Friday, March 11, 2011

Assessment of Liver Fibrosis before and after Hepatitis C Antiviral Therapy Using Noninvasive Tests

Assessment of Liver Fibrosis before and after Antiviral Therapy by Different Serum Marker Panels in Patients with Chronic Hepatitis C

S. M. Martinez; G. Fernández-Varo; P. González; E. Sampson; M. Bruguera; M. Navasa; W. Jiménez; J. M. Sánchez-Tapias; X. Forns
Authors and Disclosures
Posted: 03/08/2011; Alimentary Pharmacology & Therapeutics. 2011;33(1):138-148. © 2011 Blackwell Publishing


Abstract and Introduction

Abstract

Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.
Aim To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.

Methods
The performances of Forns' score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.

Results
Forns' score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.
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Conclusions
Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.
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Discussion Only; See Full Text Here
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Discussion

The use of routine haematological and biochemical parameters combined in panels such as Forns' score, APRI or FIB-4 index, is an 'indirect', easy and inexpensive approach to identify patients with significant fibrosis and cirrhosis. The Forns' score was developed and validated in a population where only 25% of patients had significant hepatic fibrosis,[9] whereas the prevalence of significant fibrosis in the present cohort was much higher (67%). This difference may explain why this test performed better in the present cohort than in the original study to rule in significant fibrosis, with a PPV higher than 90%, but not to exclude significant fibrosis. Similarly, the PPV for significant fibrosis obtained in this study with APRI ≥1.5, compared favourably with that reported in the original study (93% vs. 88%), although the NPV at the 0.5 cutoff point was lower (74% vs. 86%).[10] Similar results were shown with the FIB-4 index. For the outcome of cirrhosis, all scores performed well but FIB-4 showed a significantly better accuracy as compared with APRI and ELF.

The results of our study are in accordance with recent reports evaluating the effect of anti-HCV treatment using other non-invasive methods. A comparison of HCV FibroSURE (or FT-AT) and FIBROSpect II (HA, TIMP-1 and α2-macroglobulin) during a phase 2b clinical trial with albinterferon alfa-2b plus ribavirin noted a significant decline in the score values in patients with SVR compared with those in nonresponders.[32] Another study performed a longitudinal evaluation of FT-AT with HA as a comparative reference in CHC patients treated with IFN monotherapy; the authors observed a significant decrease of FT-AT in those who obtained SVR versus NR and relapsers, but with no significant changes noted in HA.[33] In a more recent study, a comparison of the effect of antiviral therapy on FT and FibroScan between treated and untreated patients showed a significant decrease of FT at the end of follow-up for those patients who obtained SVR or relapsed.[34]

In our study, the significant increase in serum TIMP-1 levels observed at the end of follow-up in nonsustained virological responders may indicate that fibrosis is progressing in these patients. Indeed, other reports found a similar TIMP-1 increase following interferon alfa therapy in nonresponder patients.[35–37] TIMP-1 protects collagen from fibrolysis by the matrix metalloproteinases and also inhibits the apoptosis of HSC.[38] In experimental models, overexpression of TIMP-1 was associated to enhanced fibrosis, supporting the hypothesis that inhibition of matrix degradation may contribute to progression of fibrosis.[39]

We also observed significant post-treatment changes of Forns' score, APRI and FIB-4 tests. However, several components of these tests, such as serum cholesterol, platelet counts and particularly transaminases, which are not directly involved in hepatic fibrogenesis or fibrolysis, may change under antiviral therapy, particularly in responders.

Of interest, by multivariate analysis, HA, a component of the ELF score showed an association with SVR. Previous studies have shown that HA levels reflect an increased production of this marker by HSC as well as a decreased removal from circulation, which depends on the uptake by specific receptors in hepatic sinusoidal endothelial cells.[40,41] Higher HA levels and lower probability of virological response could reflect dysfunction of endothelial sinusoidal cells that is present in patients with more advanced liver fibrosis, another independent predictor of virological response.

Our study has several limitations. First, the lack of a follow-up liver biopsy, which prevented us to assess directly the effect of treatment on liver fibrosis. Second, the short period of time that elapsed between baseline and follow-up evaluations. As liver fibrosis decreases progressively after a SVR,[42] the evaluation period of the study might have been too short to detect additional effects. Third, the proportion of patients with a biopsy size >20 mm was suboptimal. Finally, although this is a cohort study, ECM assays were performed on stored serum samples, which were not available for all included patients.

In summary, this study of a large cohort of patients with CHC confirms that both indirect fibrosis tests and measurement of ECM serum markers, included in the ELF score, are accurate to predict the severity of fibrosis. ECM markers and the composite ELF score significantly decreased in sustained virological responders but remained unchanged in nonsustained responders, suggesting that these markers may be useful as a non-invasive means to assess the effects of antiviral therapy on hepatic fibrosis and fibrogenesis. The potential utility of the ELF test in this setting as compared with other commercially available patented markers would require extensive validation and a cost-effective analysis.


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