Elsevier

Antiviral Research

Volume 113, January 2015, Pages 27-32
Antiviral Research

Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: A long-term cohort study

https://doi.org/10.1016/j.antiviral.2014.11.002Get rights and content

Highlight

  • IFN-λ3 polymorphism is associated with HCV spontaneous clearance.

  • IFN-λ3 is pivotal for allocating HCV cirrhotic patients to be treated with IFN based therapy.

  • IFN-λ3 genotype has no value in predicting the outcome of the disease.

Abstract

Background

Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear.

Methods

We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan–Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome.

Results

IFN-λ3 was determined in 264 patients (52% males, mean age 57 ± 8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p < 0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression.

Conclusion

IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.

Introduction

Several factors are recognized to influence disease progression of Chronic HCV infection, the main cause of liver-related mortality in developed countries (Lauer and Walker, 2001, Missiha et al., 2008). However, predicting the natural history of the disease remains difficult, while ability to identify patients at risk for rapid fibrosis progression remains an unmet clinical need. Recently, growing evidence suggested that genetic factors might influence the outcome of CHC, and several single nucleotide polymorphisms have been identified as promising candidates to play a role in small cohorts of patients (Powell et al., 2000, Mottola et al., 2014).

Interleukin (IL)-28B gene polymorphism on chromosome 19 (e.g., rs12979860, rs8099917) was found to be strongly associated with spontaneous (Mottola et al., 2014, Huang et al., 2007, Ge et al., 2009) HCV clearance, irrespective of viral genotype. However, its treatment-induced effect on achieving SVR has been well established, despite being mainly investigated in genotype 1 patients (Rauch et al., 2010). Nevertheless, reliable data on IL28B-predicting-SVR by IFN-based therapy in patients infected by non-1 easy-to-treat genotypes and/or with cirrhosis, are scarce (Mangia et al., 2010).

There has been great interest, as well, in determining whether IFN-λ3 genotype might be associated with disease progression in patients with CHC, regardless of achieving SVR. Conflicting data have emerged. Recently, the favorable IFN-λ3 genotype (e.g., CC for rs12979860) was linked to faster fibrosis progression by Bochud et al. (2012), although the association was only observed among HCV non-genotype 1 patients. Nonetheless, other cross-sectional studies detected an association between unfavorable IFN-λ3 genotypes (e.g., CT, TT for rs129769860) with advanced fibrosis and HCC (Ge et al., 2009, Fabris et al., 2011). Finally, a recent long-term study in a large cohort of patients with CHC and known date of infection (Marabita et al., 2011) did not show any relationship between IFN-λ3 genotype and fibrosis progression. Therefore, the relationship between IL28B genotype and disease progression in CHC patients remains controversial and, no study has yet evaluated its impact on the clinical outcome in patients with established cirrhosis. Consequently, in this study we aimed to: (i) assess IFN-λ3 polymorphism value in predicting SVR among cirrhotic patients infected by both easy- and difficult-to-treat genotypes and (ii) evaluate the association between IFN-λ3 polymorphism and clinical outcomes in a large cohort of patients with compensated cirrhosis HCV-related, prospectively followed for up to 20 years

Section snippets

Patients

Between January 1989 and December 1992, all consecutive cirrhotic (F4 METAVIR) Bedossa and Poynard, 1996 patients who tested positive for serum anti-HCV at three referral centers in the Milan Area (Northern Italy), were enrolled in a prospective study evaluating the long-term outcome in patients with HCV-induced cirrhosis. The cohort has been described in detail previously (Bruno et al., 2009). For the purpose of this study, we considered only patients with compensated cirrhosis. The diagnosis

Results

Among the 465 patients enrolled in the original cohort (Bruno et al., 2009), 65 were decompensated at baseline and were excluded from the current analysis. One hundred and thirty-six (34.0%) of the 400 compensated patients were excluded because biological samples were no longer available. Table 1 shows patients’ characteristics with/without biological samples. Briefly, patients removed from the analysis had the worst clinical characteristics confirmed by significant lower albumin levels, though

Discussion

IFN-λ3 polymorphism is the strongest host factor predicting for response to IFN-based therapy in CHC patients infected by HCV genotype 1. However, its impact on disease progression is still poorly investigated. To our knowledge, this is the study with the longest surveillance period ever carried out, so far, in patients with HCV-related cirrhosis. As a result, it may reliably assess the correlation between IFN-λ3 polymorphism and clinical outcome in a large, well-characterized cohort. More

Conflict of interest

All authors have no disclosures to declare and no financial support has been provided for this study

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