High-dose proton pump inhibitor treatment is associated with a higher mortality in cirrhotic patients: A multicentre study.

BACKGROUND: Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis. AIMS: This study aimed to determine whether PPI use is associated with the prognosis of cirrhotic patients. METHODS: We conducted a multicentre retrospective cohort study involving 1485 patients who had experienced hepatic encephalopathy (HE) from 7 referral centres in Korea. The primary outcome was overall survival and secondary outcomes included the development of cirrhotic complications, including recurrent HE, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and gastrointestinal bleeding. Patients treated with PPI with a mean defined daily dose (mDDD) ≥0.5 (high-dose PPI group) were compared to those treated with PPI of an mDDD < 0.5 (No or low-dose PPI group) for each outcome. RESULTS: Among 1485 patients (median age, 61 years; male, 61%), 232 were assigned to the high-dose PPI group. High-dose PPI use was independently associated with a higher risk of death (adjusted HR [aHR] = 1.71, 95% confidence interval [CI] = 1.38-2.11, p < 0.001). This result was reproducible after propensity score-matching (PSM) (aHR = 1.90, 95% CI = 1.49-2.44, p < 0.001). High-dose PPI use was an independent risk factor of recurrent HE (before PSM: aHR = 2.04, 95% CI = 1.66-2.51, p < 0.001; after PSM: aHR = 2.16, 95% CI = 1.70-2.74, p < 0.001), SBP (before PSM: aHR = 1.87, 95% CI = 1.43-2.43, p < 0.001; after PSM: aHR = 1.76, 95% CI = 1.31-2.36, p = 0.002), HRS (before PSM: aHR = 1.48, 95% CI = 1.02-2.15, p = 0.04; after PSM: aHR = 1.47, 95% CI = 0.95-2.28, p = 0.09), and gastrointestinal bleeding (before PSM: aHR = 1.46, 95% CI = 1.12-1.90, p = 0.006; after PSM: aHR = 1.74, 95% CI = 1.28-2.37, p < 0.001). CONCLUSIONS: The use of high-dose PPI was independently associated with increased risks of mortality and cirrhotic complications.

Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B.

OBJECTIVE: The association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis. DESIGN: Using a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable. RESULTS: During a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00-7.99 log10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p<0.001), followed by those with low viral loads (3.30-4.99 log10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00-6.99 log10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p<0.001) compared with those with baseline HBV DNA levels≥8.00 log10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis. CONCLUSION: Patients with moderate baseline viral load, particularly around 6 log10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.

A risk prediction model for hepatocellular carcinoma in non-alcoholic fatty liver disease without cirrhosis: HCC prediction for non-cirrhotic NAFLD.

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC), HCC risk in non-cirrhotic NAFLD received little attention. We aimed to develop and validate an HCC risk prediction model for non-cirrhotic NAFLD. METHODS: A nationwide cohort of non-cirrhotic NAFLD patients in Korea was recruited to develop a risk prediction model and validate it internally (n = 409 088). A model using a simplified point system was developed by Cox proportional hazard model. K-fold cross-validation assessed the accuracy, discrimination and calibration. The model was validated externally using a hospital cohort from Asan Medical Center (n = 8721). RESULTS: An 11-point HCC risk prediction model for non-cirrhotic NAFLD was developed using six independent factors of age, sex, diabetes, obesity, serum alanine aminotransferase level and gamma-glutamyl transferase level (c-index 0.75). The average area under receiver operating curves (AUROCs) of the model was 0.72 at 5 years and 0.75 at 10 years. In the external validation cohort, the AUROCs were 0.79 [95% confidence interval [CI], 0.59-0.95] at 5 years and 0.84 (95% CI, 0.73-0.94) at 10 years. The calibration plots showed the expected risks corresponded well with the observed risks. Risk stratification categorized patients into the low (score 0-6), moderate (7, 8) and high (9-11; estimated incidence rate >0.2%/year) risk groups. CONCLUSIONS: A novel HCC risk prediction model for non-cirrhotic NAFLD patients was developed and validated with fair performance. The model is expected to serve as a simple and reliable tool to assess HCC risk and assist precision screening of HCC.

Global incidence and prevalence of autoimmune hepatitis, 1970-2022: a systematic review and meta-analysis.

Background: Autoimmune hepatitis (AIH) varies significantly in incidence and prevalence across countries and regions. We aimed to examine global, regional, and national trends in incidence and prevalence of AIH from 1970 to 2022. Methods: We conducted a thorough search of the PubMed/MEDLINE, Embase, CINAHL, Google Scholar, and Cochrane databases from database inception to August 9, 2023, using the search term "autoimmune hepatitis" in combination with "incidence," "prevalence," or "trend." Only general population-based observational studies with larger samples sizes were considered for inclusion. Studies that recruited convenience samples, and those with fewer than 50 participants were excluded. Summary data were extracted from published reports. A random effects model was used and pooled estimates with 95% CI were used to calculate the incidence and prevalence of AIH. Heterogeneity was evaluated using the I2 statistic. The study protocol was registered with PROSPERO, CRD42023430138. Findings: A total of 37 eligible studies, encompassing more than 239 million participants and 55,839 patients with AIH from 18 countries across five continents, were included in the analysis. Global pooled incidence and prevalence of AIH were found to be 1.28 cases per 100,000 inhabitant-years (95% CI, 1.01-1.63, I2 = 99·51%; number of studies, 33; sample population, 220,673,674) and 15.65 cases per 100,000 inhabitants (95% CI, 13.42-18.24, I2 = 99·75%; number of studies, 26; sample population, 217,178,684), respectively. The incidence of AIH was greater in countries with high Human Development Index (>0.92), in North America and Oceania (compared with Asia), among females, adults (compared with children), and high latitude (>45°). Similar patterns in AIH prevalence were observed. Pooled AIH prevalence increased gradually from 1970 to 2019 (1970-1999; 9.95 [4.77-15.13], I2 = 95·58% versus 2015-2022; 27.91 [24.86-30.96], I2 = 99·32%; cases per 100,000 inhabitants). The overall incidence and prevalence of AIH, as well as some subgroup analyses of the studies, displayed asymmetry in the funnel plots, suggesting potential evidence of publication bias. Interpretation: AIH incidence and prevalence have increased significantly and exhibit substantial variation across regions worldwide. Further research is required to assess the incidence and prevalence of AIH, specifically in South America and Africa. Funding: National Research Foundation of Korea.

Risk of Hepatitis C Virus Transmission through Acupuncture: A Systematic Review and Meta-Analysis.

Background/Aims: Chronic hepatitis C is a major risk factor for liver cirrhosis, hepatocellular carcinoma, and hepatic failure. Although traditional practices, including acupuncture, tend to increase the risk of HCV infection, the association remains controversial. Therefore, the current meta-analytical study was undertaken to evaluate the risks of acupuncture and hepatitis C transmission. Methods: Two researchers independently screened studies from the databases encompassing the period from inception to May 12, 2022. Baseline demographics, HCV transmission OR, and 95% CIs were extracted, pooled, and analyzed using random-effect models. Subgroup analyses utilizing study design and ethnicity were performed. Heterogeneity and publication bias were analyzed using the Higgins I2 test and funnel plots, respectively. Results: In all, 28 studies with 194,826 participants (178,583 controls [91.7%] vs. 16,243 acupuncture users [8.3%]) were included in the final analysis. The pooled analysis showed that acupuncture users had a significantly higher HCV transmission rate than controls with heterogeneity (OR, 1.84 [1.46-2.32]; p<0.001; I2 =80%). In the subgroup analysis, both cross-sectional case-control (n=14; OR, 1.96 [1.47-2.61]; p<0.001; I2 =88%) and cross-sectional studies (n=12; OR, 1.85 [1.32-2.61]; p<0.001; I2 =0%) showed significantly higher HCV infection rates in the acupuncture group than in the control group. Both Asian and non-Asian acupuncture users showed a higher HCV transmission risk than the controls (all Ps<0.001). No significant publication bias was observed. Conclusions: Our findings indicate that acupuncture increases the risk of HCV transmission. Due to HCV's contagiousness, unsafe medical and social practices (including acupuncture) should be performed with caution.

Critical appraisal of metabolic dysfunction-associated steatotic liver disease: Implication of Janus-faced modernity.

The existing term non-alcoholic fatty liver disease (NAFLD) has raised substantial concerns due to its inherent disadvantages of using exclusionary diagnostic criteria and the stigmatizing word 'fatty.' Three pan-national liver associations set out to explore a new nomenclature to replace both NAFLD and its suggested alternative, metabolic (dysfunction)-associated fatty liver disease (MAFLD). They surveyed if a change in nomenclature and/or definition is favored and which nomenclature best communicates disease characteristics and increases awareness. In lieu of NAFLD/MAFLD, metabolic dysfunction-associated steatotic liver disease (MASLD) has been chosen, and an umbrella term, steatotic liver disease (SLD), encompassing the whole spectrum of liver disease, has been proposed. It has been suggested that cardiometabolic risk factors should be considered when categorizing SLD patients. Furthermore, a new subcategory, MASLD with increased alcohol intake (MetALD), casts light on a neglected group of patients with moderate or more alcohol consumption. The importance of metabolic dysfunction was acknowledged in this new nomenclature, but the precise contribution of metabolic dysfunction and alcohol consumption to the development and progression of SLD remains unclear. Herein, we review hepatologists' and endocrinologists' perspectives on the new nomenclature, along with its possible impact on clinical practice. Although it is premature to predict the settlement of the new nomenclature, this review may help build more evidence for a soft landing of it in the future.

Prognosis of Patients with Chronic Hepatitis C Genotype 1b Infection Treated Using Daclatasvir/Asunaprevir after Sustained Virologic Response: A 6-Year Multicenter Prospective Observational Study.

Aim and Objectives: Direct-acting antiviral (DAA) therapy can cure chronic hepatitis C (CHC), and daclatasvir (DCV)/asunaprevir (ASV) was the first interferon-free DAA therapy introduced in Korea. Patients who achieve sustained virologic response (SVR) after DAA treatment are expected to have good prognoses. Therefore, in this study, we aimed to investigate the prognosis of these patients. Materials and Methods: This multicenter prospective observational study included patients with CHC who achieved SVR after DCV/ASV treatment. The primary endpoint was hepatocellular carcinoma (HCC) occurrence, which was reviewed annually. Results: We included 302 patients (median follow-up duration: 38 [16.5-60.0] months; median age: 58 [49-67] years) in the study. Cirrhosis was observed in 103 patients (34.1%), and the median Child-Pugh score was 5.0. HCC occurred in 16 patients (5.3%) within six years post-SVR; these patients were older and had higher cirrhosis prevalence, alpha-fetoprotein levels, and fibrosis-4 index scores than did those without HCC development. Cox proportional hazards analysis revealed that age > 71 years (p = 0.005) and cirrhosis (p = 0.035) were significant risk factors for HCC occurrence. Conclusions: Although the prognoses of patients who achieved SVR with DCV/ASV therapy were generally good, the risk for HCC was present, especially in older patients and in those with cirrhosis. Hence, early treatment at younger ages and regular follow-up surveillance after achieving SVR are warranted.

Comorbidities and the use of comedications among patients with chronic hepatitis C in Korea: A nationwide cross-sectional study.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is the second leading cause of liver-related mortality and is more prevalent in the elderly population in Korea. Decisions to initiate treatment and selection of proper antiviral agents may be challenging among elderly patients due to relevant comorbidities, comedications, and drug-drug interaction (DDI). It may be helpful to understand the current demographic status and comorbidities of CHC patients in the country. METHODS: Patients aged ≥ 18 years and diagnosed with CHC (KCD-7 code B18.2) were extracted from the Korean Health Insurance Review & Assessment Service database in 2018. Data on comorbidities and comedications were assessed and potential DDIs were analyzed. RESULTS: A total of 50,476 patients with CHC, with a mean age of 60.3 years and 46.7% male patients were identified. The proportion of patients with cirrhosis, hepatocellular carcinoma, and liver transplantation was 6.0%, 4.1%, and 0.3%, respectively and 37.2% of patients were more than 65 years of age. The three most common comorbidities were diseases of the digestive system (83.7%), respiratory system (58.2%), and musculoskeletal system and connective tissue (57.6%). The three most common comedications were analgesics (91.6%), gastrointestinal agents (85%), and antibacterials (80.3%). Lipid-lowering agents and anticonvulsants were prescribed in 28.5% and 14.8% of patients. Rate of potential DDI for contraindication was 2.2%, 13.1%, and 15.6% with sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir. CONCLUSION: With the increasing age of patients with CHC, comorbidity, comedication, and potential DDI should be considered when choosing antivirals in Korea. Sofosbuvir-based regimens showed favorable DDI profiles among Korean patients.

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ALS-L1023 in Non-Alcoholic Fatty Liver Disease.

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.

Benefits of Flavored Lactose-Free Milk for Korean Adults with Lactose Intolerance.

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 ΔH2 peak exceeded 16 ppm above baseline values and with the occurrence of symptoms after WM consumption. The participants who were diagnosed with LI underwent the HBT again with 570 mL of chocolate-flavored LFM (0 g of lactose), followed by the symptom questionnaire survey after 1 week. After excluding 40 participants who did not meet the diagnostic criteria for LI and 2 who were lost to follow-up, a total of 28 lactose-intolerant individuals were enrolled in the study. The ΔH2 values in the first HBT were significantly higher than those in the second HBT (33.3 ± 21.6 ppm vs. 8.6 ± 6.3 ppm, P < .001). Similarly, there was a significant reduction in the total symptom score in the second HBT (4.18 ± 1.51 vs. 0.61 ± 0.98, P < .001). Flavored LFM is well tolerated in South Korean adults diagnosed with LI based on the HBT and symptom questionnaire results. Therefore, LFM may be a viable alternative to WM.

Incidence and Pattern of Aminotransferase Elevation During Anti-Hypertensive Therapy With Angiotensin-II Receptor Blockers.

BACKGROUND: 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. METHODS: 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) levels > 5 times the upper normal limit were assessed according to the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: 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 levels > 120 IU/L were found in 558 (2.1%) person-years, and levels > 200 IU/L were found in 155 (0.6%) person-years. The incidence of ALT elevation > 120 IU/L per 106 cumulative defined daily doses was 6.6, 3.6, 3.9, and 4.0 in the fimasartan, candesartan, valsartan, and losartan groups, respectively (P = 0.002). An ALT level > 200 IU/L with RUCAM score ≥ 6 was found in 20 patients, suggesting probable drug-induced liver injury for 11 (0.2%) patients receiving fimasartan, five (0.1%) receiving candesartan, four (0.1%) receiving valsartan, and none receiving losartan (P < 0.001). CONCLUSION: Approximately 2% of patients receiving ARB therapy had significant ALT elevation (4.24/106 cumulative defined daily doses [cDDDs]), which was associated with probable ARB-related liver injury in 0.07% of patients (0.15/106 cDDDs). Elevation of ALT was more commonly associated with fimasartan than the other ARBs. Clinicians should be aware of the possibility of ARB-related ALT elevation in patients with unexplained chronic abnormal ALT.

Association between non-alcoholic fatty liver disease and the risk of dementia: A nationwide cohort study.

BACKGROUND AND AIMS: Little is known about the association between non-alcoholic fatty liver disease (NAFLD) and dementia. Given that hepatic steatosis is linked to abnormal fat metabolism, and fat dysregulation in the brain is related to dementia, we aimed to investigate whether NAFLD is associated with an increased risk of dementia. METHODS: We conducted a nationwide cohort study involving 4 031 948 subjects aged 40-69 years who underwent ≥2 health check-ups provided by the National Health Insurance Service in Korea between January 2004 and December 2007. Based on the hepatic steatosis index (HSI), subjects were categorized into non-NAFLD (HSI <30 at all check-ups) and NAFLD (HSI >36 at one or more check-ups). Dementia defined by ICD-10 codes with prescription data was followed up until December 2017. Cox proportional hazards regression models analysed the dementia risk. RESULTS: At baseline, 31.3% had NAFLD. During the median follow-up of 9.5 years, 138 424 in NAFLD group and 69 982 in non-NAFLD group developed dementia. NAFLD group was associated with a higher risk of dementia than non-NAFLD group on multivariable-adjusted analysis (hazard ratio [HR], 1.05; p < .001), competing risk analysis (HR, 1.08; p < .001) and propensity-score matched analysis (HR, 1.09; p < .001). The association between NAFLD and dementia risk was more prominent among females (HR, 1.16; p < .001). The association was stronger among non-obese NAFLD subjects (BMI <25 kg/m2 , HR, 1.09; p < .001) than obese NAFLD subjects. CONCLUSIONS: This nationwide study found that NAFLD is associated with an increased risk of dementia. The association was prominent among females and non-obese NAFLD subjects.

Increasing on-treatment hepatocellular carcinoma risk with decreasing baseline viral load in HBeAg-positive chronic hepatitis B.

BACKGROUNDIt is unclear whether the level of serum hepatitis B virus (HBV) DNA at baseline affects the on-treatment risk of hepatocellular carcinoma (HCC) in hepatitis B e antigen-positive (HBeAg-positive), noncirrhotic patients with chronic hepatitis B (CHB).METHODSWe conducted a multicenter cohort study including 2073 entecavir- or tenofovir-treated, HBeAg-positive, noncirrhotic adult CHB patients with baseline HBV DNA levels of 5.00 log10 IU/mL or higher at 3 centers in South Korea between January 2007 and December 2016. We evaluated the on-treatment incidence rate of HCC according to baseline HBV DNA levels.RESULTSDuring a median 5.7 years of continuous antiviral treatment, 47 patients developed HCC (0.39 per 100 person-years). By Kaplan-Meier analysis, the risk of HCC was lowest in patients with baseline HBV DNA levels of 8.00 log10 IU/mL or higher, increased incrementally with decreasing viral load, and was highest in those with HBV DNA levels of 5.00-5.99 log10 IU/mL (P < 0.001). By multivariable analysis, the baseline HBV DNA level was an independent factor that was inversely associated with HCC risk. Compared with HBV DNA levels of 8.00 log10 IU/mL or higher, the adjusted HRs for HCC risk with HBV DNA levels of 7.00-7.99 log10 IU/mL, 6.00-6.99 log10 IU/mL, or 5.00-5.99 log10 IU/mL were 2.48 (P = 0.03), 3.69 (P = 0.002), and 6.10 (P < 0.001), respectively.CONCLUSIONOn-treatment HCC risk increased incrementally with decreasing baseline HBV DNA levels in the range of 5.00 log10 IU/mL or higher in HBeAg-positive, noncirrhotic adult patients with CHB. Early initiation of antiviral treatment when the viral load is high (≥8.00 log10 IU/mL) may maintain the lowest risk of HCC for those patients.FUNDINGPatient-Centered Clinical Research Coordinating Center (PACEN) (grant no. HC20C0062) of the National Evidence-based Healthcare Collaborating Agency; National R&D Program for Cancer Control through the National Cancer Center (grant no. HA21C0110), Ministry of Health and Welfare, South Korea.

Multiple imputation analysis for propensity score matching with missing causes of failure: An application to hepatocellular carcinoma data.

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.

Tenofovir disoproxil fumarate on the risk of hepatocellular carcinoma in chronic hepatitis B patients with failure to preceding treatments: A nationwide cohort study.

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.

Cost-effectiveness of antiviral treatment in adult patients with immune-tolerant phase chronic hepatitis B.

OBJECTIVE: The cost-effectiveness of antiviral treatment in adult immune-tolerant (IT) phase chronic hepatitis B (CHB) patients is uncertain. DESIGN: We 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. RESULTS: From 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 <0) if the HCC risk was ≥0.43%, suggesting that the treat-IT strategy incurs less costs than the untreat-IT strategy. The most influential parameters on cost-effectiveness of the treat-IT strategy were those related with HCC risk (HBV DNA levels, platelet counts and age) and drug cost. CONCLUSION: Starting 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.

Reduced liver cancer mortality with regular clinic follow-up among patients with chronic hepatitis B: A nationwide cohort study.

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 < .001). Regular follow-up was also associated with the lowest risk of all-cause mortality (HR, 0.60; 95% CI, 0.57-0.63, P < .001). Patients with regular follow-up received more curative treatment (23.1% vs 15.1%, P < .001). Patients were less motivated when they were female, >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.