Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Common Genetic Variants of Response to Hepatitis B Vaccines Correlate with Risks of Chronic Infection of Hepatitis B Virus: A Community-Based Case-Control Study.

Hepatitis B (HB) vaccination effectively reduces the risks of chronic infection with the hepatitis B virus (HBV). It is unknown whether there is a common genetic determinant for response to the HB vaccine and susceptibility to chronic HBV infection. This case-control study, which included 193 chronic HBV carriers and 495 non-carriers, aimed to explore the effects of the most significant single nucleotide polymorphisms (SNPs) in response to the HB vaccine on the risks of chronic HBV infection. Out of 13 tested SNPs, the genotype distributions of four SNPs at the human leukocyte antigen (HLA) class II region, including rs34039593, rs614348, rs7770370, and rs9277535, were significantly different between HBV carriers and non-carriers. The age-sex-adjusted odds ratios (OR) of chronic HBV infection for rs34039593 TG, rs614348 TC, rs7770370 AA, and rs9277535 AA genotypes were 0.51 (95% confidence interval [CI], 0.33-0.79; p = 0.0028), 0.49 (95% CI, 0.32-0.75; p = 6.5 × 10-4), 0.33 (95% CI, 0.18-0.63; p = 7.4 × 10-4), and 0.31 (95% CI, 0.14-0.70; p = 0.0043), respectively. Multivariable analyses showed that rs614348 TC and rs7770370 AA genotypes were significantly independent protectors against chronic HBV infection. The multivariable-adjusted ORs for subjects with none, either one, or both of the protective genotypes were 1.00 (referent), 0.47 (95% CI: 0.32-0.71; p = 3.0 × 10-4), and 0.16 (95% CI: 0.05-0.54; p = 0.0032), respectively. Among eight HBeAg-positive carriers, only one of them carried a protective genotype. This study shows that response to the HB vaccine and susceptibility to chronic HBV infection share common genetic determinants and indicates that HLA class II members are the main responsible host genetic factors.

Relationship Between Gallstone Disease and Cardiometabolic Risk Factors in Elderly People with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: The prevalence of gallstone disease (GSD) increases with age, and the elderly have a much higher mortality risk and incidence of surgical comorbidities. The aim of this study was to explore the relationship between GSD and cardiometabolic risk factors in elderly people with non-alcoholic fatty liver disease (NAFLD). METHODS: In this cross-sectional study, we analyzed the data of elderly people who underwent annual health check-ups at a Northern Taiwan health examination center. These data were collected from physical examination, blood tests, abdominal ultrasonography, and medical histories. We excluded those with hepatitis B or C infections, heavy alcohol consumption, or cholecystectomy. RESULTS: The analysis included 3,037 participants with a mean age of 73.6±6.0 years. Over 70% were overweight or obese, and the overall prevalence of GSD was 17.7%. In our univariate analysis, GSD was positively correlated with age, body mass index, metabolic syndrome, diabetes mellitus (DM), hypertension (HTN), and various metabolic factors (fasting plasma glucose [FPG], triglyceride, uric acid, and high-density lipoprotein cholesterol [HDL-C] levels). After adjustment for age, gender, and body mass index, metabolic syndrome showed a positive association with GSD (odds ratio [OR] 1.31 [95% confidence interval [CI], 1.05-1.64]; P=0.020). Specific components of metabolic syndrome that increased the risk for GSD in NAFLD elderly include lower levels of HDL-C (OR 1.35 [95% CI, 1.10-1.66]; P<0.001) and elevated FPG (OR 1.36 [95% CI, 1.10-1.69]; P<0.001). CONCLUSION: Our study concluded that GSD is significantly associated with metabolic syndrome in elderly people with NAFLD. Reduced HDL-C and elevated FPG both heighten the risk of developing GSD. Therefore, to lower the risk of GSD in NAFLD patients, their FPG levels and HDL-C levels must be regularly followed-up, and these patients should be educated about the symptoms of GSD if they meet the criteria for metabolic syndrome.

Response to hepatitis B vaccination is co-determined by HLA-DPA1 and -DPB1.

BACKGROUND AND AIMS: No report explored the combined effects of HLA-DPA1 and -DPB1 with long-term response to hepatitis B (HB) vaccination (HBVac). The specific aims of the study were to assess the combined effects and relative contributions of DPA1 and DPB1 genes. METHODS: The cases were 152 adolescents who had undetectable (<1.0 mIU/mL) post-booster anti-HBs titers and the controls were adolescents who had residual anti-HBs ≥ 10 mIU/mL at aged 16 years (n = 207) or had detectable (≥1.0 mIU/mL) anti-HBs titers after booster HBVac (n = 481). HLA-DPA1 and -DPB1 genotypes were determined by sequence-based typing. RESULTS: HLA-DPA1*01:03:01 was correlated with lower ORs of undetectable anti-HBs titers, while -DPA1*02:02:02 and -DPB1*05:01:01 were correlated with higher ORs. The ORs for HLA-DPA1*01:03:01-DPB1*05:01:01 and DPA1*02:02:02-DPB1*protective combinatory types were significantly less than 1.0. As compared with subjects who had no protective allele, the adjusted ORs (95% CI) were 0.545 (0.328-0.906), 0.350 (0.174-0.702), and 0.122 (0.058-0.257), for subjects who had protective alleles on DPA1only, DPB1 only, and both genes, respectively. Analyses of amino acid polymorphisms showed that subjects who carried Arg81-Pro158-Val191-Pro259α + Met234ß and Gln62-Arg82α + Met234ß combinations had 4.3-to-4.6 folds of risks. CONCLUSION: Both DPA1 and DPB1 genes contribute to the persistence of immunological response to primary infantile HBVac. The effects of HLA-DP risk alleles were dominated by the protective alleles and there were significant gene-gene interactions. Our findings provide evidences for the design of more potent HB vaccine.

A Novel Prediction Model for Bloodstream Infections in Hepatobiliary-Pancreatic Surgery Patients.

BACKGROUND: Bloodstream infections (BSI) are an important source of postoperative mortality in hepatobiliary-pancreatic surgery (HBPS) patients, and no prediction model has been analyzed before. METHODS: Using big data from the electronic medical records of the administrative and culture databases of MacKay Memorial Hospital, we identified the potential risk factors for community-acquired and healthcare-associated BSI and mortality of patients who received HBPS. Subsequently, we analyzed the microorganisms' profiles and antimicrobial susceptibility patterns for these BSI. RESULTS: BSI were found in 6.3% patients (349 of 5513 HBPS patients), and hospital mortality was 1.48% (82 of 5513). Dividing patients into low-, intermediate-, and high-risk groups on the basis of sex, age, status of comorbidity (renal failure, peptic ulcer disease, fluid and electrolyte disorders, and acute cholecystitis), a predictive BSI risk score model was developed. According to this model, BSI risk ranged from 1.43% to 11.95%; AUROC to predict BSI risk was 0.72 (95% CI 0.69-0.75). From this retrospective study, Enterobacteriaceae were the most common microorganisms that were isolated from BSI. For both community-acquired and healthcare-associated BSI, imipenem and colistin are the most successful. CONCLUSION: This novel model can be useful to predict who is at risk of BSI after HBPS, and new prophylactic protocols for these patients are needed.

Trajectories of serum hepatitis B surface antigen kinetics in patients with chronic hepatitis B receiving long-term nucleos(t)ide analogue therapy.

BACKGROUND & AIMS: The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients remains unclear. We investigated the patterns of serum HBsAg kinetics and their association with therapeutic outcomes in genotype B- or C-infected CHB patients receiving long-term NA therapy. METHODS: We enrolled 329 treatment-naive CHB patients receiving NA therapy for >5 years to analyse the kinetic patterns by using group-based trajectory models (GBTMs). RESULTS: Most patients (82.4%) received entecavir therapy. The median treatment duration was 83.6 (68.5-89.7) months. The GBTMs revealed three groups for both the hepatitis B e antigen (HBeAg)-positive and -negative patients. The median annual decline in serum HBsAg levels during the first 5 years was significantly higher in Group 1 than in Groups 2 and 3 in HBeAg-positive (0.78 vs 0.10 vs 0.10 log10 IU/mL) and HBeAg-negative (0.71 vs 0.08 vs 0.09 log10 IU/mL) patients. HBsAg levels at the baseline and 12 months combined with an HBsAg decline from the baseline to 12 months of treatment predicted trajectory pattern 1 in HBeAg-positive (sensitivity, 77.8%; specificity, 99.1%; positive predictive value [PPV], 87.5%; and negative predictive value [NPV], 98.2%) and HBeAg-negative (sensitivity, 100%; specificity, 99.5%; PPV, 88.9%; and NPV, 100%) patients. The trajectory patterns were significantly associated with HBeAg loss in the HBeAg-positive patients and the achievement of HBsAg <100 IU/mL or HBsAg loss in HBeAg-positive and HBeAg-negative patients. CONCLUSIONS: The trajectory of serum HBsAg levels predicts HBsAg loss in CHB patients receiving long-term NA therapy.

Sleep Trajectories of Women Undergoing Elective Cesarean Section: Effects on Body Weight and Psychological Well-Being.

BACKGROUND: After cesarean section (CS), women may be at great risk for sleep disturbance, but little is known about temporal changes in their sleep patterns and characteristics. We had two aims: 1) to identify distinct classes of sleep-disturbance trajectories in women considering elective CS from third-trimester pregnancy to 6 months post-CS and 2) to examine associations of sleep trajectories with body mass index (BMI), depressive symptoms, and fatigue scores. METHODS: We analyzed data from a prospective cohort study of 139 Taiwanese pregnant women who elected CS. Sleep components were assessed using the Pittsburgh Sleep Quality Index in third-trimester pregnancy, 1 day, 1 week, 1 month, and 6 months post-CS. Data were collected on depressive symptoms, fatigue symptoms, and BMI. Sleep-quality trajectories were identified by group-based trajectory modeling. RESULTS: We identified three distinct trajectories: stable poor sleep (50 women, 36.0%), progressively worse sleep (67 women, 48.2%), and persistently poor sleep (22 women, 15.8%). Poor sleep was significantly associated with pre-pregnancy BMI and more baseline (third-trimester pregnancy) depressive and fatigue symptoms. At 6 months post-CS, women classified as progressively worse or persistently poor sleepers showed a trend toward higher BMI (p<0.03), more depressive symptoms (p<0.001), and higher fatigue scores (p<0.001) than those with stable poor sleep. CONCLUSIONS: Women had three distinct sleep-disturbance trajectories before and after elective CS. These poor-sleep courses were associated with BMI and psychological well-being. Our findings suggest a need to continuously assess sleep quality among women considering elective CS and up to 6 months post-CS.

SNP rs7770370 in HLA-DPB1 loci as a major genetic determinant of response to booster hepatitis B vaccination: results of a genome-wide association study.

BACKGROUND AND AIM: Hepatitis B (HB) vaccination is highly effective in reducing the risk of hepatitis B virus infection. However, breakthrough and chronic hepatitis B virus infections in vaccinated subjects raised concern about its long-term efficacy. The specific aim of the study was to explore the host genetic determinants of long-term immunological memory against HB vaccination. METHODS: We conducted a case-control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers ≥ 10 mIU/mL at the age of 15-18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques. RESULTS: We found that 10 of the 112 candidate SNPs (P-value < 5.0 × 10(-5) ) clustered within a 47-Kb region of the HLA-DP loci. All the minor alleles of these HLA-DP candidate SNPs were correlated with lower likelihoods of nonresponse to HB vaccine. There was a significant linkage disequilibrium between these HLA-DP candidate SNPs and HLA-DPB1 protective alleles. Multivariate analyses showed that rs7770370 was the most significant genetic factor. As compared with rs7770370 GG homozygotes, adjusted odds ratios were 0.524 (95% confidence interval, 0.276-0.993) and 0.095 (95% confidence interval, 0.030-0.307) for AG heterozygotes and AA homozygotes, respectively. CONCLUSION: Our results showed that rs7770370 was the most significant genetic factor of response to HB booster. The rs7770370 and nearby SNPs may also contribute to the long-term immunological memory against HB vaccination.

Plasma adipokines and risk of hepatocellular carcinoma in chronic hepatitis B virus-infected carriers: a prospective study in taiwan.

BACKGROUND: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC. METHODS: We conducted a nested case-control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI). RESULTS: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12-2.11; OR = 4.88 (1.46-16.3); OR = 3.79 (1.10-13.0); OR = 4.13 (1.13-15.1) with each additional quintiles, respectively] with a significant dose-response trend (P(trend) = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62-4.39); OR = 3.85 (1.47-10.1); OR = 2.56 (0.96-6.84); OR = 3.76 (1.33-10.7) for the second, third, fourth, and fifth quintiles, respectively; P(trend) = 0.017] before HCC. CONCLUSIONS: Elevated adiponectin levels were independently associated with an increased risk of HCC. IMPACT: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown.

Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma.

BACKGROUND & AIMS: It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). METHODS: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09-8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001). CONCLUSIONS: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.