Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: A long-term cohort study
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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2016, Infection, Genetics and EvolutionCitation Excerpt :Thus, larger studies are required to further refine our genetic analysis and adequately assigned relatedness links between HCV cases. Intra-host genetic divergence in the HVR1 can reach up to 17%, while the inter-host divergence in unrelated cases can be as low as 5% (Bruno et al. 2015), further complicating the establishment of transmission links. In this study, the intra-host variability ranged between 0.0 and 60.0.
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2016, Journal of HepatologyCitation Excerpt :In one study of 400 untreated patients from the HALT-C trial, patients with a responder IFNλ genotype were twice as likely to develop adverse clinical outcomes, compared to subjects with the non-responder genotype during 3.8 years follow-up [86]. It is noteworthy however that another smaller Italian study of 264 compensated HCV-cirrhotic patients but with longer follow-up duration (median duration of follow up 14.8 years) failed to demonstrate any association with clinical outcomes [87]. Collectively, these data on balance imply an important role for genetic variation in IFNλ to disease progression and clinical outcomes.
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