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Preclinical data have shown that the herbal extract, ALS-L1023, from Melissa officinalis reduces visceral fat and hepatic steatosis. We aimed to assess the safety and efficacy of ALS-L1023 as the treatment of non-alcoholic fatty liver disease (NAFLD). We conducted a 24-week randomized, double-blind, placebo-controlled 2a study in patients with NAFLD (MRI-proton density fat fraction [MRI-PDFF] ≥ 8% and liver fibrosis ≥ 2.5 kPa on MR elastography [MRE]) in Korea. Patients were randomly assigned to 1800 mg ALS-L1023 (n = 19), 1200 mg ALS-L1023 (n = 21), or placebo (n = 17) groups. Efficacy endpoints included changes in liver fat on MRI-PDFF, liver stiffness on MRE, and liver enzymes. For the full analysis set, a relative hepatic fat reduction from baseline was significant in the 1800 mg ALS-L1023 group (−15.0%, p = 0.03). There was a significant reduction in liver stiffness from baseline in the 1200 mg ALS-L1023 group (−10.7%, p = 0.03). Serum alanine aminotransferase decreased by −12.4% in the 1800 mg ALS-L1023 group, −29.8% in the 1200 mg ALS-L1023 group, and −4.9% in the placebo group. ALS-L1023 was well tolerated and there were no differences in the incidence of adverse events among the study groups. ALS-L1023 could reduce hepatic fat content in patients with NAFLD.

Propensity score matching is widely used to determine the effects of treatments in observational studies. Competing risk survival data are common to medical research. However, there is a paucity of propensity score matching studies related to competing risk survival data with missing causes of failure. In this study, we provide guidelines for estimating the treatment effect on the cumulative incidence function when using propensity score matching on competing risk survival data with missing causes of failure. We examined the performances of different methods for imputing the data with missing causes. We then evaluated the gain from the missing cause imputation in an extensive simulation study and applied the proposed data imputation method to the data from a study on the risk of hepatocellular carcinoma in patients with chronic hepatitis B and chronic hepatitis C.

Although lactose-free dairy products for the clinical management of lactose intolerance (LI) are widely available, scientific evidence on their efficacy is still lacking. This study comparatively analyzed the efficacy of flavored lactose-free milk (LFM) and whole milk (WM) in reducing symptoms in South Korean adults with LI. This prospective study was conducted in adults suspected of LI. All screened participants underwent the hydrogen breath test (HBT) using 570 mL of chocolate-flavored WM (20 g of lactose) and responded to a symptom questionnaire. LI was confirmed when the

Optimal treatments for patients with advanced hepatocellular carcinoma (HCC) are still limited and their prognosis remains dismal. Yet, there have been rare cases that have shed light on longer survival in these patients assisted by various treatments. This paper aims to present an extraordinary case of far advanced HCC that had been properly managed in spite of continuous recurrence. A patient visited the hospital with a ruptured large HCC with main portal vein tumor thrombosis but survived longer than 14 years owing to active and prompt interventions. (J Liver Cancer 2020;20:148-153)

Background Regular clinic follow‐up is a prerequisite for optimal antiviral therapy and surveillance of hepatocellular carcinoma in patients with chronic hepatitis B (CHB). However, adherence to regular follow‐up stays low in practice. This study investigated whether regular follow‐up is associated with decreased liver cancer mortality in CHB patients. Methods A nationwide population‐based historical cohort study was conducted using customized data from the National Health Insurance Service of Korea. The number of hospital visits every 3‐month interval was counted for 2 years from the date of CHB diagnosis. Patients were classified into three follow‐up groups: regular (four to eight visits), irregular (one to three visits), and no follow‐up. The risk of liver cancer mortality was compared among the groups using Cox proportional hazard regression analysis. Results Of the 414 074 CHB patients, 22.9% had regular follow‐up. In multivariable analysis, regular follow‐up was independently associated with decreased risk of liver cancer mortality compared to no follow‐up (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.50‐0.63, P 60 years, of low socioeconomic status, disabled, lived in a rural area, had a higher comorbidity rate, or did not have cirrhosis. Conclusions Regular follow‐up at least every 3‐6 months is significantly associated with reduced liver cancer mortality in patients with CHB., Of the 414 074 CHB patients, 22.9% had regular follow‐up. Regular follow‐up was independently associated with decreased risk of liver cancer mortality compared to no follow‐up (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.50‐0.63, P

There is an urgent need for new biomarkers that address the shortcomings of current screening methods which fail to detect a large proportion of cases with hepatocellular carcinoma (HCC) at early stage. To develop a robust, multiple‐biomarker panel based on multiple reaction monitoring–mass spectrometry with high performance in detecting early‐stage HCC within at‐risk populations. In the discovery set, 150 samples were analyzed to identify candidate biomarkers. The resulting list of candidates was tested in the training set (713 samples) to establish a multimarker panel, which was evaluated in the validation set (305 samples). We identified 385 serum HCC biomarker candidates in the discovery set and developed a multimarker panel consisting of 28 peptides that best differentiated HCC from controls. The area under the receiver operating characteristic curve of multimarker panel was significantly higher than alpha‐fetoprotein (AFP) in the training (0.976 vs. 0.804; P

ObjectiveDirect comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study.DesignsThis multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC).ResultsDuring follow-up (median=26.9 months, IQR=12.2–49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38).ConclusionThe discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.

Angiotensin type II receptor blockers (ARBs) are the most widely used anti-hypertensive drugs. This study aimed to elucidate the likelihood and pattern of ARB-induced liver injury in a hospital-based cohort.Data of patients receiving fimasartan (n = 5,543), candesartan (n = 6,406), valsartan (n = 6,040), and losartan (n = 9,126) were retrieved from the clinical data warehouse of two tertiary hospitals. Patients with alanine aminotransferase (ALT) levels5 times the upper normal limit were assessed according to the Roussel Uclaf Causality Assessment Method (RUCAM).A total of 27,115 patients were enrolled, including 14,630 (54.0%) men, with a mean age of 64.6 years (standard deviation, 13.6). During 31,717 person-years of ARB therapy, serum ALT levels120 IU/L were found in 558 (2.1%) person-years, and levels200 IU/L were found in 155 (0.6%) person-years. The incidence of ALT elevation120 IU/L per 10Approximately 2% of patients receiving ARB therapy had significant ALT elevation (4.24/10

Little is known about how quality of life (QOL) can assist clinical decision-making for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the reliability and validity of QOL as well as its prognostic value and utility.A prospective cohort of 300 HCC patients at various stages was recruited from 2015 to 2017 in Korea. The subjects answered the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and QLQ-HCC18 and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Prognostic nomograms including the QOL scales were developed. The prediction performance of the Barcelona Clinic Liver Cancer (BCLC) and the American Joint Committee on Cancer (AJCC) staging systems when they were incorporated with QOL was investigated.The EORTC QLQ-C30 and QLQ-HCC18 subscales showed higher reliability than FACT-Hep subscales. With regard to the validity, both questionnaires discriminated the patients by stages, treatment modalities, and performance status effectively. Multivariable analysis revealed that EORTC role functioning and EORTC appetite loss subscales were statistically associated with overall survival and disease progression. The developed nomograms accurately estimated the 1-year overall survival and disease progression-free rates. Incorporating the EORTC role functioning subscale or Hepatobiliary Cancer Subscale of FACT-Hep with the BCLC and AJCC systems improved the prognostic classification. Incorporating QOL into the AJCC system showed better predictive accuracy than incorporating performance status into it did.The findings suggest that QOL data can serve as a reliable predictive factor and assist prognostic calculation for HCC patients.

BACKGROUND It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. AIM To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN). METHODS This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA

Tenofovir disoproxil fumarate (TDF) monotherapy is recommended for the treatment of chronic hepatitis B (CHB) patients who are refractory to other drugs. Yet, little data are available for the effectiveness of TDF monotherapy compared with TDF-based combination therapy on the risk of hepatocellular carcinoma (HCC) and death/transplantation. This nationwide population-based cohort study included 11,289 CHB patients who initiated TDF rescue therapy after failure of preceding treatments between 2012 and 2014 in Korea. The risks of HCC and death/transplantation were compared between TDF combotherapy (n = 2,499) and TDF monotherapy (n = 8,790) groups. The findings were validated in a hospital cohort of 1,163 CHB patients. In the nationwide cohort, during 44.2 months of overall treatment duration, 529 patients developed HCC and 190 died or received transplantation. In the 2,499 propensity score-matched pairs, compared with TDF combotherapy, TDF monotherapy showed no significantly different risks of HCC (1.11/100 person-year [PY] vs. 1.32/100 PY; HR 1.23, 95% CI 0.95-1.60, p = .12) and death/transplant (0.43/100 PY vs. 0.42/100 PY; HR 1.04, 95% CI 0.67-1.60, p = .87). However, in the 469 propensity score-matched pairs of cirrhosis subcohort, TDF monotherapy was associated with a higher risk of HCC than TDF combotherapy (HR 1.46, 95% CI 1.002-2.12, p = .049). In the validation hospital cohort, TDF monotherapy was not associated with significantly different risks of HCC and death/transplant in the entire cohort and cirrhosis subcohort. In CHB patients with failure to preceding treatments, TDF monotherapy showed no higher risks of HCC and death/transplantation compared with TDF combotherapy. However, the comparative effectiveness of rescue TDF monotherapy should be further clarified in cirrhotic patients since the findings were not consistent in the nationwide and hospital cohorts.

Background/Aims: Sarcopenia has emerged as an important risk factor for nonalcoholic fatty liver disease (NAFLD). Although aging is the main cause of sarcopenia, the longitudinal association between age-related body composition changes and NAFLD development has not been fully investigated. Thus, we evaluated whether age-related increased fat mass or decreased muscle mass is an independent risk factor for incident NAFLD. Methods: We conducted a retrospective cohort study involving 4,398 initially NAFLD-free subjects who underwent routine health examinations during 2004 to 2005 and returned for a follow-up during 2014 to 2015. Their body composition was measured by bioelectrical impedance analysis, and fatty liver was diagnosed by abdominal ultrasonography. Results: At the 10-year follow-up, 591 out of 4,398 participants (13.4%) had developed NAFLD. In men and women, both increased fat mass and decreased appendicular skeletal muscle mass (ASM) with aging were significantly associated with incident NAFLD after adjustment. A subgroup analysis according to the baseline obesity status showed that increased fat mass was significantly associated with incident NAFLD in obese and nonobese subjects. However, decreased ASM was significantly associated with incident NAFLD in nonobese but not in obese subjects. According to ΔASM tertiles (decrease of ASM), the odds ratios for incident NAFLD in nonobese subjects were 1.38 (95% confidence interval [CI], 1.04 to 1.84) for the second tertile and 1.81 (95% CI, 1.34 to 2.45) for the third tertile after adjustment (p=0.001). Conclusions: A progressive increase in fat mass and a loss of ASM with aging were significantly associated with incident NAFLD. This association was more prominent in nonobese subjects. (Gut Liver 2019;13:67-76)

ObjectiveThe cost-effectiveness of antiviral treatment in adult immune-tolerant (IT) phase chronic hepatitis B (CHB) patients is uncertain.DesignWe designed a Markov model to compare expected costs and quality-adjusted life-years (QALYs) of starting antiviral treatment at IT-phase (‘treat-IT’) vs delaying the therapy until active hepatitis phase (‘untreat-IT’) in CHB patients over a 20-year horizon. A cohort of 10 000 non-cirrhotic 35-year-old patients in IT-phase CHB (hepatitis B e antigen-positive, mean serum hepatitis B virus (HBV) DNA levels 7.6 log10 IU/mL, and normal alanine aminotransferase levels) was simulated. Input parameters were obtained from previous studies at Asan Medical Center, Korea. The incremental cost-effectiveness ratio (ICER) between the treat-IT and untreat-IT strategies was calculated.ResultsFrom a healthcare system perspective, the treat-IT strategy with entecavir or tenofovir had an ICER of US$16 516/QALY, with an annual hepatocellular carcinoma (HCC) incidence of 0.73% in the untreat-IT group. With the annual HCC risk ≥0.54%, the treat-IT strategy was cost-effective at a willingness-to-pay threshold of US$20 000/QALY. From a societal perspective considering productivity loss by premature death, the treat-IT strategy was extremely cost-effective, and was dominant (ICER ConclusionStarting antiviral therapy in IT phase is cost-effective compared with delaying the treatment until the active hepatitis phase in CHB patients, especially with increasing HCC risk, decreasing drug costs and consideration of productivity loss.

This study aimed to analyze the dose of radiation to which the physician is exposed during endoscopic retrograde cholangiopancreatography (ERCP) and to identify predictive factors of radiation exposure during the procedure. Furthermore, we evaluated the patient characteristics and procedural factors associated with prolonged fluoroscopy time (FT). A cross-sectional retrospective analysis of 780 ERCPs performed at a tertiary academic hospital over a 2-year period was conducted. The primary outcome was radiation exposure during ERCP as determined by FT; additionally, the association between variables and radiation exposure was determined. Moreover, we evaluated their correlations with age, sex, body mass index (BMI), diagnosis, duration of procedure, procedure name, and procedure complexity. According to the analysis of the 780 ERCPs performed in 2 years, the mean FT was 5.07 minutes (95% confidence interval [CI], 4.87–5.26). The mean radiation durations were as follows: cholelithiasis, 5.76 minutes (95% CI, 4.75–6.80); malignant biliary obstruction, 6.13 minutes (95% CI, 5.91–6.35); pancreatic disease, 5.28 minutes (95% CI, 4.45–6.28); and benign biliary stricture, 5.32 minutes (95% CI, 5.02–5.94). Significant differences affecting fluoroscopy duration between the 2 endoscopists were not observed in the present study. Multivariate analysis revealed that prolonged fluoroscopy duration was related to specific characteristics, including higher BMI (BMI >27.5 kg/m2) (+4.1 minutes; 95% CI, 2.56–5.63), mechanical lithotripsy (+4.85 minutes; 95% CI, 0.45–9.25), needle-knife use (+4.5 minutes; 95% CI, 2.15–6.86), and malignant biliary obstruction (+2.34 minutes; 95% CI, 0.15–4.53). ERCPs are associated with significantly higher radiation exposure of patients on the specific procedure. Endoscopists should be aware of the determining factors, including patients with obesity, who underwent mechanical lithotripsy, who had malignant biliary obstruction, and who underwent a procedure using a needle knife, that affect FT during ERCP.

Background & Aims Little is known about the association between non-alcoholic fatty liver disease (NAFLD) and cancer development. This study investigated the cancer incidence rates in NAFLD and analysed the association between NAFLD and cancer development. Methods This historical cohort study included subjects who were followed up for >1 year after having a heath checkup at a tertiary hospital in Korea from September 1, 2004 to December 31, 2005. NAFLD was diagnosed by ultrasonographic detection of hepatic steatosis in the absence of other known liver disease, including alcoholic or viral hepatitis. Cox proportional hazards regression model was conducted to assess the association between NAFLD and cancer development. Results Of 25,947 subjects, 8,721 (33.6%) had NAFLD. During the total follow-up of 164,671 person-years (median 7.5 years), the cancer incidence rate of the NAFLD group was higher than that of the non-NAFLD group (782.9 vs. 592.8 per 100,000 person-years; hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.17–1.49; p p = 0.008), colorectal cancer in males (HR 2.01; 95% CI 1.10–3.68; p = 0.02), and breast cancer in females (HR 1.92; 95% CI 1.15–3.20; p = 0.01). A high NAFLD fibrosis score (NFS) and a high fibrosis-4 (FIB-4) score were associated with the development of all cancers and HCC. Conclusion NAFLD was associated with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NFS and a high FIB-4 score showed a strong association with the development of all cancers and HCC. Lay summary Non-alcoholic fatty liver disease (NAFLD) is associated with developing hepatocellular carcinoma (HCC). There have been limited data on the association between NAFLD and extrahepatic cancers. This study demonstrated that patients with NAFLD showed a higher association with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NAFLD fibrosis score and a high fibrosis-4 score showed a strong association with the development of all cancers and HCC.

ObjectiveHigh serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality.DesignThis historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, ResultsThe IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; pConclusionsUntreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg-interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow-up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30-3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg-interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.

It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB.We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA15 IU/mL.During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6-12, 12-24, and24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk.In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.

Background Hepatitis B virus (HBV) infection leads to hepatic and extrahepatic manifestations including chronic kidney disease (CKD). However, the association between HBV and CKD is not clear. This study investigated the association between chronic HBV infection and CKD in a nationwide multicenter study. Methods A total of 265,086 subjects who underwent health-check examinations in 33 hospitals from January 2015 to December 2015 were enrolled. HBV surface antigen (HBsAg) positive cases (n = 10,048), and age- and gender-matched HBsAg negative controls (n = 40,192) were identified. CKD was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 or proteinuria as at least grade 2+ of urine protein. Results HBsAg positive cases showed a significantly higher prevalence of GFR < 60 mL/min/1.73 m2 (3.3%), and proteinuria (18.9%) than that of the controls (2.6%, P < 0.001, and 14.1%, P < 0.001, respectively). In the multivariate analysis, HBsAg positivity was an independent factor associated with GFR < 60 mL/min/1.73 m2 along with age, blood levels of albumin, bilirubin, anemia, and hemoglobin A1c (HbA1c). Likewise, HBsAg positivity was an independent factor for proteinuria along with age, male, blood levels of bilirubin, protein, albumin, and HbA1c. A subgroup analysis showed that HBsAg positive men but not women had a significantly increased risk for GFR < 60 mL/min/1.73 m2. Conclusion Chronic HBV infection was significantly associated with a GFR < 60 mL/min/1.73 m2 and proteinuria (≥ 2+). Therefore, clinical concern about CKD in chronic HBV infected patients, especially in male, is warranted., Graphical Abstract

Background Nucleos[t]ide analogues (NUCs) treatment in HBe-negative chronic hepatitis B (CHB) patients would maintain a similar virologic and biochemical state compared to inactive hepatitis. And, sustained reduction of hepatitis B viral load by NUCs is helpful in lowering the risk of HCC. The purpose of this study was to evaluate the cumulative incidence of hepatocellular carcinoma (HCC) and death/transplantation in patients with inactive patients compared with HBeAg-negative CHB patients treated with NUCs. Methods We performed a retrospective analysis of data from 3202 consecutive adult patients with non-cirrhotic CHB, inactive hepatitis (n=2,677) and HBeAg-negative hepatitis treated with NUCs between January 2000 and December 2013. Data were collected from patients for median 5.4 years and analysed by a multivariable Cox proportional hazards model for the entire cohort and propensity score-matched cohort. Results During the study period, 127 (4.0%) developed HCC, 156 (4.8%) died or received transplantation. The annual risk of developing HCC and death/transplantation of inactive hepatitis and NUC treated HBeAg-negative hepatitis were 0.49% vs. 1.60% (hazard ratio [HR], 3.36; 95% confidence interval [CI], 1.20–4.82; p Conclusions Inactive hepatitis develops significantly fewer HCCs compared to HBeAg-negative CHB hepatitis treated with NUCs with similar biochemical and virologic profile. In the NUC era, inactive hepatitis could be still evaluated as stable enough in the area where genotype C is dominant.

Background The REVEAL-HBV studies on the natural history of chronic hepatitis B (CHB) showed a linear correlation between serum HBV DNA levels and the risk of hepatocellular carcinoma (HCC). However, virus titers above 106 copies/mL were not quantified, and most of the patients were HBeAg-negative (85%). The progression of these HBeAg-negative patients would not be identical to that of young HBeAg-positive immune-tolerant phase patients. Methods The study subjects were recruited from a historical cohort of 4367 treatment-naive, non-cirrhotic CHB patients (1240 HBeAg-positive and 3127 HBeAg-negative) with serum ALT levels lower than 2 x upper limit of normal (females, Results During the total follow-up of 23 690 person-years, 221 patients (5.1%) developed HCC. Old age, male gender, and lower platelet counts were found to be associated with an increased risk of HCC. Among HBeAg-negative patients, HBV DNA levels were linearly associated with increased risk of HCC. In contrast, among HBeAg-positive patients, HBV DNA levels were inversely associated with the risk of HCC. The risk of HCC was the lowest in HBeAg negative patients with HBV DNA level below 4 log10IU/mL (reference group) and was the highest in HBeAg positive patients with HBV DNA levels between 4 log10IU/mL and 6 log10IU/mL (HR 6.89; 95% CI 4.20–11.29). HBeAg-positive patients with HBV DNA levels above 8 log10IU/mL showed the similar risk of HCC compared with the reference group (HR 1.36; 95% CI 0.65–2.84). Conclusions In our cohort, the association between HBV DNA levels and HCC risk was not linear but was parabolic. HCC risk was the highest in patients with HBV DNA levels between 4 log10IU/mL and 6 log10IU/mL. These data may help assess the HCC risk among the patients who are not subject to antiviral treatment which consequently calls attention to the necessity of developing a new treatment indication.

We aimed to determine the surveillance performance of alpha-fetoprotein (AFP), lectin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), and their combinations for the early detection of hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow-up in a 1:4 ratio. Levels of AFP, AFP-L3, and DCP at the time of HCC diagnosis, month -6, and month -12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early-stage HCC (single

Background & Aims Little is known about whether surveillance for hepatocellular carcinoma (HCC) is worthwhile in chronic hepatitis B virus (HBV)-infected patients who have achieved HBsAg seroclearance. Methods A retrospective analysis of 829 patients (mean age: 52.3years; 575 males; 98 with cirrhosis) achieving HBsAg seroclearance was performed at a tertiary hospital in Korea between 1997 and 2012. We evaluated incidence rates of HCC, and validated CU-HCC score based on data at the time of HBsAg seroclearance. Results During a follow-up of 3464 patient-years, 19 patients developed HCC (annual rate: 0.55%). Liver cirrhosis (hazard ratio [HR]: 10.80; 95% confidence interval [CI]: 4.25–27.43), male gender (HR: 8.96; 95% CI: 1.17–68.80), and age ⩾50years at the time of HBsAg seroclearance (HR: 12.14; 95% CI: 1.61–91.68) were independently associated with HCC. The estimated annual incidence of HCC was 2.85% and 0.29% in patients with and without cirrhosis, respectively. Among the non-cirrhotic patients, the annual rate of HCC was higher in the male patients than in the females (0.40% vs. 0%, respectively), and all the HCCs developed after age 50. The time-dependent area under the receiver operating characteristic curves for the CU-HCC score for 5year and 10year HCC prediction were 0.85 and 0.74, respectively. Conclusions HCC surveillance should be considered for cirrhotic patients and non-cirrhotic male patients over age 50, even after HBsAg seroclearance, especially those infected with HBV genotype C. HBsAg seroclearance at age ⩾50years was also an independent predictor for HCC.

We appreciate the interest given to our article1 by Chu and Liaw.2 Determining disease phases of patients with chronic hepatitis B (CHB) is essential for assessing patient prognosis and need for treatment. Distinguishing between the immune-tolerant and immune-active phases among patients with hepatitis B e antigen (HBeAg)-positive CHB is best determined by identifying significant necroinflammation and/or fibrosis through liver biopsy. However, given the dynamic nature of CHB and the risks and costs of repeated liver biopsy, this recommendation may not always be realistic, especially …

Table S1. Serological, virological, and biochemical responses at week 48 by baseline HBeAg-positivity. Table S2. Serological, virological, and biochemical responses at week 48 by status of liver cirrhosis. Table S3. Serological, virological, and biochemical responses at week 48 by gender. Table S4. Characteristics of the patients at virologic breakthrough. (DOCX 51 kb)

Little is known about the benefits of statin use on liver cancer mortality among patients with chronic hepatitis B (CHB) considering hypercholesterolemia and obesity. A nationwide retrospective cohort study was conducted using data from a Health Examination Cohort of the National Health Insurance Service of Korea. Data on CHB patients with no other concurrent liver disease were acquired, and statin use was defined as a cumulative daily dose ≥28. A 3-year landmark analysis was performed to avoid immortal time bias. Patients who started statin therapy within the landmark date were considered statin users. A Cox regression analysis was applied to assess associations between statin use and liver cancer mortality considering hypercholesterolemia and obesity. Among 13063 patients, 193 (1.5%) died of liver cancer during the mean follow-up period of 10.6 years. After adjusting for demographic and metabolic factors, statin use [hazard ratio (HR), 0.17; 95% confidence interval (CI), 0.04–0.70] and hypercholesterolemia (HR, 0.46; 95% CI, 0.24–0.88 for total cholesterol ≥240 mg/dL) were associated with a decreased risk of liver cancer mortality, whereas body mass index (BMI) ≥30 kg/m2 was associated with an increased risk of liver cancer mortality (HR, 2.46; 95% CI, 1.20–5.06). This study showed that statin use was associated with decreased liver cancer mortality when adjusting for cholesterol levels and BMI. This study found that hypercholesterolemia was independently associated with decreased liver cancer mortality regardless of statin use.

We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT).271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time-dependent receiver operating characteristic curves (AUC) estimation.Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to-seven model. Higher AUC values were observed with the size method only in the up-to-seven model (p0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method (p0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method (p=0.017).The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion.