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Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/ mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed >10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n 5 14) in CC compared to 13% (n 5 7) in non-CC, genotype carriers (P 5 0.039). Baseline HBV DNA levels <6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P 5 0.001), ALT levels >136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P 5 0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P 5 0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P 5 0.025) independently predicted HBsAg clearance. Conclusions: IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV. (HEPATOLOGY 2013;57:890-896) See Editorial on Page 870 P ersistent infection with the hepatitis B virus (HBV) is associated with an increased risk of cirrhosis, hepatocellular carcinoma (HCC), and anticipated liver-related mortality worldwide. [1][2][3][4] To attenuate or prevent these long-term sequelae of HBV, interruption of HBV replication by means of inhibitors of HBV polymerase nucleos(t)ide analogs or interferon (IFN) is the only practical approach. IFN therapy, which is recommended as a first-line therapy in patients with less-advanced liver disease and moderately replicating HBV. However, IFN has limited application in virtue of its suboptimal tolerability and restricted antiviral activity in general, and this is particularly true in the hepatitis B e antigen (HBeAg)-Abbreviations: ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis e antigen; anti-HBs, antibody to hepatitis B surface antigen; AST, aspartate

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 proportionalhazard 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.

BACKGROUND & AIMS:Patients with cirrhosis and hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs) are still at risk for developing hepatocellular carcinoma (HCC). We aimed to identify features of de novo or recurrent HCCs in these patients, and factors associated with HCC development, in a large cohort of patients with cirrhosis who received treatment with DAAs. METHODS:In a retrospective study, we collected data from 565 patients with cirrhosis (median age, 64 years; range, 28-87 years; 60% male, 49% infected with HCV genotype 1; median liver stiffness measurement [LSM], 19.1 kPa; 87% Child-Pugh-Turcotte score A) treated with DAAs at a single center in Italy, from December 2014 through 2016. Cirrhosis was defined based on clinical features, histologic factors (METAVIR F4), or LSM >11.9 kPa. Patients were assessed (complete blood analysis and HCV-RNA quantification) every 4 weeks during treatment; at weeks 4, 12, and 24 afterward; and at 6-month intervals thereafter. HCC surveillance was performed by ultrasound or CT scans every 3-6 months, based on history of HCC. Non-invasive markers of fibrosis, such as ratio of aspartate aminotransferase to platelets, fibrosis-4 (FIB-4) score, and LSMs were assessed. RESULTS:During a median 25 months of follow up (range, 3-39 months), HCC developed in 28/505 patients without a history of HCC (de novo HCC); the 3-year estimated cumulative probability for HCC was 6% (95% CI, 4%-9%). Of patients with de novo HCC, 75% had a single tumor and 82% of these were Barcelona liver cancer stage 0-A; the median level of alpha-fetoprotein was 6 ng/mL (range, 1.0-9240 ng/mL). Male sex (hazard ratio [HR], 6.17; 95% CI, 1.44-26.47; P [ .01), diabetes (HR, 2.52; 95% CI, 1.08-5.87; P [ .03), LSM (HR, 1.03; 95% CI, 1.01-1.06; P [ .01), and FIB-4 score (HR, 1.08; 95% CI, 1.01-1.14; P [ .01) were independently associated with de novo HCC. HCC developed in 20/60 patients with a history of HCC (HCC recurrence); the 3year cumulative probability for recurrence was 43% (95% CI, 20%-61%). In the 20 patients with HCC recurrence, 11 had a single tumor and 90% were Child-Pugh-Turcotte score A. Diabetes was independently associated with HCC recurrence (HR, 4.12; 95% CI, 1.55-10.93; P [ .004).Abbreviations used in this paper: CONCLUSIONS:In a large, single-center cohort of consecutive patients with cirrhosis and who received DAA treatment for HCV infection, most liver tumors were identified at early stages. Male sex, diabetes, and non-invasive markers of liver fibrosis can be used to identify patients at increased risk for HCC following DAAs therapy.

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BaCKgRoUND aND aIMS: Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct-acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin-like phospholipase domain containing 3), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs. appRoaCH aND ReSUltS: We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H 1 spectrometry in the general population (Dallas Heart Study). During a median followup of 43 (3-57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95% confidence interval 7%-12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence. CoNClUSIoNS: In a large cohort of DAA-treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a condition known to influence the progression of liver fibrosis and the response to pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained virological response (SVR) after antiviral therapy prevents the development of IR in the long term. Members of the Milan Safety Tolerability study cohort, who received PEGIFNa2a/RBV or PEG-IFNa2b/RBV, underwent a homeostasis model assessment (HOMA) at the baseline and 24 months after treatment completion. For all patients (n 5 431), a liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline, IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body weight (P 5 0.03), an HCV load < 0.6 3 10 6 IU/L (P 5 0.006), fibrosis staging ! 4 (P 5 0.01), and moderate to severe steatosis (P 5 0.03). IR did not influence the rates of endof-treatment response (75% versus 69%, P 5 0.4), SVR (63% versus 60%, P 5 0.8), or relapse (19% versus 24%, P 5 0.5). After treatment, IR developed in 49 of the 384 nondiabetic patients (14%). Although the mean baseline and posttreatment HOMA values were similar in SVR patients (1.11 6 0.8 versus 1.18 6 1.1, P 5 0.25), patients experiencing treatment failure showed a significant increase in the mean HOMA value at the followup visit (1.20 6 0.85 versus 1.49 6 1.3, P 5 0.007), and there was an increased rate of de novo IR in non-SVR patients versus SVR patients (17% versus 7%, P 5 0.007). According to a logistic regression analysis, treatment failure (odds ratio 5 2.81, 95% confidence interval 5 1.39-5.67, P 5 0.004) and a 10% body mass index increase (odds ratio 5 6.42, 95% confidence interval 5 1.69-24.3, P 5 0.006) were significantly associated with the development of de novo IR. Conclusion: In nondiabetic patients with chronic HCV, the achievement of SVR with PEG-IFN and RBV prevents the development of de novo IR.

Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region are the strongest baseline predictors of a sustained virologic response (SVR) to peg-interferon (PegIFN) and ribavirin (Rbv) in patients with hepatitis C virus (HCV) genotype 1 infection. Whether this holds true for HCV-4 patients too is unknown. The aim was to investigate the predictive power of the rs12979860 IL28B SNP for a response to Peg-IFN and Rbv in HCV-4 patients. All HCV-4 patients consecutively treated between September 2004 and June 2010 with PegIFN and Rbv at two liver centers at the Maggiore Hospital Milan (Italy) underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype. Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis) 103 were included in the final analysis; five discontinued treatment for nonvirologic reasons and four did not consent to genetic testing. Twenty-four (23%) were genotype CC, 65 (63%) CT, and 14 (14%) TT. Overall, 50 (49%) achieved an SVR: 21 (88%) CC patients versus 29 (37%) CT/TT (P < 0.0001). CC patients more often had a rapid virologic response (RVR) than CT/TT patients (12, 50% versus 23, 29%; P 5 0.08), while also showing lower relapse rates (0% [0/ 21] versus 36% [16/45] P 5 0.0013). In non-RVR patients, SVR rates were higher in CC than CT/TT patients (9 [75%] versus 13 [23%] P 5 0.001). By logistic regression, the IL28B rs12979860 CC genotype was an independent predictor of SVR with an odds ratio of 8.0 (95% confidence interval 2.00-32.01; P 5 0.003). Conclusion: The IL28B rs12979860 SNP may have an added value in the treatment algorithm of HCV-4 patients because it is the strongest predictor of an SVR to PegIFN/Rbv therapy. (HEPATOLOGY 2012;55:336-342) C hronic infection with hepatitis C virus (HCV) is a global health problem, affecting %3% of the world's population, and a major cause of anticipated liver-related death worldwide.1,2 Pegylated interferon (PegIFN) and ribavirin (Rbv) therapy is the consolidated standard of care (SOC), with achievable rates of viral clearance that are largely influenced by virus and host-related factors. 3,4 Recently, single nucleotide polymorphisms (SNP) on chromosome 19 were found to predict treatment outcome in the more difficult to cure Abbreviations: ETR, end-of-treatment response; EVR, early virological response; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IL28B, interleukin 28B; PegIFN, peg-interferon; Rbv, ribavirin; RVR, rapid virologic response; SNP, single nucleotide polymorphism; SVR, sustained virologic response.From the