Tolloid‐like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to ...interferon or direct‐acting antiviral (DAA)‐based regimens. We investigated whether this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014 and December 2016 in a single centre were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM > 11.9 kPa). TLL1 rs17047200 was analysed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28‐87) years, 58% males, 47% HCV‐1b, LSM 19.1 (12.0‐75.0) kPa and Fibrosis‐4 (FIB‐4) score 4.9 (0.3‐46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%) and AT/TT in 123 (27%) (MAF = 0.14, HWE P > 0.05). Patients’ clinical features were similar across TLL1 genotypes. After 33 (3‐47) months from DAA start, 31 patients developed HCC, with a 3‐year estimated cumulative probability being 7.5% (95% CI: 5%‐10%). The cumulative incidence of HCC was 9% in TLL1 AA vs 7% in AT/TT patients (P = 0.55). Male sex (HR: 3.78, 95% CI: 1.4‐10.1, P = 0.008), diabetes (HR: 3.5, 95% CI: 1.68‐7.27, P = 0.001) and FIB‐4 (HR: 1.09, 95% CI: 1.03‐1.14, P = 0.001) were baseline‐independent predictors of HCC. The incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.
Polymorphisms in the interleukin‐28B (IL28B) region are associated with spontaneous and treatment‐induced viral clearance in hepatitis C virus (HCV) infection. Nevertheless, it is unknown whether ...genetic variation at the IL28B locus influences the natural history of chronic HCV infection. Thus, we asked whether an association between IL28B polymorphisms and liver fibrosis progression existed. We studied 247 consecutive patients with chronic HCV, an accurate estimate of the date of infection, and a liver biopsy performed before any treatment. No patient had a history of alcohol abuse or coinfection with other viruses. We assessed the role of rs8099917 and rs12979860 polymorphisms and the effect of host and environmental factors on fibrosis progression. Blood transfusion (75%) was the main modality of infection. Median age at infection was 21 years, and median interval between infection and liver biopsy was 25 years. One hundred twenty‐nine patients (52%) were infected by HCV‐1, 74 (30%) by HCV‐2, 34 (14%) by HCV‐3, and 10 (4%) by HCV‐4. Bridging fibrosis/cirrhosis (Ishak ≥4) was detected in 24% of patients. Age at infection had a marked effect on fibrosis progression by both a linear model and Cox proportional‐hazard regression (P < 2E‐16). A 12.1% increase in the hazard of advanced fibrosis was estimated for each additional year at infection, suggesting that this was the major explanatory variable in this cohort. Male gender (P < 0.05), HCV genotype 3 (P < 0.001) and steatosis (P < 0.05) were also associated with faster fibrosis progression. Conversely, the two IL28B polymorphisms had no impact on fibrosis progression. Conclusion: In HCV patients with a known date of infection, IL28B genotype was not associated with fibrosis progression rate or with the risk of developing advanced liver fibrosis. (HEPATOLOGY 2011;)
ObjectiveExhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients ...with different capacity to control infection and reconstitute antiviral function.DesignHBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients.ResultsSeverely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2.ConclusionsThe possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.
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