Elsevier

Journal of Hepatology

Volume 51, Issue 4, October 2009, Pages 655-666
Journal of Hepatology

Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C

https://doi.org/10.1016/j.jhep.2009.05.016Get rights and content

Background/Aims

While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression.

Methods

We identified 1189 patients from the Swiss Hepatitis C Cohort database with at least one biopsy prior to antiviral treatment and assessable date of infection. Stage-constant fibrosis progression rate was assessed using the ratio of fibrosis Metavir score to duration of infection. Stage-specific fibrosis progression rates were obtained using a Markov model. Risk factors were assessed by univariate and multivariate regression models.

Results

Independent risk factors for accelerated stage-constant fibrosis progression (>0.083 fibrosis units / year) included male sex (OR = 1.60, [95% CI 1.21–2.12], P < 0.001), age at infection (OR = 1.08, [1.06–1.09], P < 0.001), histological activity (OR = 2.03, [1.54–2.68], P < 0.001) and genotype 3 (OR = 1.89, [1.37–2.61], P < 0.001). Slower progression rates were observed in patients infected by blood transfusion (P = 0.02) and invasive procedures or needle stick (P = 0.03), compared to those infected by intravenous drug use. Maximum likelihood estimates (95% CI) of stage-specific progression rates (fibrosis units / year) for genotype 3 versus the other genotypes were: F0  F1: 0.126 (0.106–0.145) versus 0.091 (0.083–0.100), F1  F2: 0.099 (0.080–0.117) versus 0.065 (0.058–0.073), F2  F3: 0.077 (0.058–0.096) versus 0.068 (0.057–0.080) and F3  F4: 0.171 (0.106–0.236) versus 0.112 (0.083–0.142, overall P < 0.001).

Conclusions

This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates. This observation may have important consequences for the management of patients infected with this genotype.

Introduction

Hepatitis C virus (HCV) is a single-stranded RNA virus that is distributed worldwide, with an estimated 170 million persons chronically infected, that is ∼3% of the world’s population [1]. Chronic hepatitis C is associated with significant morbidity and mortality, that result mainly from the progression towards cirrhosis and hepatocellular carcinoma [2].

Since the natural course of chronic hepatitis C infection has important inter-individual variability, the identification of predictors of fibrosis progression is critical [3]. Several risk factors for progression have been unequivocally identified, such as older age at infection, male gender, alcohol abuse and coinfection with other pathogens, such as the hepatitis B virus or the human immunodeficiency virus [3], [4]. However, the role of other factors remains controversial. For instance, HCV genotype 3 has been clearly associated with the occurrence of steatosis [4], but its role with regard to fibrosis progression has not been clearly established [5], [6].

The assessment of risk factors for fibrosis progression has been limited by several factors, including small sample size, use of different definitions (e.g. for alcohol abuse or grading of histological lesions) and absent or insufficient data on HCV genotypes. Several studies estimated risk factors for fibrosis at a given time point, which does not take into account the duration of infection. This problem has been solved, in part, by the use of cumulative incidence curves of progression to a certain level of fibrosis [7] and the estimation of fibrosis progression rate based on the ratio of fibrosis stage (usually expressed using the METAVIR score) to the duration of infection [8], [9]. However, this method assumes that the progression rates are constant across fibrosis stages (constant fibrosis progression rate), an assumption that was shown to be incorrect [7], [10], [11]. This limitation can be overcome by using a Markov maximum likelihood estimation that allows a more accurate estimation of stage-specific progression rates and does not require the assumption that fibrosis progression rate is constant [12], [13], [14]. In this study, we used both the stage-constant and stage-specific methods as well as cumulative incidence curves to assess predictors for fibrosis progression in a large cohort of treatment naı¨ve patients with known HCV genotype.

Section snippets

Patients and methods

Patients were within the framework of the Swiss Hepatitis C Cohort Study (SCCS), a multicenter study carried out at 8 major Swiss hospitals and their local affiliated centers [15]. The SCCS was approved by the ethical committees of each participating center. The characteristics of the SCCS and methodology for data collection have been described elsewhere [15]. Briefly, consecutive adult patients aged 18 years or more with HCV antibody positive by immunoblot and signed informed consent were

Patients

Among 3412 patients included in the SCCS up to December 2008, 1275 patients with chronic HCV infection had an assessable date of infection and at least one liver biopsy performed before any antiviral treatment (Table 1). Of these, 86 patients with concomitant liver disease were excluded, leaving 1189 patients for the present analyses. Most study patients were males (61%), Caucasians (96%), and the majority were infected with HCV genotype 1 (54%, Table 2). The median age at biopsy was 42 years,

Discussion

In this study, we analyzed the risk factors associated with fibrosis progression in patients from the SCCS. Our results confirmed the influence of known risk factors of fibrosis progression, including male sex, age at infection, histological activity and HIV infection, but also revealed a new association with HCV genotype 3 and rapid progression [3]. Patients infected by blood transfusion, invasive procedures or needle stick have slower progression compared to intravenous drug users.

To our

Acknowledgements

The Swiss Hepatitis C Cohort Study is supported by the Swiss National Science Foundation (3347C0-108782/1), the Swiss Federal Office for Education and Sciences (03.0599), and the European Commission (LSHM-CT-2004-503359; VIRGIL Network of Excellence on Antiviral Drug Resistance). This work was supported in part by the Leenaards Foundation (to P.Y.B and to F.N.), and by the Swiss National Science Foundation Grants no. 3200B0-111361/2 (PROSPER grant, to M.B.) and 320000-116544 (to F.N.).

The

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    The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.

    1

    The members of the Swiss Hepatitis C Cohort Study Group are listed in the Appendix.

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