology patients were divided according to steatosis in four classes: 1 (no steatosis), 2 (steatosis < 30%), 3 (steatosis 30 – 50 %), 4 (steatosis > 50 %). Histological Activity Index (HAI) was evaluated according to ISHAK’ s score. Median fibrosis value was S 2 (ranging 0 – 6; 23 patients showed liver cirrhosis) in all the 4 classes and no statistical significance was found between groups. Virological and epidemiologic characteristics, biochemical data, BMI, Apparent Duration of Disease (ADD) of all patients were recorded and statistical correlation checked. A univariate and multivariate analysis vs fibrosis were performed in all the patients and tested statistically significant only for age, ADD, diabetes and ALT (p< 0.00), but non for steatosis.

Conclusion

Steatosis does not seem to be an independent adjunctive risk factor of liver disease progression in CAH/genotype 1b HCV infected patients and age, ADD, diabetes and increase of ALT seem to be the only independent factors associated to liver fibrosis progression.

BIOCHEMICAL MARKERS OF LIVER FIBROSIS AND ACTIVITY IN PATIENTS WITH CHRONIC HEPATITIS C AND MIXED CRYOGLOBULINEMIA SYSTEMIC VASCULITIS

D. Sène¹, D. Messous², P. Ghillani-Dalbin³, F. Charlotte⁴, A. Piton², N. Limal¹, J-C. Piette¹, F. Imbert-Bismut², T. Poynard⁵, P. Cacoub¹

¹Internal Medicine Deprtment, La Pitié-Salpêtrière Hospital, Paris, France,²Biochemistry Department, La Pitié-Salpêtrière Hospital, Paris, France,³Immunochemistry Department, La Pitié-Salpêtrière Hospital, Paris, France,⁴Pathology Department, La Pitié-Salpêtrière Hospital, Paris, France,⁵Hepatogastroenterology Department, La Pitié-Salpêtrière Hospital, Paris, France

Objective

To assess the reliability of Fibrotest-Actitest (FT-AT) and other biochemical scoring indexes [Forns, APRI, Age-Platelet, Platelet, hyaluronic acid (HA)] for the diagnosis of significant liver fibrosis in HCV-infected patients with mixed cryoglobulinemia systemic vasculitis or non septic serum inflammation.

Methods

138 HCV-infected patients (50% males, mean age 5717 years). Liver biopsy (LB) was analysed using the Metavir scoring system. FT-AT (alpha2-macroglobulin, apolipoprotein A1, haptoglobin, gamma-GT, and total bilirubin, plus ALT for AT), Forns, APRI (AST/platelet ratio), Age-Platelet, Platelet and HA indexes were calculated according to respective authors recommandations. Serum inflammation was defined as C reactive protein ≥10mg/L, Orosomucoïd ≥150%, Haptoglobin ≥150% upper limit of normal value or fibrinogen ≥4.5g/L. Systemic vasculitis was defined by the presence of skin purpura, rheumatological, neurological or renal involvements. The diagnostic value of fibrosis scoring indexes was assessed by the area under the ROC curves (AUC). The main end-point was the identification of patients with significant fibrosis (Metavir F2F3F4).

Results

36/138 (26%) patients had systemic vasculitis and 37 (27%) serum inflammation. On LB a significant fibrosis (F2F3F4) was found in 47% of patients. The LB size was ≥25mm in 20% of patients and 13% fulfilled the Regev’s criteria for a good quality biopsy. 1) The diagnostic value of FT (F2F3F4 vs F0F1) was assessed by: AUC (SE) 0.83(0.03), without difference between patients with and those without systemic vasculitis (0.81 vs 0.84; p=0.7), or between patients with and those without serum inflammation (0.91 vs 0.79; p=0.2). 2) Discordances ≥2 points between FT-AT and Metavir scoring indexes, evidenced in 29% of patients, were associated with serum haemolysis (OR=7.9), male sex (0R=2.4) and advanced age (OR=1.04) but not with the presence of a systemic vasculitis or serum inflammation. 3) Although the accuracy of other non invasive scoring indexes was not influenced by the presence of serum inflammation or systemic vasculitis, FT showed a higher reliability for the diagnosis of significant fibrosis (p<0.05).

Conclusion

FT-AT scoring index is a reliable biochemical non-invasive alternative to liver biopsy in HCV-infected patients with systemic vasculitis or serum inflammation. The exclusion of a serum haemolysis seems mandatory to approach a greater accuracy.

CLUSTERING OF POOR PROGNOSTIC FACTORS IN PATIENTS WITH CHRONIC HEPATITIS C

M. Swain¹, G.R. Foster², M.W. Fried³, S.J. Hadziyannis⁴, E.J. Heathcote⁵, D. Jensen⁶, S.S. Lee¹, P.J. Pockros⁷, M. Sulkowski⁸, C. Trepo⁹

¹University of Calgary, Calgary AB, Canada, ²Digestive Disease Research Centre, QMUL, London, UK, ³University of North Carolina, Chapel Hill NC, USA, ⁴Henry Dunant Hospital, Athens, Greece, ⁵University of Toronto, Toronto ON, Canada, ⁶Rush University Medical Center, Chicago IL, USA, ⁷The Scripps Clinic, La Jolla CA, USA, ⁸Johns Hopkins University, Baltimore MD, USA, ⁹Hopital de L'Hotel-Dieu, Lyon, France

Introduction

Body weight is a modifiable factor that influences the outcome of interferon-based therapy for chronic hepatitis C. Sustained virological response (SVR) rates tend to decrease as body weight increases. The mechanism whereby body weight affects the response to treatment is not completely understood, but is likely to be multifactorial. We assessed the complex relationship between body weight and a range of baseline host- and hepatitis C virus (HCV)-related factors that influence the outcome of interferon-based therapy.

Methods

Baseline data from two multinational, randomized, controlled phase III studies assessing the efficacy and safety of peg-IFNα-2a (40KD)/ribavirin for the treatment of hepatitis C were combined (NEJM 2002;347:975; Ann Intern Med 2004;140:346). Patients were classified into 3 groups: <65 kg, 65–<85 kg, and ≥85 kg. Baseline patient- and HCV-related characteristics were analyzed according to body weight.

Results(table): Data from a total of 2404 patients were included in the analysis. Body weight was positively correlated with body mass index (BMI), the proportion of male patients, the proportion of black patients, those reported to have acquired HCV through intravenous drug use (IVDU), and with a histological diagnosis of cirrhosis. A greater proportion of patients infected with HCV genotype 1 were in the highest weight group (≥85 kg) than in the other lower weight groups, although this was not statistically significant. There was no apparent correlation between body weight and ALT levels.

Conclusions

Body weight has a complex relationship with a range of patient- and disease-related characteristics. In general, patients in the highest weight group were much more likely to be male, black, to have cirrhosis and to have been infected through IVDU. This clustering of poor prognostic characteristics may explain the lower SVR rates observed in heavier patients.

AWARENESS OF HEALTH CARE STAFF, HCV INFECTED PATIENTS AND HOUSEHOLD CONTACTS OF HCV TRANSMISSION ROUTES

A. Tiftikci¹, D. Zeytinoglu², S. Sagnic², S. Taneroglu², I. Arer², N. Bekiroglu³, V. Tahan¹, N. Tozun¹

¹Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
²Junior Medical Student, Marmara University School of Medicine, Istanbul, Turkey
³Department of Biostatistics, Marmara University School of Medicine, Istanbul, Turkey

Background&Aims

The worldwide seroprevalence of HCV infection is around 3%. Chronic hepatitis develops in approximately 85% of infected patients. Since there is no effective vaccine or post-exposure prophylaxis against HCV, emphasis should be given on counseling and public awareness on HCV transmission routes. Our aim was to study the awareness about HCV transmission routes among health care staff (HCstaff), HCpatients and their household- contacts.

Materials&Methods

A reliable and valid self-report inquiry consisting of 28 questions was completed by 397 HCstaff (75 first year, 75 last year medical students, 89 dentists, 71 pharmacists, 87 nurses), 68 HCpatients and 62 household-contacts. All subjects were asked about various modes of transmission of HCV.Statistical package SPSS (version 11,0) was used for all statistical analysis.

Results:

Ninety-seven percent of the HCstaff,85% of HCV patients and 85 % of household contacts were aware of the parenteral transmission of HCV. Ninety percent of HCstaff, 85% of HCV patients and 90% of household contacts admitted sexual transmission with significant difference between subgroups in HCstaff (p<0,05). Sharing personal items such as toothbrushes, razors and nail scissors were considered as risk factors for transmission by 94.4% HCstaff, 51% of HCV patients and 71% of household contacts. Using the same toilet, skin contact and sharing clothes were considered hazardous by 26%, 18% and 14% of the HCstaff, respectively. •Skin contact and using the same toilet were considered as risk factors by 30% and 42% of the HCpatients and by 35% and 50% of the household-contacts respectively.

Conclusions

Awareness of HCV transmission routes and mistaken believes regarding risks for transmission showed significant differences among all groups and HCstaff subgroups. Transmission by blood and blood products was better recognized in all groups tested.Sexual route was accepted as an important risk factor by HCstaff apart from 15% of first year medical students. Other means of transmission were either overestimated (skin contact, sharing toilet, clothes) or under recognized (sharing of blood contaminated personal items) especially by the patients and their household contacts. More vigorous education programs are needed regarding awareness of HCV in various risk groups.

THE VIROLOGIC AND HISTOLOGIC STATUS IN ANTI-HCV+VE SUBJECTS WITH NORMAL ALT LEVELS: RESULTS OF A TEN-YEAR PROSPECTIVE FOLLOW-UP STUDY

C. Vandelli¹, F. Renzo¹, M. Vandelli¹, A. Bagni², M. Ponz de Leon¹

¹Dipartimento di Medicine e Specialità Mediche, Modena-Reggio Emilia University, Modena, Italy, ²Anatomia Patologica, Policlinico, Modena, Italy

Background

The natural history of patients (pts) HCVAb+ve and normal ALT (nALT) is not well defined.

Aim

The aims of our investigation were: to assess the presence of viral replication in subjects HCVAb+ve with nALT and the relationship between viremia, nALT, histologic liver damage; to characterize its natural history in ten years follow-up study. 207 subjects (mean age 49.7 ± 11.6 ys) were selected based on their anti HCV positivity and normality of ALT value. They were enrolled into the study and observed for 10 years. Normal ALT values were defined as £ 30 IU obtained at serial monthly evaluation during 6 months. These data were obtained at 0, 5 and 10 years. ALT value was also collected four times every year during the study. HCV RNA was detected by PCR yearly. Liver histology was examined in all pts at baseline and in 75% of the cases at the end of the study. 189 pts were HCV RNA+ve at baseline, 23 tested HCV RNA-ve at the end of follow-up. Mean viral load was 1.320.500 IU/ml. 101 (48.8%) pts had persistently nALT values; in 106 (21.2%) sporadic ALT elevations of 2-3xUNL occurred. The majority of pts was infected by genotype 1. At baseline, liver histology showed no lesions in 1.4% of pts, minimal changes in 24.2%, chronic moderate hepatitis in 40.6%, severe hepatitis with or without cirrhosis in 33.8%. In 96.3% of pts with nALT value a variable degree of grading and staging was observed. Of 101 pts with nALT, 5 had ALT elevations after 5 years follow-up. 72/96 pts with persistently nALT underwent to a 2nd liver biopsy. A deterioration of liver histology was detected in 15 pts (20.83%). Most patients remained asymptomatic. The majority of anti HCV+ve pts with nALT is HCV-RNA+ve; persistently nALT is observed in 45.4%. Despite absence of biochemical abnormality, liver histology worsened in 20.8% of anti HCV+ve pts with persistently nALT, with some showing significant fibrosis. Neither serum HCV-RNA nor ALT level can reliably predict activity or degree of fibrosis, therefore, more sensitive tests for diagnosis of liver damage in anti-HCV+ve pts are required.

STEATOSIS DOES NOT AFFECT THE RESULT OF ANTIVIRAL TREATMENT IN HCV GENOTYPE 3 INFECTED PATIENTS

J. Westin¹, L.M. Lagging², A.P. Dhillon³, K. Hellstrand², G. Norkrans¹, A. Romero², J-M. Pawlotsky⁴, S. Zeuzem⁵, S.W. Schalm⁶, E. Verheij-Hart⁶, F. Negro⁸, G. Missale⁹, A.U. Neumann⁷

¹Department of Infectious Diseases, Sahlgrenska University Hospital, Göteborg, Sweden, ²Department of Clinical Virology, Sahlgrenska University Hospital, Göteborg, Sweden, ³Department of Histopathology, Royal Free Hospital, London, UK , ⁴Hopital Henri Mondor, Universite Paris XII, Creteil, France, ⁵Saarland University Hospital, Homburg/Saar, Germany
⁶University Hospital Rotterdam Dijkzigt, Rotterdam, The Netherlands , ⁷Bar-Ilan University, Ramat Gan, Israel, ⁸Hospital University of Geneve, Geneve, Switzerland , ⁹Azienda Ospedaliera di Parma, Parma, Italy

Background and aims

Liver steatosis in chronic hepatitis C is associated with genotype 3 infection as well as overweight and accelerates liver fibrosis development. Recently published data suggest that genotype 3 is more difficult to treat than genotype 2, possibly due to the high prealence of steatosis in this group. The aim of this study was to investigate the influence of steatosis according to HCV genotype on the outcome of antiviral treament.

Methods

272 interferon naïve patients with chronic hepatitis C (genotype 1-5) viral infection underwent therapy with Peginterferon alfa-2a (40KD) in combination with ribavirin in accordance with the DITTO-HCV multi-center trial. 231 of these patients had a liver biopsy that could be evaluated centrally in a blinded fashion by two independent observers according to the Ishak protocol. Steatosis was scored as absent, mild (< 30% of the hepatocytes involved), moderate (30-70%) or severe (> 70%). Equivocal issues were debated after the independent scores were noted, and a consensus score was obtained. HCV-RNA levels were determined centrally using the Roche AMPLICOR HCV Test.

Results

Steatosis was present in 83/185 (45%) genotype non-3 and in 42/46 (91%) genotype 3 patients. In the genotype non-3 group, steatosis was associated with BMI (p<0.0001), age (p=0.001), serum-cholesterol (p=0.003) and serum-triglycerides (p=0.003). Among the genotype 3-infected patients, steatosis was associated only with baseline viral load (p=0.01), although the number of patients without steatosis was small which may have affected the analysis. Sustained virologic response (SVR) was achieved in 66/102 (65%) of the genotype non-3-patients without and in 38/83 (46%) patients with steatosis (p=0.01). All 4 patients with genotype 3 without steatosis reached SVR compared with 37/42 (88%) with steatosis. A high BMI was associated with absence of SVR in genotype non-3 (p=0.01).

Conclusion

Presence of steatosis did not affect the outcome of antiviral treatment in genotype 3-infected patients despite the high baseline viral load in patients with steatosis. In genotype non-3 patients, however, lack of SVR was associated with steatosis as well as a high BMI.

SLOW FIBROTIC PROGRESS IN A HEPATITIS C GENOTYPE 1B SINGLE SOURCE OUTBREAK IN GERMANY - A 25 YEARS MULTICENTER STUDY

M. Wiese^{1, 3}, I. Schiefke^{2, 3}

¹Dpt. Hepatology, Hospital St. Georg, Leipzig, Germany, ²2. Clinic Internal Med., University of Leipzig, Leipzig, Germany, ³For The East German Hepatitis C Study Group

Introduction

The cohort of German women infected with hepatitis C virus (HCV) genotype 1b via contaminated anti-D immunoglobulin in 1978 /79 represent a unique homogenous group to investigate the natural course of HCV infection. Studies of HCV lb infection with a high rate of cirrhosis face studies that showed slow progression of fibrosis.

Methods

In our study the natural course of a defined HCV 1b infection (from August 1978 until March 1979) due to HCV contaminated anti-D immuneglobulin was analysed in a representative random sample (n = 1980) over 25 years.

Results

After 25 years, 1573/1980 (79%) of the affected women still tested positive for anti-HCV and 46% for HCV RNA. HCV RNA positive patients had a significant higher histological staging than those without HCV RNA in serum (p=0.001). Rates of fibrosis progression differ markedly between HCV RNA status. In addition, pegylated interferon and ribavirin therapy non-responder had a higher staging compared with sustained responders (p=0.004). There was an steadily accrual of fibrosis between 15th - 20th year and the 20th –25th year of infection. Repeated biopsy (interval >5 years) showed only minor changes in histologic signs of fibrosis – 6/100 (6%) decreased by 1 stage, 55/100 (55%) of paired biopsies remained unchanged and 21/100 (21%) had only a minor increase in fibrotic changes (+1 stage).

Conclusions

In this well characterized group of patients with identical HCV 1b infection virus the degree of fibrosis is usually mild 25 years after infection. In 0,5% a cirrhosis was found. The risk of progression to cirrhosis is low. Fibrotic changes depends on the response to antiviral therapy.

PHARMACOKINETICS AND PHARMACODYNAMICS OF VALOPICITABINE (NM283), A NEW NUCLEOSIDE HCV POLYMERASE INHIBITOR: RESULTS FROM A PHASE I/II DOSE-ESCALATION TRIAL IN PATIENTS WITH HCV-1 INFECTION

X.J. Zhou¹, N. Afdhal², E. Godofsky³, J. Dienstag⁴, V. Rustgi⁵, L. Schick⁶, D. McInery⁷, B.A. Fielman¹, N.A. Brown¹

¹Idenix Pharmaceuticals, Inc, Cambridge MA, USA, ²Beth Israel Deaconess Medical Center, Boston MA, USA, ³Bach & Godofsky, Bradenton FL, USA, ⁴Massachusetts General Hospital, Boston MA, USA, ⁵Metropolitan Research, Fairfax VA, USA, ⁶University of Massachusetts Health Center, Worcester MA, USA, ⁷Northwest Medical Specialties, Tacoma WA, USA

Background

Valopicitabine (NM283), an orally bioavailable valine prodrug of NM107, is a nucleoside analog exhibiting anti-HCV activity via direct inhibition of viral RNA polymerase. As a part of a first-in-man dose-escalation trial, we investigated NM283 pharmacokinetics (PK) and its pharmacodynamic (PD) implications.

Patients and Methods

Patients (12/dose cohort) were randomized 10:2 to treatment with NM283 (50-800 mg/day) or placebo for 15 days, with 14 days of follow-up. Assessments included safety, PK, and serum HCV RNA reduction. Patients were HCV-1-infected adults (18-65 yrs; 87% nonresponders to prior IFN-based therapies) with compensated, noncirrhotic chronic liver disease, ALT<10 xULN and serum HCV RNA >5 log10 copies/mL by COBAS Amplicor PCR assay. Results: After oral administration, NM283 was rapidly absorbed and extensively converted to NM107, the target moiety, and a minor metabolite, NM106. NM283 exhibited a short plasma half-life (T1/2) of ~1.4 h with comparable single dose and steady-state plasma exposures. No pre-dose or trough NM283 was detected. NM106 was only transiently detected at lower doses (50 and 100 mg), but became more consistently measurable with repeat daily dosing, and with higher doses. This metabolite exhibited a plasma T1/2 of ~12 h. NM107 was the major plasma species detected, representing ~80% of plasma exposure on a molar basis, followed by NM106 (~15%) and NM283 (<5%). Systemic exposure of NM107, NM106 and NM283 (AUC and Cmax) increased proportionally with NM283 dose. The AUC and Cmax of NM107 and NM106 correlated significantly with serum HCV RNA viral load reduction at day 16 (r >0.7, P <0.001), evidence of dose-related anti-HCV activity.

Conclusions

NM283 is efficiently absorbed and converted to NM107, the target moiety, upon oral administration with dose proportional plasma exposure. Higher plasma exposure is associated with better antiviral efficacy.