MONITORING LIVER ELASTICITY:  A NEW TOOL TO MEASURE LIVER FIBROSIS DURING THERAPY

B. Coco, F. Oliveri, P. Colombatto, P. Ciccorossi, R. Sacco, F. Bonino, M.R. Brunetto  

 

Introduction

Hepatic fibrosis is the major indicator of progressive liver disease. However histology, the gold standard for fibrosis, requires an invasive procedure, that is unsuitable for monitoring disease progression and may be affected by sampling errors.

 

Aim

Our aim was to evaluate the diagnostic accuracy (DA) of liver elasticity by Fibroscan (a device equipped with a vibrator and an ultrasound system; Echosens, Paris, France) for detection of hepatic fibrosis and cirrhosis in a cohort of patients with viral (HBV and HCV) chronic hepatitis.

 

Patients

We measured liver elasticity in 178 consecutive patients: 105 had liver biopsy showing chronic hepatitis with or without cirrhosis and 56 had compensated (Child A) cirrhosis. Histological grading and staging were scored according to Ishak classification. Liver elasticity measurement were reproducible and operator-indipendent. Seventeen patients  were excluded from the analysis (liver biopsy not suitable for staging in 8 and technical limitation to Fibroscan in 9). 

 

Results

Stiffness values at the Fibroscan significantly correlated with fibrosis scores (Table n1). Liver elasticity  value higher than 14 KPa (cut-off defined by ROC analysis) identified patients with cirrhosis with 72,6% sensitivity and 93,5% specificity (DA 82,6%). Among cirrhotic patients those with IFN/antiviral induced biochemical remission (23 of 60) had significantly lower elasticity mean values (13,2 vs 24,3 KPa, p<0,001). In the group of patients with persistent disease activity Fibroscan showed a better AD (88,2%), with 83,9% sensitivity, 92,9% specificity. 

 

Conclusion

Liver elasticity measured  by Fibroscan correlates with fibrosis at histology significantly and lower stiffness values in patients with biochemical remission prompt its clinical usefulness to monitor treatment efficacy.


 


SUSTAINED VIRAL RESPONSE IMPROVES SURVIVAL IN PATIENTS WITH EITHER COMPENSATED OR DECOMPENSATED HEPATITIS C

B.D. Cecil, M. Lavelle  

Background and aims

We report the survival experience of our prospective cohort of 312 American military veterans treated with antiviral therapy. We examine the effect of sustained viral response (SVR) and other explanatory variables on survival.

 

Methods

We treated 312 patients with HCV with antiviral therapy at the Louisville VAMC between May 1998 and November 2004. 43 patients were lost to follow up, leaving 269 for analysis. We compared the survival of the 74 patients achieving SVR to the experience of 195 who did not achieve SVR. The mean duration of observation was 3.9 years (range 0.3-6.5 years). We used multiple logistic regression (Stata 8) to choose important explanatory variables for all cause mortality.

 

Results

3 of 74 (4%) patients with SVR died while 49 of 195 (25%) without SVR died. 5 of 28 (18%) decompensated patients achieved SVR, and 4 (80%) are alive. 1 died from HCC.  20 of 23 (87%) decompensated patients without SVR died. Multiple logistic regression analysis indicated that decompensated liver disease, lack of SVR and history of alcohol or drug abuse predicted mortality. LR chi2 (3) = 83.09 Prob > chi2  = 0.0000 Two of our patients received liver transplants, one for HCC and one for decompensated liver disease. Both were nonresponders to antiviral therapy. Variable, Odds, Std. Err., Ratio z, P> z, 95% Conf. Interv Decomp, 22.4, 12.9, 5.41, 0.000, 7.3  69.0 No SVR, 9.4, 6.8, 4.14, 0.002, 2.3, 38.4 Drug or Alcohol Abuse, 5.4, 2.5, 3.71, 0.000, 2.2, 13.3

 

Conclusions

Patients who achieved SVR demonstrated greatly improved survival in this cohort of US military veterans. This survival benefit of SVR was demonstrated in the cohort as a whole and in the subgroup of decompensated patients. Successful antiviral therapy for HCV is a life saving intervention.


INDUCTION OF TH1/TC1 TYPE IMMUNITY IN CHRONIC HEPATITIS C NON-RESPONDER PATIENTS WITH THE THERAPEUTIC PEPTIDE VACCINE IC41

H. Wedemeyer, T. Berg, M.P. Manns, H. Hinrichsen, G Cholewinska, S. Zeuzem, H. Blum, V. Buerger, E. Tauber, S. Jelovcan, M. Buschle, J. Frisch, C. Klade

 

Introduction

IC41 is a vaccine consisting of five synthetic peptides harboring relevant CD4+ and CD8+ T-cell epitopes of Hepatitis C Virus (HCV) and the synthetic Th1/Tc1 adjuvant poly-L-Arginine. IC41 has been investigated in a number of clinical trials including up to date about 240 subjects confirming both its excellent safety profile and its immunogenicity. Recently, results of a double blind, controlled, randomized, multicenter phase-2 study in chronic hepatitis C patients who did not respond to standard interferon-based therapies were presented (Manns et al., AASLD 2004). IC41 treatment involved 6 s.c. vaccinations in 4-weekly intervals.

 

Aim/Methods

To investigate the mode-of-action of IC41 in chronically infected patients more specifically, we now performed a detailed analysis of frequencies, kinetics and phenotypes of T cell responses induced by IC41. Peripheral blood mononuclear cells (PBMC) were isolated and cryo-preserved at 8 time points before, during and after IC41-vaccination. T-cell responses were assessed with a combination of standardized assays in one central laboratory: interferon-gamma ELIspot, lympho-proliferation and HLA-tetramer analysis.

 

Results

21 out of 36 patients (58%) treated in the verum groups showed a T-cell response to IC41-vaccination. Both, interferon-gamma secreting CD4+ helper and CD8+ cytotoxic T-cells (CTL) were induced by IC41. Importantly, Poly-L-Arginine was required to induce this type of response. Overall, the strength of IC-41-peptide-specific CD4+ and CD8+ T cell responses increased during treatment, peaked 4 weeks after the last vaccination and declined thereafter. A significant decline of HCV RNA levels during vaccination was observed in 6 of 21 patients with a T-cell response. 3 of those achieved a greater than 1-log decrease which was however transient. Interestingly, these patients showed a strong and sustained reactivity to one particular CTL-epitope. CD8+ T-cells recognizing this epitope as well as non-HCV control peptides were characterized in detail involving staining for surface markers (CD8, CD45RA, CCR7, CD27, CD28, CD38, CD69 and HLA-DR) and intracellular perforin revealing significant differences between HCV and CMV- or EBV-specific CTLs.

 

Conclusion

In summary, cellular immunity against HCV can be enhanced by therapeutic vaccination with IC41. These data could be the basis for novel treatment strategies in chronic HCV infection, either as monotherapy or in combination antiviral therapies.

 


A PHASE 2 STUDY TO ASSESS ANTIVIRAL RESPONSE, SAFETY, AND PHARMACOKINETICS OF ALBUFERON IN IFNALFA NAIVE SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C

V. Bain, K. Kaita, E. Yoshida, M. Swain, J. Heathcote, J. McHutchison, A. Neumann, P. Bagchi, B. Osborn, P. Cronin, L. Novello, W. Freimuth, M. Subramanian

 

 

Background

AlbuferonTM is a novel recombinant protein consisting of IFNalfa genetically fused to human serum albumin. The resulting polypeptide combines in one molecule the antiviral properties of IFNalfa with the long serum half-life of albumin.

 

Aim

This Phase 2, randomized, dose-ranging study was conducted in IFNalfa naïve, genotype 1 HCV subjects. 

 

Methods

Subjects were enrolled in parallel into 3 dose cohorts (200 mcg, 450 mcg and 670 mcg). Within each dose group, 10 subjects were enrolled to receive 2 SC injections of Albuferon 14 days apart.  Two additional dose cohorts of 900 mcg and 1200 mcg are ongoing. 

 

Results

32 subjects are currently enrolled. Mean baseline viral load was 6.63 log10 IU/mL and mean BMI was 28.2.  Albuferon was well tolerated.  Adverse events were transient, most were mild to moderate, and were not dose related. The most common adverse events were headache (52%), arthralgia (48%), and myalgia (45%). There was 1 SAE (acute colitis that has resolved). Reversible neutropenia (ANC<750) occurred in 2 subjects and did not preclude repeat dosing. Cmax was dose-proportional, with a 17-30% drug accumulation after the second dose.  The median terminal half-life was 141 hours and consistent with previous data from IFNa experienced subjects. VR4 response (>2 log HCV RNA reduction at week 4) and mean HCV RNA change (log10 IU/mL) at week 4 were as follows- 200 mcg: 2/10 (-1.8); 450 mcg: 7/10 (-2.5); 670 mcg: 3/9 (-1.7).  Reductions in ALT levels concomitant with or parallel to viral load reductions were observed in all subjects with an elevated ALT at baseline.  Mathematical modeling of viral kinetics demonstrates a biphasic response, with a mean first phase decline of 0.85 (range 0-2.3) log during the first 1-4 days, followed by a second phase decline of mean 0.3 (range 0-1.0) log/week. 12 patients showed a second phase slope greater than 0.3 log/week after the first and second injections until day 28. 

 

Conclusions

Albuferon was safe, well tolerated and showed robust antiviral activity after two doses in IFNalfa naive, genotype 1 HCV subjects. Dosing every 2-4 weeks is supported by the pharmacokinetics and anti-viral response.


LONG-TERM PROGRESSION OF FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) NON-RESPONDERS TO INTERFERON THERAPY (IFN). A LONGITUDINAL STUDY OF REPEAT LIVER BIOPSIES

I. Cirera, I. Ojanguren, M.D. Giménez, M. Rivera, M. Gimeno, M. Barranco, C. Tural, R. Planas, R. Solà  

 

Introduction

Few studies have examined the degree of fibrosis progression in patients with CHC non-responders to IFN.

 

Aims

To assess the rate of fibrosis progression in CHC patient’s non-responders to IFN and to identify associated variables.

 

Patients and methods

84 patients (50.5±1.3 years) with CHC non-responders to IFN, and without cirrhosis in their initial biopsy, followed for 8.1±0.2 years. In 67 of them a second liver biopsy was performed after 8.6±1.7 years. In the remaining 17 cases the second biopsy was not performed because the diagnosis of cirrhosis was established after hepatic decompensation (10) or hepatocellular carcinoma (7). Liver biopsy samples were re-examined blindly by a pathologist who was unaware of the clinical and biochemical data of the patients or the order of the biopsies. Studies on the liver biopsies included assessment of fibrosis (METAVIR), and of steatosis.

 

Results

In the basal biopsy, fibrosis was F0 in 19 patients, F1 in 19, F2 in 10 and F3 in 36. Steatosis was absent in 40 cases, but was grade I in 36 and grade II in 8 cases. The overall rate of fibrosis progression was 0.104 units per year. Fibrosis progression was found in 52 patients (62%) (13/19 patients with F0 in the basal biopsy, 11/19 F1, 6/10 F2, and 22/36 F3). Variables associated with fibrosis progression were age, HCV-RNA, GGTP, AP, AST/ALT, platelets, cholesterol and steatosis in the initial biopsy. The independent predictors for fibrosis progression were platelet count (OR 0.09; 95%IC: 0.01-0.67) and steatosis (OR 4.96; 5%IC: 1.11-25.5). 27 patients (32%) developed cirrhosis (1 with F0 in the basal biopsy, 3 F1, 1 F2, and 22 F3), and 11 patients (13%) developed hepatocellular carcinoma.

 

Conclusions

1) The results of this longitudinal study have shown progression of liver fibrosis, cirrhosis and hepatocellular carcinoma development in approximately one half, one third and one tenth, respectively, of CHC patients non-responders to IFN in a median follow-up of 8 years.

2) The variables independently associated with fibrosis progression were thrombocytopenia and steatosis in the initial biopsy.

3) Re-treatment is highly indicated in this subgroup of patients with high risk of fibrosis progression.


CHARACTERISTICS ASSOCIATED WITH PROGRESSION OF FIBROSIS IN WOMEN WITH HEPATITIS C : EVIDENCE FOR THE ROLE OF ESTROGEN

L. Codes, T. Asselah, D. Cazals-Hatem, F. Tubach, D. Vidaud, D. Valla, P. Marcellin

 

Background and aims

The rates of fibrosis progression in chronic hepatits C are significantly different between males and females. An antifibrogenic effect of estrogen is proposed, probably via the inhibition of stellate cells. The aim of this study was to evaluate the evolution of hepatitis C in women, according to use of oral contraceptives, number of pregnancies, menopause and substitutive hormonal therapy.

 

Methods

From November2001 to October2002, women with chronic hepatitis C were enrolled prospectively. Patients without liver histology or with other cause of liver dysfunction were excluded. A questionnaire was completed prospectively and a blood sample was obtained on the day of liver biopsy. Liver biopsies were evaluated according to the METAVIR. We identified predictive factors of liver fibrosis by using univariate and multivariate (logistic regression) analysis.

 

Results

Our study included 251 women. Average age was 46.7 +/- 10.8 years-old, duration of the infection was 24.2 +/- 6.7 years. Pregnancy was distributed as follows : 24.8% no pregnancies, 56.4% with 1 or 2 pregnancies and 18.8% with 3 or more pregnancies, 50.8% had antecedents of use of contraceptives. A total of 122 patients (52.1%) were menopaused and 65 received substitutive hormonal therapy. We didn't identify relationship between number of pregnancies, use of contraceptives and fibrosis. Patients with a high stage of fibrosis(F2-F4) were older, had a longer duration of infection, a higher BMI. They presented liver steatosis more frequently and received hormonal therapy less frequently then patients with low stage fibrosis (F0-F1). Among 65 menopaused women treated with substitutive hormonal therapy, 53 presented fibrosis F0-F1. When we analyzed all of patients that received hormones (contraceptive pills or replacement therapy), we found a predominance of treated women (86.3%) in the group F0-F1 (p < 0.0001). A high stage of fibrosis was associated with higher AST levels [OR 3.5 (95% CI 1.5-8.2), p=0.0038] and previous anti-viral therapy [OR 2.8 (1.2-6.6), p=0.0171]. The probability of high stage fibrosis was lower in the group of patients who had received hormonal therapy [OR 0.26 (95% CI 0.11-0.62), p=0.002].

 

Conclusions

These results reinforce the hypothesis of a probable antifibrogenic role of estrogens.