HBV genotype-dependent association of HLA variants with the serodecline of HBsAg in chronic hepatitis B patients.

Seroclearance of hepatitis B surface antigen (HBsAg) is regarded as the functional cure for chronic hepatitis B (CHB). The relationship between human leukocyte antigen (HLA) variants, hepatitis B virus genotype, and longitudinal HBsAg serodecline remains to be explored. A total of 1735 HBeAg-seronegative CHB patients with genotype B or C infection of the community-based REVEAL-HBV cohort were genotyped for rs1710 (HLA-G) and rs2770 (HLA-B) using TaqMan assay. Cox proportional hazard regression and generalized linear mixed models were used to analyze the association of HLA genetic variants with the rate of HBsAg seroclearance and longitudinal HBsAg serodecline. Rs1710 G allele was differentially associated with the HBsAg seroclearance in genotype B [aRR (95% CI) = 0.74 (0.56-0.98)] and genotype C [aRR (95%CI) = 1.43 (1.08-1.88)] infection. Rs2770 G allele was associated with HBsAg seroclearance only in genotype B infection [aRR (95% CI) = 0.69 (0.52-0.91)]. The alleles associated with HBsAg seroclearance were significant predictors for the serodecline of HBsAg levels in an HBV genotype-dependent manner (genotype B infection: rs1710, P = 0.013; rs2770, P = 0.0081; genotype C infection: rs1710, P = 0.0452). Our results suggest both spontaneous HBsAg seroclearance and serodecline are modified by the interaction between HLA variants and HBV genotype.

Serum soluble programmed death-1 levels predict the spontaneous HBeAg seroclearance in chronic hepatitis B.

BACKGROUND AND AIMS: In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 (sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance. METHODS: Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively. RESULTS: Lower baseline sPD-1 levels [aRR (95% CI): 2.19 (1.47-3.27)] and long-term decline in sPD-1 levels [aRR (95% CI): 4.08 (2.79-5.97)] were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection [aRR (95% CI): 4.47 (2.38-8.37)] but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71-7.88) and 2.95 (1.68-5.17), respectively, for genotypes B and C. CONCLUSION: Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.

Serum soluble programmed cell death 1 levels predict spontaneous functional cure in inactive carriers with chronic hepatitis B.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is difficult to achieve due to the impaired HBV-specific immunity, such as programmed cell death 1 (PD-1)-associated T cell exhaustion. We assessed soluble PD-1 (sPD-1) as a novel seromarker for predicting spontaneous HBsAg loss. METHODS: Serial serum levels of sPD-1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)-seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD-1 levels, HBsAg decline during follow-up, and spontaneous HBsAg seroclearance. RESULTS: A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person-years of follow-up. Baseline sPD-1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow-up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person-years for sPD-1 levels of ≥4000, 536-3999, 125-535 and <125 pg/mL, respectively (Ptrend  < 0.0001). Compared with baseline sPD-1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1-3.9), 3.0 (1.6-5.5) and 5.1 (2.8-9.5), for baseline sPD-1 levels of 536-3999, 125-535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels. CONCLUSION: sPD-1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg-negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250).

Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: A genome-wide association study.

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.

Level of Hepatitis B (HB) Core Antibody Associates With Seroclearance of HBV DNA and HB Surface Antigen in HB e Antigen-Seronegative Patients.

BACKGROUND & AIMS: Although a low level of hepatitis B surface antigen (HBsAg) is a marker of hepatitis B virus (HBV) seroclearance, additional biomarkers are needed for more accurate prediction. We investigated whether quantification of antibody against HBV core protein (anti-HBc) can identify patients with undetectable levels of HBV DNA and HBsAg seroclearance among those who were HBV e antigen (HBeAg)-seronegative. METHODS: We performed a retrospective analysis of data from a community-based cohort of individuals (30-65 years old) in Taiwan who were HBsAg seropositive, anti-HCV negative, and free of cirrhosis and/or liver cancer, recruited from 1991 through 1992, and evaluated every 6-12 months until June 30, 2004. We measured levels of anti-HBc in blood samples from 2500 participants who were seronegative for HBeAg. The first date at which a sample tested negative for HBV DNA or HBsAg, and remained negative in subsequent tests, was designated as the date of spontaneous HBV DNA undetectability or HBsAg seroclearance. We calculated cumulative incidences of HBV DNA undetectability and HBsAg seroclearance; associations between level of anti-HBc and undetectability of HBV DNA or HBsAg seroclearance were estimated by Cox proportional hazard regression. The effects of time on the associations between level of anti-HBc and HBsAg seroclearance was assessed by the area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: After a 12-year follow-up period, higher proportions of subjects with levels of anti-HBc <3 log IU/mL had undetectable levels of HBV DNA (58%) and HBsAg seroclearance (53%) than subjects with higher levels of anti-HBc (29.6% and 19.8%, respectively) (P < .001). For subjects with levels of HBsAg <102 IU/mL and anti-HBc <3 log IU/mL, the adjusted rate ratio of HBV DNA undetectability was 16.45 (95% CI, 11.15-24.28) and of HBsAg seroclearance was 17.95 (95% CI, 12.49-25.81), compared to subjects with higher levels of HBsAg and anti-HBc. A model that included level of anti-HBc as a parameter identified subjects with HBsAg seroclearance within 10 years with an AUROC of 82%; this value was significantly higher than that from models that include only level of HBV DNA and HBsAg (P < .0001). CONCLUSIONS: In a retrospective analysis of a large cohort of patients with chronic HBV infection in Taiwan, we associated levels of anti-HBc <3 log IU/mL with undetectable HBV DNA and HBsAg seroclearance occurred within 10 years; patients who also have levels of HBsAg <102 IU/mL have greater odds. Combining data on levels of HBsAg, HBV DNA, and anti-HBc is able to identify HBeAg-seronegative patients who can achieve HBsAg seroclearance with an AUROC value of 82%.

Association Between High Levels of Hepatitis B Core Antibody and Seroclearance of Hepatitis B e Antigen in Individuals With Chronic Hepatitis B Virus Infection.

For chronic hepatitis B patients, hepatitis B e antigen (HBeAg) seroclearance signals a transition from an immunologically active phase to an inactive carrier state with a reduction in hepatitis B virus (HBV) DNA levels and a reduced risk of hepatocellular carcinoma (HCC).1 Predictors of HBeAg seroclearance include lower HBV DNA levels, viral genotype, the precore mutation, and higher serum alanine aminotransferase (ALT) levels.2.

A Glycomarker for Short-term Prediction of Hepatocellular Carcinoma: A Longitudinal Study With Serial Measurements.

OBJECTIVES: Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) is a glycomarker. The present community-based long-term follow-up study repeatedly determined the serum WFA+-M2BP level and examined its short- and long-term associations with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS: A total of 921 participants with antibodies against HCV seropositive, but seronegative for hepatitis B surface antigen were enrolled from seven townships in Taiwan during 1991-1992. The participants were regularly followed and their serum WFA+-M2BP levels were measured at baseline and follow-up. HCC was ascertained through active follow-up and computerized data linkage with the National Cancer Registration System until December 31, 2013. Cox proportional hazards and logistic regression models were applied to estimate the magnitude of associations between serum WFA+-M2BP levels and HCC. RESULTS: During a median follow-up of 21.7 years, 122 new-onset HCC cases were identified. Elevated serum WFA+-M2BP levels were associated with an increased risk of HCC (p < 0.001). Patients with increasing changes in serum WFA+-M2BP levels, relative to their baseline levels, had a 4.36-fold risk of HCC. The areas under receiver operating curves (AUROCs) of WFA+-M2BP for predicting HCC showed that the prediction efficacy was significantly higher while closer to HCC diagnosis (p = 0.024). The AUROC was 0.91 for predicting HCC within 1 year by including the predictors of age, sex, alanine aminotransferase, alpha-fetoprotein (AFP) and WFA+-M2BP. CONCLUSIONS: Serum WFA+-M2BP level may elevate before HCC onset and is a short-term predictor of HCC among patients infected with HCV.

Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption.

BACKGROUND: Hepatocarcinogenicity of aflatoxin B1 (AFB1) has rarely been studied in populations with hepatitis C virus (HCV) infection and those without hepatitis B virus (HBV) and HCV infection (non-B-non-C). This case-control study nested in a community-based cohort aimed to investigate the HCC risk associated with AFB1 in HCV-infected and non-B-non-C participants. METHODS: Baseline serum AFB1-albumin adduct levels were measured in 100 HCC cases and 1767 controls seronegative for anti-HCV and HBsAg (non-B-non-C), and another 103 HCC cases and 176 controls who were anti-HCV-seropositive and HBsAg-seronegative. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. RESULTS: In 20 years of follow-up, the follow-up time to newly developed HCC was significantly shorter in participants with higher serum AFB1-albumin adduct levels in non-B-non-C (p = 0.0162) and HCV-infected participants (p < 0.0001). Within 8 years of follow-up, HCV infection and AFB1 exposure were independent risk factors for HCC. Elevated serum AFB1-albumin adduct levels were significantly associated with an increased risk of HCC newly developed within 8 years of follow-up in non-B-non-C participants with habitual alcohol consumption [crude OR (95% CI) for high vs. low/undetectable levels, 4.22 (1.16-15.37)] and HCV-infected participants [3.39 (1.31-8.77)], but not in non-B-non-C participants without alcohol drinking habit. AFB1 exposure remained an independent risk predictor for HCV-related HCC after adjustment for other HCC predictors (multivariate-adjusted OR [95% CI], 3.65 [1.32-10.10]). CONCLUSIONS: AFB1 exposure contributes to the development of HCC in participants with significant risk factors for cirrhosis including alcohol and HCV infection.

Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study.

We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome-wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 × 10-8 ) in the genome-wide association study. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2018;67:651-661).

Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients.

This study examines the role of M2BPGi, a novel seromarker for chronic hepatitis, in predicting hepatocellular carcinoma (HCC) among untreated chronic hepatitis B (CHB) patients. In this nested case-control study, 1070 samples were assayed for M2BPGi, including 357 samples from HCC cases, and 713 samples from non-HCC controls, collected at various times throughout follow-up. HCC case samples were stratified according to years prior to diagnosis. Associations between M2BPGi and HCC were examined with multivariate logistic regression. M2BPGi, α-fetoprotein (AFP), and hepatitis B surface antigen (HBsAg) levels were significant independent short-term predictors of HCC, while M2BPGi was insignificant in long-term analyses. Compared to M2BPGi levels <1.0 cut-off index (COI), those with levels ≥2.0 COI had multivariate odds ratios (95% CI) for HCC of 7.40 (2.40-22.78), 6.46 (2.58-16.18), and 2.24 (0.97-5.15), respectively, for prediction of HCC within 1-2, 2-5, and ≥5 years. Higher proportions of individuals had M2BPGi levels ≥2.0 COI in samples closer to HCC diagnosis. Areas under receiver operating characteristic curves for models with M2BPGi, AFP, and HBsAg levels predicting HCC within 1-2, 2-5, and >5 years were 0.84, 0.81, and 0.75. M2BPGi is a strong and independent short-term predictor of HCC in CHB patients.

Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers.

The relation between aflatoxin B1 (AFB1 ) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1 -albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly (p < 0.0001) shorter in participants with high serum levels of AFB1 -albumin adducts than those with low/undetectable levels. There were significant dose-response relations with serum AFB1 -albumin adduct level at study entry for cirrhosis (p-trend = 0.0001) and cirrhotic HCC (p-trend < 0.0001) newly diagnosed within 9 years after entry as well as non-cirrhotic HCC (p-trend = 0.021) newly diagnosed within 4 years after entry. The aORs (95% CIs) for high versus undetectable serum AFB1 -albumin adduct levels were 2.45 (1.51-3.98) for cirrhosis (p = 0.0003), 5.47 (2.20-13.63) for cirrhotic HCC (p = 0.0003), and 5.39 (1.11-26.18) for non-cirrhotic (p = 0.0368) HCC, respectively. There remained a significant dose-response relation between serum AFB1 -albumin adduct level and HCC risk (p-trend = 0.0291) in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11-8.30) for high versus undetectable serum levels (p = 0.0299). It is concluded that AFB1 exposure may increase the risk of cirrhosis and HCC in a dose-response manner among chronic HBV carriers.

Risk of hepatitis C virus related hepatocellular carcinoma between subjects with spontaneous and treatment-induced viral clearance.

BACKGROUND/AIMS: Both spontaneous hepatitis C virus (HCV) clearance and the achievement of sustained virological response (SVR) by anti-viral therapy greatly reduce the incidence of hepatocellular carcinoma (HCC). The current study aimed to compare the risk of HCC between the two patient groupsMethods: A total of 313 subjects with spontaneous HCV clearance (SC) and 564 age- and sex-matched patients in the treatment-induced SVR group were enrolled for analysis. RESULTS: Nineteen (2.2%) of the 877 patients developed HCC during 6,963 person-years of follow-up. Fourteen (2.5%) SVR patients and 5 (1.6%) SC patients developed HCC (P=0.004). Cox regression analysis of factors predictive of HCC included SVR (versus SC: hazard ratio [HR]/ 95% confidence interval [CI]: 5.83/1.27-26.88), diabetes (HR/CI:3.41/1.21-9.58), and age (HR/CI: 1.07/1.01-1.14). Of the 564 SVR patients, eleven (5.9%) of the 187 patients with fibrosis stage 2-4 (F2-4) and 2 (0.9%) of the 226 patients with F01 developed HCC (P=0.01). Compared to SC subjects, only SVR patients with F2-4 (P<0.001) but not F0-1(P=0.60) had a higher risk of HCC development. Cox-regression analysis using liver fibrosis as a variable demonstrated that factors associated with HCC included SVR with F2-4 (versus SC: HR/CI: 10.06/2.20-45.98), diabetes (HR/CI:3.23/1.14-9.19), and age (HR/CI: 1.08 1.02-1.15). CONCLUSIONS: Compared to subjects with spontaneous viral clearance, subjects with antiviral treatment-induced HCV viral clearance remain at high risk for HCC development, especially if they have significant hepatic fibrosis. These results may provide important information for decision-making regarding the prioritization of current direct antiviral agents in resource-limited countries.

Chronic hepatitis C virus infection and the risk for diabetes: a community-based prospective study.

BACKGROUND: The association between hepatitis C virus (HCV) infection and the occurrence of type II diabetes remains controversial. Prospective studies are needed to assess its causal temporality. METHODS: A cohort of 21 559 adults enrolled from seven townships in Taiwan during 1991-1992 and followed till the end of 2010. Incident diabetes over a study time period from 2000 to 2010 was ascertained through computerized linkage with the National Health Insurance database and the National Death Certification profiles. Cox's proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Antibodies against HCV (anti-HCV) were tested for all participants, and serum HCV RNA levels were measured for anti-HCV seropositives. RESULTS: During 180 244 person-years of follow-up, there were 1917 incident diabetes cases recorded. The cumulative risk for diabetes was 10.9% for anti-HCV seronegatives and 16.7% for anti-HCV seropositives respectively. The HR for diabetes of anti-HCV seropositivity was 1.53 (95% CI: 1.29-1.81) compared with anti-HCV seronegatives after adjustment for risk predictors. The adjusted HRs were 1.63 (1.31-2.02) for anti-HCV seropositives with positive HCV RNA compared to anti-HCV seronegatives (P<.001). CONCLUSION: Chronic HCV infection was associated with an increased risk for diabetes after adjustment for other risk predictors.

Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis.

BACKGROUND AND AIMS: Most studies on risk predictors of hepatocellular carcinoma (HCC) among cirrhotic chronic hepatitis B patients do not confirm the date at cirrhosis diagnosis. We examined HCC risk and predictors in chronic hepatitis B patients with newly diagnosed cirrhosis. METHODS: 4155 HBsAg seropositive participants were followed every 6-12 months with seromarker testing. Cirrhosis was ascertained through abdominal ultrasonography and computerized linkage with national health insurance profiles. Predictors included in Cox proportional hazards models were age, HBeAg serostatus, serum levels of HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and ALDH2 rs671 genotypes. RESULTS: A total of 301 patients developed cirrhosis, 76 of whom later developed HCC after 2462 person-years, showing an average annual incidence of 3.1%. The 15-year cumulative HCC risk among cirrhotics was 39.8% with a lifetime (30-80 years old) HCC risk of 78.5%. The adjusted HR's (95% CI, P-value) were 14.26 (3.17-64.08, P = 0.0005) for age at cirrhosis diagnosis of ≥60 years (vs 30-39 years), 2.85 (1.49-5.46, P = 0.0015) for HBeAg seropositivity (vs HBeAg seronegativity with HBsAg levels <1000 IU/mL), 0.35 (0.20-0.59, P < 0.0001) for AA/AG genotypes of rs671 (vs GG genotype), 3.68 (1.70-7.99, P = 0.0010) for ALT levels >45 U/L (vs <15 U/L), 3.52 (1.78-6.93, P = 0.0003) for AFP levels >20 ng/mL (vs <10 ng/mL), and 2.64 (1.38-5.07, P = 0.0035) for HBsAg levels ≥1000 IU/mL (vs <1000 IU/mL among HBeAg seronegatives). CONCLUSIONS: Older age, GG genotype of ALDH2 rs671, HBeAg seropositivity, and elevated serum levels of ALT, AFP, and HBsAg at cirrhosis diagnosis were HCC risk predictors in cirrhotic chronic hepatitis B patients.

Serum Levels of Hepatitis B Surface Antigen and DNA Can Predict Inactive Carriers With Low Risk of Disease Progression.

UNLABELLED: Serum levels of hepatitis B virus (HBV) DNA (≤2000 IU/mL) and hepatitis B surface antigen (HBsAg) (<1000 IU/mL) have been shown to distinguish inactive carriers with high accuracy. The goal of this study was to validate the predictability of one-time measurement of quantitative HBsAg and HBV DNA levels for inactive carrier status and chronic hepatitis B (CHB) progression in a community-based cohort. This study included 1529 participants chronically infected with HBV genotype B or C from the REVEAL-HBV cohort. They were ascertained as inactive or active CHB after 18 months of follow-up. Validity of the one-time measurement was assessed by sensitivity, specificity, and receiver operating characteristic curves, while associations with clinical outcomes were calculated with Cox proportional hazards regressions. The one-time baseline measurement of HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL distinguished inactive carriers from active CHB with a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 71%, 85%, 83%, 74%, and 78%, respectively. Those identified as inactive carriers using the one-time baseline measurement had multivariate adjusted hazard ratios of 0.36 (95% confidence interval [CI], 0.20-0.63) and 0.36 (0.23-0.56) for hepatocellular carcinoma and liver cirrhosis, respectively, and an adjusted rate ratio of 6.97 (95% CI, 5.21-9.33) for HBsAg seroclearance. Areas under the receiver operating characteristic curve of predicting these outcomes using the one-time definition were similar to those obtained when using long-term follow-up defined carrier status for prediction. CONCLUSION: This study confirms the predictability of a one-time combined HBsAg and HBV DNA measurement for future inactive carriers. This single-point strategy provides new and complementary information useful for management of patients with chronic hepatitis B infection. (Hepatology 2016;64:381-389).

Alcohol Drinking Mediates the Association between Polymorphisms of ADH1B and ALDH2 and Hepatitis B-Related Hepatocellular Carcinoma.

BACKGROUND: The role of polymorphisms on ADH1B and ALDH2 in patients with chronic hepatitis B is unclear. This study aims to examine whether alcohol drinking mediates the association between two ADH1B and ALDH2 polymorphisms and the risk of hepatocellular carcinoma among chronic hepatitis B patients. METHODS: A total of 3,824 individuals were enrolled in this study. Two SNPs, rs1229984 (ADH1B) and rs671 (ALDH2), were genotyped using the Affymetrix Axiom Genome-Wide CHB1 Array (Affymetrix, Inc). Multivariate unconditional logistic regression and mediation analyses were used, comparing CT or TT with CC for rs1229984 and GA and AA with GG for rs671. RESULTS: There were 602 cases of hepatocellular carcinoma and 3,222 controls. Frequencies of the rs1229984 (ADH1B) T allele and rs671 (ALDH2) A allele were 72.9% and 28.8%, respectively. Individuals who carried at least one deficient allele for both SNPs were significantly less likely to become habitual alcohol drinkers, with an OR and 95% confidence interval (CI) of 0.24 (0.15-0.40). Alleles for rs1229984 (ADH1B) and rs671 (ALDH2) were not associated with hepatocellular carcinoma in multivariate analyses. However, mediation analyses showed that the rs1229984 T allele, rs671 A allele, and two SNPs combined were significantly associated with decreased hepatocellular carcinoma risk, mediated through alcohol drinking, with an OR (95% CI) of 0.87 (0.79-0.96), 0.70 (0.61-0.82), and 0.73 (0.58-0.88), respectively. CONCLUSIONS: Polymorphisms on ADH1B and ALDH2 had significant indirect effects on hepatocellular carcinoma risk, mediated through alcohol drinking. IMPACT: Future genetic studies of chronic hepatitis B and hepatocellular carcinoma must take mediation effects into consideration. Cancer Epidemiol Biomarkers Prev; 25(4); 693-9. ©2016 AACR.

The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.

OBJECTIVE: The sodium taurocholate co-transporting polypeptide (NTCP), encoded by SLC10A1, was recently identified as a receptor for HBV. We assessed the association of the p.Ser267Phe variant (rs2296651) with chronic hepatitis B (CHB) serostatus, cirrhosis and hepatocellular carcinoma (HCC) in patients with CHB. DESIGN: The variant was genotyped in 3801 patients with CHB and 3801 matched hepatitis B surface antigen (HBsAg) seronegative individuals. ORs with 95% CIs for the variant's association with CHB, cirrhosis and HCC were estimated using logistic regression. RESULTS: In patients with CHB, the S267F variant was observed in 515 (18.5%) controls, 40 (17.2%) cirrhosis only cases, 49 (13.2%) non-cirrhotic HCC cases, and 52 (12.7%) cirrhotic-HCC cases. After adjustment for known risk factors, S267F was significantly associated with decreased risk for cirrhosis (OR 0.65 (95% CI 0.49 to 0.86), p=0.002) and HCC (OR 0.55 (95% CI 0.42 to 0.72), p<0.001). This association persisted for non-cirrhotic and cirrhotic-HCC. Compared with patients with HBV DNA levels greater than 10(5) copies/mL who carried the GG genotype, patients who had undetectable HBV DNA and the GA or AA genotypes had a 25-fold decreased risk of developing HCC (OR 0.04 (95% CI 0.02 to 0.11), p<0.001). The AA genotype was also associated with HBsAg seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p<0.001). CONCLUSIONS: The SLC10A1 (NTCP) S267F variant is independently associated with decreased risk of cirrhosis and HCC, and resistance to CHB infection. Together with serum HBV DNA levels, S267F may help to identify patients with CHB with very low risk of HCC.

Polymorphisms near the IFNL3 Gene Associated with HCV RNA Spontaneous Clearance and Hepatocellular Carcinoma Risk.

The aims of this study were to investigate associations between single nucleotide polymorphisms (SNPs) near the genes IFNL2, IFNL3, and IFNL4 and spontaneous clearance of hepatitis C virus (HCV) and to evaluate variants for their risk of hepatocellular carcinoma (HCC) among subjects in whom spontaneous HCV RNA clearance did not occur. In the first study, 889 untreated anti-HCV-seropositive patients without HCC symptoms were followed from 1991 to 2005. The spontaneous HCV clearance rate was found to be 33.1%. The TT variant of rs8099917 near IFNL3 was associated with increased spontaneous HCV RNA clearance, with an adjusted odds ratio (95% CI) of 2.78 (1.43-5.39), as was the newly-identified TT/TT dinucleotide variant rs368234815 near IFNL4 (adjusted odds ratio 2.68, 95% CI: 1.42-5.05). In the second study, associations between SNPs and HCC risk were examined in 483 HCC cases with detectable HCV RNA and 516 controls. In participants with HCV genotype 1, unfavorable genotypes for HCV clearance near IFNL3 were associated with increased HCC risk, the adjusted odds ratio (95% CI) for rs12979860 and rs8099917 being 1.73 (1.00-2.99) and 1.84 (1.02-3.33), respectively. Host characteristics should be considered to identify high-risk patients to prioritize the use of new antiviral agents and intensive screening.

Predicting Hepatitis B Virus (HBV) Surface Antigen Seroclearance in HBV e Antigen-Negative Patients With Chronic Hepatitis B: External Validation of a Scoring System.

BACKGROUND: Hepatitis B virus (HBV) surface antigen (HBsAg) seroclearance is the ultimate serological end point in chronic hepatitis B. This study aimed to develop and validate a prediction score for spontaneous HBsAg seroclearance in HBV e antigen (HBeAg)-negative patients with chronic hepatitis B due to HBV genotype B or C. METHODS: The development cohort included 2491 untreated participants from the community-based REVEAL-HBV study, who were HBeAg negative, anti-hepatitis C virus negative, and cirrhosis free. The independent validation cohort consisted of 1934 hospital-based individuals from the National Taiwan University Hospital. Clinical markers included in the model were age and serum HBV DNA and HBsAg levels. Cox proportional hazards regression models were used to create the prediction model. RESULTS: A prediction score ranging from 0 to 27 was developed. Predicted probabilities of 5- and 10-year HBsAg seroclearance ranged from 0.95% to 30.49% and from 2.58% to 62.52%, respectively. When applied to the independent validation cohort, the areas under the receiver operating characteristic curves for the 5- and 10-year prediction of HBsAg seroclearance in the validation cohort were 0.82 (95% confidence interval [CI], .76-.88) and 0.74 (95% CI, .70-.78). Model fit was still adequate, according to Hosmer-Lemeshow goodness of fit tests. CONCLUSIONS: A clinically applicable prediction score for HBsAg seroclearance was developed and externally validated. This model can assist clinicians in further stratifying risk groups.

Development and validation of a clinical scoring system for predicting risk of HCC in asymptomatic individuals seropositive for anti-HCV antibodies.

BACKGROUND: The development of a risk assessment tool for long-term hepatocellular carcinoma risk would be helpful in identifying high-risk patients and providing information of clinical consultation. METHODS: The model derivation and validation cohorts consisted of 975 and 572 anti-HCV seropositives, respectively. The model included age, alanine aminotransferase (ALT), the ratio of aspirate aminotransferase to ALT, serum HCV RNA levels and cirrhosis status and HCV genotype. Two risk prediction models were developed: one was for all-anti-HCV seropositives, and the other was for anti-HCV seropositives with detectable HCV RNA. The Cox's proportional hazards models were utilized to estimate regression coefficients of HCC risk predictors to derive risk scores. The cumulative HCC risks in the validation cohort were estimated by Kaplan-Meier methods. The area under receiver operating curve (AUROC) was used to evaluate the performance of the risk models. RESULTS: All predictors were significantly associated with HCC. The summary risk scores of two models derived from the derivation cohort had predictability of HCC risk in the validation cohort. The summary risk score of the two risk prediction models clearly divided the validation cohort into three groups (p<0.001). The AUROC for predicting 5-year HCC risk in the validation cohort was satisfactory for the two models, with 0.73 and 0.70, respectively. CONCLUSION: Scoring systems for predicting HCC risk of HCV-infected patients had good validity and discrimination capability, which may triage patients for alternative management strategies.