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.

Updated Reference Intervals for Alanine Aminotransferase in a Metabolically and Histologically Normal Population.

BACKGROUND & AIMS: This study aims to reevaluate upper reference limit (URL) for alanine aminotransferase (ALT) by considering the changing epidemiology of major liver diseases. We employed histological and metabolic parameters in Asian living liver donors. METHODS: We performed a retrospective analysis of 5455 potential living liver donors from 2005 to 2019. Participants were screened for hepatitis B, C, HIV, and alcohol use. Histologically and metabolically healthy participants were assessed using the Prati criteria (body mass index <23 kg/m2, triglyceride ≤200 mg/dL, fasting glucose ≤105 mg/dL, total cholesterol ≤220 mg/dL). The updated ALT-URL was determined as the 95th percentile among participants without hepatic steatosis and who met the Prati criteria. RESULTS: The median age was 30 years, with a male predominance (66.2%). Among 5455 participants, 3162 (58.0%) showed no hepatic steatosis, with 1553 (49.1%) meeting both the criteria for no steatosis and the Prati criteria for metabolic health. The updated URL for ALT in these participants was 34 U/L for males and 22 U/L for females, which was significantly lower than conventionally accepted values. Using this revised ALT-URL, 72.8% of males with ALT levels ≥34 U/L and 55.0% of females with ALT levels ≥22 U/L showed signs of steatosis, whereas 32.7% of males and 22.2% of females met the criteria for metabolic syndrome. CONCLUSIONS: Our study provided the newly established reference intervals for ALT levels in a metabolically and histologically verified Asian population. The proposed URL for ALT are 34 U/L and 22 U/L for males and females, respectively.

Increased Risk of Osteoporotic Fracture in Patients With Autoimmune Hepatitis.

INTRODUCTION: Few large-scale studies have been published regarding the association between autoimmune hepatitis (AIH) and risk of osteoporotic fracture. This study aimed to determine the risk of developing an osteoporotic fracture in patients with AIH. METHODS: We used claims data from the Korean National Health Insurance Service between 2007 and 2020. Patients with AIH (n = 7,062) were matched with controls (n = 28,122) based on age, sex, and duration of follow-up using a ratio of 1:4. Osteoporotic fractures included fractures of the vertebrae, hip, distal radius, and proximal humerus. The incidence rate (IR) and IR ratio of osteoporotic fracture were compared between the 2 groups, and their associated factors were evaluated. RESULTS: During a median follow-up period of 5.4 years, 712 osteoporotic fractures occurred in patients with AIH with an IR of 17.5 per 1,000 person-years. Patients with AIH had a significantly higher risk of osteoporotic fractures than matched controls, with an IR ratio of 1.24 (95% confidence intervals, 1.10-1.39, P < 0.01) in the multivariable analysis. Female sex, older age, history of stroke, presence of cirrhosis, and use of glucocorticoids were associated with an increased risk of osteoporotic fractures. In the 2-year landmark analysis, longer duration of glucocorticoid exposure was associated with an incremental increased risk of osteoporotic fracture. DISCUSSION: Patients with AIH had an increased risk of osteoporotic fracture compared with controls. The presence of cirrhosis and long-term use of glucocorticoids further adversely affected osteoporotic fracture in patients with AIH.

The associations between fibrosis changes and liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with liver fibrosis. We investigated the associations between changes in liver stiffness measurement (LSM) over 3-year period and the development of cirrhosis or hepatocellular carcinoma (HCC) in patients with MASLD. METHODS: This study involved patients with MASLD who underwent transient elastography at baseline and 3 years after baseline from 2012 to 2020. Low (L), indeterminate (I) and high (H) LSM values were classified as <8 kPa, 8-12 kPa and >12 kPa respectively. RESULTS: Among 1738 patients, 150 (8.6%) were diagnosed with cirrhosis or HCC. The proportions of patients with L, I and H risk were 69.7%, 19.9% and 10.5% at baseline, and 78.8%, 12.8% and 8.4% at 3 years after baseline, respectively. The incidence rates of cirrhosis or HCC per 1000 person-years were 3.7 (95% confidence interval [CI], 2.4-5.5) in the L → L + I group, 23.9 (95% CI, 17.1-32.6) in the I → L + I group, 38.3 (95% CI, 22.3-61.3) in the H → L + I group, 62.5 (95% CI, 32.3-109.2) in the I → H group, 67.8 (95% CI, 18.5-173.6) in the L → H group and 93.9 (95% CI 70.1-123.1) in the H → H group. Two risk factors for the development of cirrhosis or HCC were LSM changes and low platelet counts. CONCLUSION: LSM changes could predict clinical outcomes in patients with MASLD. Thus, it is important to monitor changes in the fibrotic burden by regular assessment of LSM values.

Response to atezolizumab plus bevacizumab specific for lung and lymph node metastases affects survival of patients with HCC.

BACKGROUND & AIMS: Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. RESULTS: The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. CONCLUSIONS: The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.

Improving the hepatitis C virus care cascade with the in-hospital Reflex tEsting ALarm-C (REAL-C) model.

BACKGROUND: The World Health Organization (WHO) has set targets to eliminate viral hepatitis, including hepatitis C virus (HCV) infection, by 2030. We present the results of the in-hospital Reflex tEsting ALarm-C (REAL-C) model, which incorporates reflex HCV RNA testing and sending alerts to physicians. METHODS: We conducted a retrospective study analysing the data of 1730 patients who newly tested positive for anti-HCV between March 2020 and June 2023. Three distinct periods were defined: pre-REAL-C (n = 696), incomplete REAL-C (n = 515) and complete REAL-C model periods (n = 519). The primary outcome measure was the HCV RNA testing rate throughout the study period. Additionally, we assessed the referral rate to the gastroenterology department, linkage time for diagnosis and treatment and the treatment rate. RESULTS: The rate of HCV RNA testing increased significantly from 51.0% (pre-REAL-C) to 95.6% (complete REAL-C). This improvement was consistent across clinical departments, regardless of patients' comorbidities. Among patients with confirmed HCV infection, the gastroenterology referral rate increased from 57.1% to 81.1% after the REAL-C model. The treatment rate among treatment-eligible patients was 92.4% during the study period. The mean interval from anti-HCV positivity to HCV RNA testing decreased from 45.1 to 1.9 days. The mean interval from the detection of anti-HCV positivity to direct-acting antiviral treatment also decreased from 89.5 to 49.5 days with the REAL-C model. CONCLUSION: The REAL-C model, featuring reflex testing and physician alerts, effectively increased HCV RNA testing rates and streamlined care cascades. Our model facilitated progress towards achieving WHO's elimination goals for HCV infection.

Dynamic liver volume change in predicting hepatic decompensation and long-term effects of stereotactic body radiation therapy.

BACKGROUND AND AIM: This study aimed to investigate the association between liver volume change and hepatic decompensation and compare the risk of hepatic decompensation in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) who underwent stereotactic body radiation therapy (SBRT). METHODS: A retrospective review of SBRT-treated HCC and compensated LC without HCC patients was conducted. Liver volume was measured using auto-segmentation software on liver dynamic computed tomography scans. The decompensation event was defined as the first occurrence of refractory ascites, esophageal variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis. We evaluated the association between the rate of liver volume decrease and hepatic decompensation and compared decompensation events between the SBRT and LC cohorts using propensity score matching. RESULTS: A total of 138 patients from the SBRT cohort and 488 from the LC cohort were analyzed. The rate of liver volume decrease was associated with the risk of decompensation events in both cohorts. The 3-year rate of decompensation events was significantly higher in the group with a liver volume decreasing rate > 7%/year compared with the group with a rate < 7%/year. In the propensity score-matched cohort, the 3-year rate of decompensation events after a single session of SBRT was not significantly different from that in the LC cohort. CONCLUSIONS: The rate of liver volume decrease was significantly associated with the risk of hepatic decompensation in both HCC patients who received SBRT and LC patients. A single session of SBRT for HCC did not result in a higher decompensation rate compared with LC.

Revisiting the steatosis-associated fibrosis estimator score in young Asian subjects with steatotic liver disease and consideration for population variability.

BACKGROUND AND AIM: The steatosis-associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy-proven SLD and in different subgroups according to age, sex, and body mass index. METHODS: We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy-proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 index (FIB-4). RESULTS: The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low-risk" SAFE score was the highest (91.0%), followed by those with "intermediate-risk" (7.8%) and "high-risk" (1.2%) scores. The prevalence of fibrosis in subjects with low-risk, intermediate-risk, and high-risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB-4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB-4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30-39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99). CONCLUSION: While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited.

Detecting Early Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Using Longitudinal α-Fetoprotein Screening.

BACKGROUND & AIMS: This study aimed to evaluate the parametric empirical Bayes (PEB) longitudinal α-fetoprotein (AFP) screening algorithm performance in patients with hepatitis B compared with AFP surveillance with a fixed threshold. METHODS: The serum AFP of 588 patients was measured. Patients were screened at least once every 6 months with AFP and ultrasound or computed tomography/magnetic resonance imaging. Age, aspartate aminotransferase level, alanine aminotransferase level, platelet count, total bilirubin, prothrombin time, and hepatitis B virus DNA level were adjusted in the PEB algorithm. All variables were abstracted at the time of hepatocellular carcinoma (HCC) diagnosis for cases or last follow-up for controls and at months -6, -12, -18, -24, -30, -36, -42, -48, and -54, up to month -60. RESULTS: Overall, 62 (10.5%) HCC cases developed during a median follow-up of 52.7 months. Moreover, 55 (88.7%) cases were detected at Barcelona Clinic Liver Cancer stage 0 or A. The area under the receiver-operating characteristic curve of the patient-level true positive rate against the screening-level false positive rate was significantly higher in the PEB algorithm than that in AFP alone (area under the receiver-operating characteristic curve: 0.94 vs 0.86; P < .0005). At 80% specificity, the PEB algorithm significantly improved the patient-level true positive rate within 2 years prior to HCC diagnosis compared with AFP alone (80.6% vs 67.7%, respectively; P = .0485; adjusted P = .1663). The PEB algorithm more effectively enabled first positive screening. CONCLUSIONS: The longitudinal assessment of AFP by the PEB algorithm improved HCC screening performance compared to AFP alone in patients with hepatitis B. This algorithm may improve HCC screening without additional cost or inconvenience to patients.

Low Level of Hepatitis B Viremia Compared With Undetectable Viremia Increases the Risk of Hepatocellular Carcinoma in Patients With Untreated Compensated Cirrhosis.

INTRODUCTION: The initiation of antiviral treatment in patients with chronic hepatitis B with compensated cirrhosis and low-level viremia (LLV; HBV DNA 15-2,000 IU/mL) remains controversial. We sought to compare the long-term outcomes of these untreated patients according to their viremic status. METHODS: Six hundred twenty-seven untreated patients with chronic hepatitis B with compensated cirrhosis were analyzed retrospectively. The risk of hepatocellular carcinoma (HCC) and liver-related clinical events, including hepatic decompensation, were compared between patients with LLV and undetectable HBV DNA. Patients who received antiviral treatment were censored during treatment initiation. RESULTS: The mean age of the patients was 54.7 years, 64.4% of whom were male. During the study period, 59 patients developed HCC (20 and 39 in the undetectable and LLV groups, respectively) with an annual incidence of 2.44/100 person-years. Multivariable analysis revealed that the LLV group was associated with a significantly higher risk of HCC (adjusted hazard ratio: 2.36, P = 0.002) than the undetectable group. In the 204 propensity score-matched cohort, the LLV group had a 2.16-fold greater risk of HCC than the undetectable group ( P = 0.014). Liver-related clinical events occurred in 121 patients with an annual incidence of 5.25/100 person-years. Despite not reaching statistical significance, the LLV group tended to have a higher risk of liver-related events in the propensity score-matched cohort (hazard ratio: 1.14, P = 0.50). DISCUSSION: Compared with patients with undetectable HBV DNA, those with compensated cirrhosis and LLV had a significantly higher risk of HCC. Antiviral treatment should be advised for these patients.

Liver Cirrhosis Increases the Risk of Herpes Zoster: A Nationwide Population-Based Cohort Study.

INTRODUCTION: Limited data are available regarding the association between liver cirrhosis (LC) and the risk of herpes zoster (HZ). This study aimed to determine the risk of HZ in patients with LC. METHODS: HZ was defined as the presence of the International Classification of Diseases-10th revision code for HZ and concomitant prescription of antiviral medication. The incidence rates and standardized incidence ratios (SIRs) of HZ in patients with LC were analyzed using data from the Health Insurance Review and Assessment Service in Korea claims database from 2009 to 2019. RESULTS: A total of 504,986 Korean patients with LC were included. The mean age was 52.4 years, and 60.8% were men. Chronic hepatitis B was the most common cause of LC. The incidence rates for HZ and HZ-related hospitalization were 21.6 of 1,000 and 1.81 of 1,000 person-years, respectively. The SIRs for HZ and HZ-related hospitalization were 1.09 (95% confidence interval [CI]: 1.08-1.09) and 1.48 (95% CI: 1.44-1.52), respectively, which were significantly higher than those in the general population. Patients with LC aged 20-29, 30-39, and 40-49 years had SIRs for HZ of 1.41 (95% CI: 1.33-1.48), 1.16 (1.13-1.19), and 1.17 (1.13-1.19), respectively. In multivariable analysis, woman (adjusted hazard ratio [AHR]: 1.48), steroid (AHR: 1.20), immunosuppressant use (AHR: 1.26), and combined comorbidities were associated with an increased risk of HZ among patients with LC. DISCUSSION: Patients with LC, particularly those who are not currently recommended for HZ vaccination, were at an increased risk of HZ and HZ-related hospitalization compared with the general Korean population.

Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.

BACKGROUND & AIMS: It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence. METHODS: This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling. RESULTS: The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness-death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance. CONCLUSIONS: HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection. LAY SUMMARY: Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. METHODS: This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. RESULTS: The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. CONCLUSIONS: In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Tenofovir Alafenamide for Drug-Resistant Hepatitis B: A Randomized Trial for Switching From Tenofovir Disoproxil Fumarate.

BACKGROUND & AIMS: It remains unknown whether tenofovir alafenamide (TAF) could replace tenofovir disoproxil fumarate (TDF) in patients with drug-resistant hepatitis B virus (HBV). METHODS: In this multicenter randomized non-inferiority trial, 174 patients with HBV resistant to multiple drugs (lamivudine, entecavir, and/or adefovir) under TDF monotherapy for ≥96 weeks were randomized 1:1 to switch to TAF (n = 87) or continue TDF (n = 87) for 48 weeks. The primary endpoint was proportion of patients with HBV DNA <60 IU/mL at week 48. RESULTS: At baseline, 84 and 80 patients had HBV DNA <60 IU/mL in the TAF and TDF groups, respectively. At week 48, the proportion of patients with HBV DNA <60 IU/mL was 98.9% (86/87) in TAF group, showing non-inferiority to TDF group (97.7%, 85/87; difference, 1.1%; 95% confidence interval, -2.7% to 5.0%). Changes in median alanine aminotransferase at week 48 from baseline were statistically different between TAF and TDF groups (-3 IU/L vs +2 IU/L; P = .02). TAF group showed a statistically greater increase in bone mineral density at spine (+1.84% vs +0.08%; P = .01) and numerically higher increase in mean estimated glomerular filtration rate (+8.2% vs +4.5%; P = .06) compared with TDF group. Compared with TDF group, TAF group showed significantly greater increases in mean body weight (0.71 vs -0.37 kg; P = .01) and total, low-density lipoprotein, and high-density lipoprotein cholesterol levels (P < .001 for all) at week 48 from baseline. CONCLUSIONS: TAF could be substituted for TDF in patients with multidrug-resistant HBV for improved bone and renal safety without a loss of efficacy. However, increases in body weight and cholesterol levels with TAF treatment would be a concern. ClinicalTrials.gov no.: NCT03241641.

Tenofovir Versus Entecavir on Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma After Surgical Resection.

BACKGROUND AND AIMS: Studies have suggested that tenofovir disoproxil fumarate (TDF) treatment is associated with a significantly lower risk of hepatocellular carcinoma (HCC) occurrence when compared with entecavir (ETV) therapy in patients with chronic hepatitis B. We aimed to compare HCC recurrence and survival of patients treated with TDF or ETV after surgical resection for hepatitis B virus (HBV)-related HCC. APPROACH AND RESULTS: This historical cohort study included 1,695 consecutive patients treated with ETV (n = 813) or TDF (n = 882) after curative-intent hepatectomy for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2010 and 2018. HCC recurrence and overall survival of patients were compared between ETV and TDF groups by propensity score-matched and multivariable-adjusted Cox regression analyses from the date of hepatectomy for HCC. The mean age of the study patients was 54.8 years, and 1,294 patients (76.3%) were male. During the median follow-up duration of 37.6 months with continued ETV or TDF therapy, 561 (33.1%) patients developed HCC recurrence, 144 (8.4%) died, and 22 (1.3%) received liver transplant. Compared with ETV, TDF therapy was associated with significantly higher recurrence-free (P = 0.02) and overall survival (P = 0.03) rates by propensity score-matched analysis. By multivariable-adjusted analysis, the TDF group was associated with significantly lower rates of HCC recurrence (hazard ratio [HR], 0.82; 95% confidence interval, 0.68-0.98; P = 0.03), and death or transplantation (HR, 0.62; 95% confidence interval, 0.44-0.88; P = 0.01). TDF therapy was an independent protective factor for both early (<2 years; HR, 0.79; P = 0.03) and late (≥2 years; HR, 0.68; P = 0.03) postoperative HCC recurrence. CONCLUSIONS: Among patients who underwent curative hepatectomy for HBV-related HCC, TDF therapy was associated with a significantly lower risk of HCC recurrence and better overall patient survival compared with ETV therapy.

Comparison of Long-Term Clinical Outcomes Between Spontaneous and Therapy-Induced HBsAg Seroclearance.

BACKGROUND AND AIMS: HBsAg seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as "functional cure." However, it remains elusive whether nucleos(t)ide analogue (NUC)-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long-term clinical outcomes. APPROACH AND RESULTS: A total of 1,972 CHB patients with confirmed HBsAg seroclearance at least two consecutive times, 6 months apart, were retrospectively analyzed. Risks of HCC development and composite clinical events, including HCC, liver-related death, and liver transplantation, were compared between spontaneous and NUC-induced HBsAg seroclearance. Of 1,972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 (15.1%) patients. HBsAg seroclearance was achieved spontaneously in 1,624 (82.4%) patients and by NUC treatment in 348 (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person-years (PY) during a median follow-up of 5.6 years. With 336 propensity-score-matched pairs, risks of HCC (P = 0.52) and clinical events (P = 0.14) were not significantly different between NUC-induced and spontaneous HBsAg seroclearance. By multivariable analysis, NUC-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted HR [AHR], 1.49; P = 0.26) and clinical events (AHR, 1.78; P = 0.06). CONCLUSIONS: Risks of HCC and clinical events were not significantly different between spontaneous and NUC-induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cutoff for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.

Stereotactic body radiation therapy as a salvage treatment for single viable hepatocellular carcinoma at the site of incomplete transarterial chemoembolization: a retrospective analysis of 302 patients.

BACKGROUND: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE). METHODS: Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03. RESULTS: A total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6-41.7) and the median tumor size was 2.0 cm (range, 0.7-6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9-4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field. CONCLUSION: SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.

Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in treatment-naïve chronic hepatitis B.

BACKGROUND AND AIMS: We used real-world data to evaluate the efficacy and safety of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) in treatment-naïve patients with CHB. METHODS: We analysed 2747 patients with CHB under TAF (n = 502) or TDF (n = 2245) treatments. Virological responses (VR: HBV DNA <15 IU/ml), on-treatment ALT normalization, the incidence of HCC, renal function and lipid profiles were compared between these groups. Propensity score matching of 495 pairs was conducted for these comparisons. RESULTS: The mean age of the total cohort was 48.6 years and 58.2% of the subjects were male. Cirrhosis had a 33.3% prevalence in the population. VRs at 12, 24 and 36 months were achieved in 70.3%, 81.2% and 83.3% of the TAF and 67.9%, 84.3% and 86.1% in the TDF cases respectively (p > 0.05 for all). Normalized ALT, as determined by local laboratory criteria (<40 U/L), occurred in 79.7%, 90.6% and 86.2% of TAF the group and 78.2%, 85.8% and 85.7% of the TDF group at 12, 24 and 36 months respectively (p > 0.05 for all). The HCC risk did not statistically differ across the entire cohort or in the PS-matched cohort. The TAF group showed a lower median increase in serum creatinine from baseline during the early study period. Compared with the TAF, the TDF group showed significant decreases in total cholesterol, triglyceride and HDL, but not in LDL. CONCLUSIONS: Real-word data indicate that TAF has comparable efficacies to TDF in terms of VR and ALT normalization, with no higher risk of HCC.

Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) and entecavir are recommended as first-line treatments for chronic hepatitis B virus (HBV) infection. However, there is debate over the comparative effectiveness of these drugs in preventing hepatocellular carcinoma (HCC). We performed a systematic review and meta-analysis of the effectiveness of TDF vs entecavir in reducing the incidence of HCC among patients with chronic HBV infection. METHODS: We performed a systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library from 2010 through 2019 for full-text articles and conference abstracts on studies of effects of TDF vs entecavir in patients with HBV infection. Extracted data were analyzed with the random-effects model. Potential sources of heterogeneity were investigated using sensitivity, meta-regression, and subgroup analyses. RESULTS: Our final analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir). TDF treatment was associated with a significantly lower risk of HCC than entecavir (hazard ratio, 0.80; 95% CI, 0.69-0.93; P = .003; I2 = 13%). The lower risk of HCC in patients given TDF compared with entecavir persisted in sensitivity and subcohort analyses performed with propensity score-matched cohorts and cirrhosis subcohorts. Inclusion of patients with decompensated cirrhosis and the sample size were the factors with the largest effects on between-study heterogeneity in meta-regression analyses. Subsequent subgroup analyses showed no statistical differences in the incidence of death or transplantation (hazard ratio, 0.93; 95% CI, 0.73-1.17; P = .519; I2 = 6%) between patients given TDF vs entecavir. CONCLUSIONS: In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.

The role of muscle depletion and visceral adiposity in HCC patients aged 65 and over undergoing TACE.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has been increasing among the elderly populations. Trans-arterial chemoembolization (TACE), a widely used first-line non-curative therapy for HCCs is an issue in geriatrics. We investigated the prognosis of elderly HCC patients treated with TACE and determined the factors that affect the overall survival. METHODS: We included 266 patients who were older than 65 years and had received TACE as initial treatment for HCC. We analyzed the skeletal muscle index (SMI) and visceral-to-subcutaneous fat ratio (VSR) around the third lumbar vertebrae using computed tomography scans. Muscle depletion with visceral adiposity (MDVA) was defined by falling below the median SMI and above the median VSR value sex-specifically. We evaluated the overall survival in association with MDVA and other clinical factors. RESULTS: The mean age was 69.9 ± 4.5 years, and 70.3% of the patients were men. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, 29, 136, and 101 patients were classified as BCLC 0, A, and B stages, respectively, and 79 (29.7%) had MDVA. During the median follow-up of 4.1 years, patients with MDVA had a shorter life expectancy than those without MDVA (P = 0.007) even though MDVA group had a higher objective response rate after the first TACE (82.3% vs. 75.9%, P = 0.035). Multivariate analysis revealed that MDVA (Hazard ratio [HR] 1.515) age (HR 1.057), liver function (HR 1.078), tumor size (HR 1.083), serum albumin level (HR 0.523), platelet count (HR 0.996), tumor stage (stage A, HR 1.711; stage B, HR 2.003), and treatment response after the first TACE treatment (HR 0.680) were associated with overall survival. CONCLUSIONS: MDVA is a critical prognostic factor for predicting survival in the elderly patients with HCC who have undergone TACE.