Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

BACKGROUND: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. METHODS: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. RESULTS: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. CONCLUSION: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Incidence, Factors, and Patient-Level Data for Spontaneous HBsAg Seroclearance: A Cohort Study of 11,264 Patients.

INTRODUCTION: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics. METHODS: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed. RESULTS: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state. DISCUSSION: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).

Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection, but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations. METHODS: We searched PubMed, Embase, and the Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model. RESULTS: We analyzed 34 published studies (with 42,588 patients, 303,754 person-years of follow-up, and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24). There were no significant differences between the sexes. A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P < .01). Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 log10 IU/mL; 95% CI, 5.94-7.27) vs not having HBsAg seroclearance (7.71 log10 IU/mL; 95% CI, 7.41-8.02) (P < .01) and with a lower level of HBsAg at baseline (2.74 log10 IU/mL; 95% CI, 1.88-3.60) vs not having HBsAg seroclearance (3.90 log10 IU/mL, 95% CI, 3.73-4.06) (P < .01). HBsAg seroclearance was not associated with HBV genotype or treatment history. Heterogeneity was substantial across the studies (I2 = 97.49%). CONCLUSION: In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.

Correction: Spontaneous Evolution in Bilirubin Levels Predicts Liver-Related Mortality in Patients with Alcoholic Hepatitis.

[This corrects the article DOI: 10.1371/journal.pone.0100870.].

Body Fat Distribution and Risk of Incident and Regressed Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Some studies have examined correlations between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with nonalcoholic fatty liver disease (NAFLD) or between VAT and NAFLD. We investigated the longitudinal association between body fat distribution (VAT vs SAT) and incidence and regression of NAFLD, adjusting for risk factors, in a large population-based cohort. METHODS: We collected data from adults who underwent abdominal ultrasonography (to identify liver fat), abdominal fat computed tomography scan, and blood tests from March 2007 through December 2008. Each patient underwent an anthropometric assessment and completed a questionnaire about their medical history, physical activity, and diet. Our final analysis involved 2017 subjects from the initial cohort who participated in a voluntary follow-up health screen performed in 2011 and 2013. The median follow-up time was 4.43 years. RESULTS: We found 288 incident cases of NAFLD; 159 patients had NAFLD regression during the follow-up period. An increasing area of VAT was associated with higher incidence of NAFLD in the multivariable analysis (highest quintile vs lowest quintile of VAT hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.28-3.89; P for trend = .002; HR, 1.36 [per 1 standard deviation]; 95% CI, 1.16-1.59). An increased area of SAT was significantly associated with regression of NAFLD (highest quintile vs lowest quintile of SAT HR, 2.30; 95% CI, 1.28-4.12; P for trend = .002; HR, 1.36 [per 1 standard deviation]; 95% CI, 1.08-1.72). CONCLUSIONS: In a large cohort study, larger areas of VAT were longitudinally associated with higher risk of incident NAFLD (during a period of approximately 4 years). In contrast, larger areas of SAT were longitudinally associated with regression of NAFLD. These data indicate that certain types of body fat are risk factors for NAFLD, whereas other types could reduce risk for NAFLD.

Viral Hepatitis in Korea: Past, Present, and Future.

Korea has been one of the endemic areas of hepatitis B virus (HBV; exclusively genotype C) infection since ancient times. The epidemiology of HBV in Korea is easily expected to have changed over the last two decades owing to the high coverage rate of universal HBV vaccination. The main mode of hepatitis C virus (HCV) infection may have been effectively blocked since 1992 when compulsory blood screening for anti-HCV was implemented, and consequently, the prevalence of anti-HCV is also expected to have markedly decreased during the last two decades. This review will briefly describe what really happened during the last couple of decades in the epidemiology of HBV and HCV and in the incidence and mortality rates of liver cirrhosis (hepatic failure) and hepatocellular carcinoma in Korea. HOW TO CITE THIS ARTICLE: Lee H-S. Viral Hepatitis in Korea: Past, Present, and Future. Euroasian J Hepato-Gastroenterol 2016;6(1):62-64.

Sorafenib inhibits cancer side population cells by targeting c­Jun N­terminal kinase signaling.

Sorafenib is a systemic chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the anticancer effect of sorafenib in cancer stem cell­like cells, such as side population (SP) cells, in HCC and to analyze the signaling pathway for drug­resistance. To evaluate the anticancer effects of sorafenib, Huh7 and Huh­BAT cells were treated with sorafenib, fluorouracil (5­FU), and sorafenib plus 5­FU. These cells were examined for growth rates, the SP fraction, sphere­forming efficacy and expression of c­Jun N­terminal kinase (JNK) signaling molecules. Sorafenib and 5­FU treatment decreased growth rates in Huh7 and Huh­BAT cells; however, the treatments exerted different effects in SP cells and on the expression levels of JNK signaling molecules. Treatment with 5­FU increased the SP cell number and upregulated the expression of JNK signaling molecules. By contrast, sorafenib decreased the SP cell number and downregulated the expression of JNK signaling molecules. No significant differences in sphere­forming efficacy were observed subsequent to 5­FU and sorafenib treatment in Huh7 and Huh­BAT cells. These results indicate that sorafenib exerted anticancer effects in HCC and SP cells by targeting JNK signaling.

Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice.

Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury.

Comparison of the Efficacy of Entecavir and Tenofovir in Nucleos(T)ide Analogue-Experienced Chronic Hepatitis B Patients.

The efficacy of entecavir (ETV) and tenofovir (TDF) for the treatment of nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients has been little studied. Here, we compare the efficacy of both ETV and TDF in NA-experienced CHB patients without detectable genotypic resistance. This retrospective cohort study included consecutive NA-experienced patients who had neither current nor previous genotypic resistance and had received ETV or TDF for at least 6 months. Overall, 202 patients (146 patients in the ETV group and 56 in the TDF group) were analyzed. The cumulative probabilities of complete virologic suppression (CVS) at month 12 were 76.1% in the ETV group and 95.0% in the TDF group (P<0.001), respectively. The TDF-treated group achieved CVS more rapidly than the ETV group for both Hepatitis B e antigen (HBeAg)-negative and -positive patients (P = 0.006 and < 0.001, respectively), and for those with both low (< 2,000 IU/mL) and high (≥ 2,000 IU/mL) HBV DNA levels (P = 0.01 and 0.002, respectively). TDF group had an increased probability of achieving CVS (hazard ratio, 2.242; 95% confidence interval, 1.587-3.165; P = 0.001), after adjustment for HBV DNA level, the presence of HBeAg, and a history of CVS during prior treatment. During the treatment period, 23 patients (15.8%) in the ETV group developed virologic breakthrough, compared to none in the TDF group. The cumulative probabilities of developing virologic breakthrough and ETV-resistance at month 24 were 9.7% and 5.3%, respectively. In conclusion, TDF is preferable to ETV for achieving CVS in NA-experienced CHB patients without genotypic resistance.

Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model.

PURPOSE: A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. METHODS: An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then, doxorubicin with or without flavopiridol was injected. The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism. RESULTS: Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression. CONCLUSIONS: These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.

Post-treatment intracranial hemorrhage of brain metastases from hepatocellular carcinoma.

PURPOSE: To evaluate the incidence and risk factors of post-treatment intracranial hemorrhage of brain metastases from hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Medical records of 81 patients who have been diagnosed of brain metastases from HCC and underwent surgery, radiosurgery and/or whole brain radiotherapy (WBRT) between January 2000 and December 2013 were retrospectively reviewed. RESULTS: Intracranial hemorrhage was present in 64 patients (79%) at the time of diagnosis. Median value of alpha-fetoprotein (AFP) level was 1,700 ng/mL. The Eastern Cooperative Oncology Group (ECOG) performance status for 20 patients was greater than 2. Fifty-seven patients underwent WBRT and the others were treated with surgery and/or radiosurgery without WBRT. During follow-up, 12 events of intracranial hemorrhage after treatment were identified. Three-month post-treatment hemorrhage rate was 16.1%. Multivariate analyses revealed that ECOG performance status, AFP, and WBRT were associated with post-treatment hemorrhage (p = 0.013, 0.013, and 0.003, respectively). Kaplan-Meier analysis showed that 3-month post-treatment hemorrhage rate of new lesion was higher in patients treated without WBRT, although statistical significance was not reached. (18.6% vs. 4.6%; p = 0.104). Ten of 12 patients with post-treatment hemorrhage died with neurologic cause. CONCLUSION: WBRT should be considered to prevent post-treatment hemorrhage in the treatment of brain metastases from HCC.

Nonalcoholic fatty liver disease is associated with coronary artery calcium score in diabetes patients with higher HbA1c.

BACKGROUND: In patients with diabetes, studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and coronary artery calcium score (CACS) have shown conflicting results. The aim of this study was to evaluate the association between NAFLD and CACS in diabetic patients. METHODS: This is the cohort study performed in Seoul National University Hospital Gangnam Healthcare Center. NAFLD was defined as cases with the typical ultrasonographic findings without excessive alcohol consumption, medications causing hepatic steatosis or other chronic liver diseases. CACS was evaluated using the Agatston method. Diabetes was defined as cases with fasting serum glucose ≥ 126 mg/dl, glycated hemoglobin (HbA1c) ≥ 6.5%, or those taking anti-diabetic medications. Multivariate linear regression analyses were performed with use of the interaction term of NAFLD × glycemic level and other confounders of CACS such as age, sex, hypertension, body mass index, waist circumference, HDL cholesterol and triglyceride. RESULTS: A total of 213 participants with diabetes were included in the study. As 77 subjects (36.2%) had CACS 0, causing left sided skewness, CACS was analyzed after log transformation to Ln (CACS + 1). A statistically significant interaction was observed between NAFLD and HbA1c ≥ 7% (P for interaction = 0.014). While NAFLD was not associated with CACS in the group with HbA1c < 7% (P = 0.229), it was significantly associated in the group with HbA1c ≥ 7% (P = 0.010) after adjusting for covariates in multivariate analyses. CONCLUSIONS: This study demonstrated an effect modification of glycemic level on the association between NAFLD and CACS. NAFLD was independently associated with CACS only in diabetes patients with higher HbA1c, after adjustment for confounders.

Comparison of transarterial chemoembolization and hepatic resection for large solitary hepatocellular carcinoma: a propensity score analysis.

PURPOSE: To compare long-term survival after hepatic resection and transarterial chemoembolization of large solitary hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Analysis of 91 and 68 consecutive patients with large (≥ 5 cm) solitary HCCs who underwent hepatic resection and transarterial chemoembolization, respectively, was performed. Overall survival and time to progression (TTP) were estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model. To control for treatment-selection bias, matched groups of patients were selected using a propensity score matching method, and survival analysis was repeated. RESULTS: During the follow-up period (median, 60.7 mo; range, 0.5-122.2 mo), 42 (46%) patients in the hepatic resection group and 35 (51%) patients in the transarterial chemoembolization group died. The 1-year, 3-year, and 5-year overall survival rates of the hepatic resection and transarterial chemoembolization groups were 91.1%, 80.0%, and 66.4% (hepatic resection group) and 89.8%, 72.8%, and 49.6% (transarterial chemoembolization group) (P = .023). TTP was significantly longer in patients who underwent hepatic resection (P < .001). Hepatitis B surface antigen positivity and the absence of portal hypertension were independent predictors for favorable overall survival. For patients with platelet counts ≤ 100,000/mm(3), Child-Pugh score of 6, smaller HCCs (≤ 7 cm), or portal hypertension, hepatic resection and transarterial chemoembolization yielded similar overall survival rates. After propensity score matching, transarterial chemoembolization was comparable to hepatic resection in overall survival (P = .293), whereas TTP remained longer in patients who underwent hepatic resection (P = .001). CONCLUSIONS: Transarterial chemoembolization can lead to results comparable to hepatic resection in the treatment of large solitary HCCs, particularly in patients with clinically presumed portal hypertension.

Hepatitis B virus-related glomerulonephritis: not a predominant cause of proteinuria in korean patients with chronic hepatitis B.

Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN. Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea. Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group. Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV-GN.

Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments.

Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA.

The effect of therapeutic vaccination for the treatment of chronic hepatitis B virus infection.

Although oral nucleos(t)ide analogues can lead to suppression of serum hepatitis B virus (HBV) DNA to undetectable levels efficiently, they usually fail to achieve seroclearance of hepatitis B surface antigen (HBsAg), which indicates eradication of HBV infection. In this study, the efficacy of therapeutic vaccination in patients with chronic HBV infection was evaluated by comparing to the control patients. Patients who had achieved complete virologic response following oral nucleos(t)ide analogue treatment for at least 6 months were included. Vaccinated patients were given three intramuscular injections of hepatitis B vaccine that each contains 20 µg of HBsAg. The efficacy of vaccination was assessed by testing for HBsAg seroclearance. A total of 32 consecutive patients were analyzed, which included 15 vaccinated patients and 17 control patients. At month 6, 1 out of 15 vaccinated patients (6.7%) and 1 out of 17 control patients (5.9%) were determined to clear HBsAg from their sera (P = 1.000). A baseline HBsAg titer of ≤100 IU/mL tended to be predictive of HBsAg seroclearance, but the relationship was not significant (P = 0.097). During the follow-up period, virologic relapse occurred in 29 patients, and 9 patients developed hepatitis flare. The cumulative incidences of virologic relapse and hepatitis flare were similar between the vaccinated and control patients (P = 0.077 and P = 0.667, respectively). In conclusion, therapeutic HBV vaccination in patients who had stopped nucleos(t)ide analogue treatment showed limited efficacy for HBsAg seroclearance. To enhance the efficacy and safety of therapeutic HBV vaccination, rational patient selection and novel therapeutic approaches are needed.

Forns index predicts recurrence and death in patients with hepatitis B-related hepatocellular carcinoma after curative resection.

BACKGROUND & AIMS: Advanced liver fibrosis is associated with recurrence after curative resection of hepatocellular carcinoma (HCC). This study aimed to investigate whether noninvasive fibrosis indices could predict intrahepatic recurrence and death after curative resection of HCC. METHODS: Patients who underwent curative resection for hepatitis B virus (HBV)-related HCC between 2006 and 2010 at a single tertiary hospital were included. This study analysed the association of noninvasive fibrosis indices with recurrence and overall survival. RESULTS: A total of 303 patients were included. During a median follow-up period of 56.0 (interquartile range, 42.0-70.0) months, 151 (49.8%) patients experienced HCC recurrence and 54 (17.8%) died. Based on multivariate analysis, Forns index [hazard ratio (HR), 1.238; 95% confidence interval (CI), 1.097-1.398; P = 0.001] was independently associated with tumour recurrence after adjustment for anti-HBe positivity, histological cirrhosis, tumour size and number. Patients with Forns index <6.9 had a significantly longer recurrence-free survival rate than patients with Forns index ≥6.9 (P < 0.001 by log-rank test). Forns index (HR, 1.246; 95% CI, 1.034-1.501; P = 0.02) could also predict overall survival after adjustment for tumour size and number. Forns index detected cirrhosis with an AUROC of 0.700 (95% CI, 0.641-0.758). Aspartate aminotransferase-to-platelet ratio index, cirrhosis discriminant score, FIB-4 index, P2/MS and Lok index detected cirrhosis comparably to Forns index, but were not associated with tumour recurrence or death. CONCLUSIONS: Our data suggest that Forns index could be a useful predictor of recurrence and overall survival after curative resection of HBV-related HCC.

Association of VARS2-SFTA2 polymorphisms with the risk of chronic hepatitis B in a Korean population.

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is the most serious risk factor for chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) identified important variants associated with the risk of CHB in Asian populations. Specifically, our previous GWAS identified the VARS2-SFTA2 gene region as one of the genetic risk loci for CHB. METHODS: To further characterize this association and to isolate possible causal variants within it, we performed an additional association study by genotyping more SNPs in the vicinity of the VARS2 and SFTA2 genes. In all, 14 SNPs of VARS2-SFTA2 were analysed among a total of 3902 subjects (1046 cases and 2856 controls). RESULTS: Logistic regression analysis revealed that six SNPs, including the previously reported rs2532932, were significantly associated with the risk of CHB (P = 1.7 × 10(-10) ~0.002). Further linkage disequilibrium and conditional analysis identified two variants (rs9394021 and rs2517459) as new markers of genetic risk factors for CHB rather than the reported SNP from our previous study (rs2532932). To evaluate the cumulative risk for CHB based on all known genetic factors, genetic risk score (GRS) were calculated. As anticipated, the distribution of the number of risk alleles in cases vs. controls clearly differed according to the GRS. Similarly, the odds ratios (ORs) were increased (OR = 0.32-3.97). CONCLUSION: Our findings show that common variants in the VARS2-SFTA2 gene region are significantly associated with CHB in a Korean population, which may be useful in further understanding genetic susceptibility to CHB.

Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P=0.562 and P=0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.