MELD-GRAIL-Na Is a Better Predictor of Mortality Than MELD in Korean Patients with Cirrhosis.

Background and Objectives: The Child-Pugh (CP) score and Model for End-Stage Liver Disease (MELD) are classical systems for predicting mortality in patients with liver cirrhosis (LC). The MELD-GFR assessment in liver disease-sodium (MELD-GRAIL-Na) was designed to better reflect renal function and, therefore, provide better mortality predictions. This study aimed to compare the prediction accuracy of MELD-GRAIL-Na compared to CP and MELD in predicting short-term (1- and 3-month) mortality in Korean patients. Materials and Methods: Medical records of patients with LC admitted to the Konkuk University Hospital from 2015 to 2020 were retrospectively reviewed. Predictive values of the CP, MELD, and MELD-GRAIL-Na for 1-month and 3-month mortality were calculated using the area under the receiver operating curve (AUROC) and were compared using DeLong's test. Results: In total, 1249 patients were enrolled; 102 died within 1 month, and 146 within 3 months. AUROCs of CP, MELD, and MELD-GRAIL-Na were 0.831, 0.847, and 0.857 for 1-month mortality and 0.837, 0.827, and 0.835 for 3-month mortality, respectively, indicating no statistical significance. For patients with CP classes B and C, AUROCs of CP, MELD, and MELD-GRAIL-Na were 0.782, 0.809, and 0.825 for 1-month mortality and 0.775, 0.769, and 0.786 for 3-month mortality, respectively. There was a significant difference between CP and MELD-GRAIL-Na in predicting 1-month mortality (p = 0.0428) and between MELD and MELD-GRAIL-Na in predicting 1-month (p = 0.0493) and 3-month mortality (p = 0.0225). Conclusions: Compared to CP and MELD, MELD-GRAIL-Na was found to be a better and more useful system for evaluating short-term (1- and 3-month) mortality in Korean patients with cirrhosis, especially those with advanced cirrhosis (CP class B and C).

Switching from Tenofovir-Based Combination Therapy to Tenofovir Monotherapy in Multidrug-Experienced Chronic Hepatitis B Patients: a 5-Year Experience at Two Centers.

Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.

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.

Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks. METHODS: One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks. RESULTS: At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (-2.48%, p <0.001). CONCLUSIONS: Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092). LAY SUMMARY: In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.

Monotherapy with tenofovir disoproxil fumarate for multiple drug-resistant chronic hepatitis B: 3-year trial.

Combination therapy has been recommended for the treatment of patients harboring multiple drug-resistant hepatitis B virus (HBV). However, we recently demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) for 48 weeks displayed noninferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with HBV resistant to multiple drugs, including ETV and adefovir. Nonetheless, whether prolonged TDF monotherapy would be safe and increase the virologic response rate in these patients was unclear. Among 192 patients with HBV-resistance mutations to ETV and/or adefovir, who were randomized to receive TDF monotherapy (n = 95) or TDF/ETV combination therapy (n = 97) for 48 weeks, 189 agreed to continue TDF monotherapy (TDF-TDF group) or to switch to TDF monotherapy (TDF/ETV-TDF group) and 180 (93.8%) completed the 144-week study. Serum HBV DNA <15 IU/mL at week 48, the primary efficacy endpoint, was achieved in 66.3% in the TDF-TDF group and 68.0% in the TDF/ETV-TDF group (P = 0.80). At week 144, the proportion with HBV DNA <15 IU/mL increased to 74.5%, which was significantly higher compared with that at week 48 (P = 0.03), without a significant difference between groups (P = 0.46). By on-treatment analysis, a total of 79.4% had HBV DNA <15 IU/mL at week 144. Transient virologic breakthrough occurred in 6 patients, which was due to poor drug adherence. At week 144, 19 patients who had HBV DNA levels >60 IU/mL qualified for genotypic resistance analysis, and 6 retained some of their baseline resistance mutations of HBV. No patients developed additional resistance mutations throughout the study period. CONCLUSION: TDF monotherapy was efficacious and safe for up to 144 weeks, providing an increasing rate of virologic response in heavily pretreated patients with multidrug-resistant HBV. (Hepatology 2017;66:772-783).

Prognosis of Spontaneous Bacterial Peritonitis in Hepatocellular Carcinoma Patients.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a serious infectious complication in patients with liver cirrhosis. However, information about prognosis of SBP in hepatocellular carcinoma (HCC) patients is limited. We investigated the clinical course of SBP in HCC patients. METHODS: This study enrolled patients diagnosed with SBP between 2005 and 2017. Medical records of patients were reviewed and clinical course was compared between the non-HCC and HCC groups. RESULTS: In total, 123 SBP cases including 49 HCC cases were enrolled. Men were predominant (48/74, 64.9% vs. 34/49, 69.4%; P = 0.697); median age was 58 years in both non-HCC and HCC groups (P = 0.887). The most common etiology was alcohol (32/74, 43.2%) in non-HCC group and hepatitis B (30/49, 61.2%) in HCC group (P = 0.009). Antibiotic resistance rate was higher in non-HCC than in HCC group (29.7% vs. 12.2%; P = 0.028); in-hospital mortality did not differ between the groups (25/74, 33.8% vs. 13/49, 26.5%; P = 0.431). Development rate of hepatorenal syndrome did not differ between non-HCC and HCC group (14/74, 18.9% vs. 10/49, 20.4%; P = 1.000), but hepatic encephalopathy was less common in HCC group (26/74, 35.2% vs. 9/49, 18.3%; P = 0.008). The most important predictor of in-hospital mortality in patients with HCC was white blood cell count above 11,570 cells/mm3 (odds ratio, 6.629; 95% confidence interval, 1.652-26.590; P = 0.008). CONCLUSION: Prognosis of SBP in HCC patients is relatively less severe. This result may be related with reduced antibiotics resistance and lower development rates of other complications, such as hepatic encephalopathy. Degree of systemic inflammation may be the most important factor for in-hospital mortality.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial.

OBJECTIVE: Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV. DESIGN: In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks. RESULTS: Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log10 IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs. 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs. -3.74 log10 IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. CONCLUSIONS: TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID NCT01639092.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial.

OBJECTIVE: Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV. DESIGN: In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks. RESULTS: Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups. CONCLUSIONS: In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks. TRIAL REGISTRATION NUMBER: NCT01639066.

Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load.

UNLABELLED: Controversy exists about whether antiviral therapy (AVT) should be recommended for compensated cirrhosis patients with chronic hepatitis B virus (HBV) infection and detectable, but low, serum HBV-DNA levels. A retrospective cohort of 385 treatment-naïve, HBV-related compensated cirrhosis patients (mean age: 51.1 ± 9.7 years; 66% male) with low HBV-DNA levels (<2,000 IU/mL) was assessed for the development of hepatocellular carcinoma (HCC). During a median of 5.6 years of follow-up, HCC had developed in 37 (9.6%) patients. The 5-year cumulative HCC incidence rate was 2.2%, 8.0%, and 14.0% for patients with undetectable HBV DNA (<12 IU/mL), low HBV-DNA levels plus normal alanine aminotransferase (ALT) levels, and low HBV-DNA levels plus elevated ALT levels at baseline (P = 0.011). During follow-up, 71 patients maintained undetectable HBV-DNA levels, and 126 experienced HBV-DNA elevation over 2,000 IU/mL. AVT was initiated in 77 patients. In patients without AVT, the 5-year cumulative HCC incidence rates were 13.3%, 8.8%, and 1.4% for those who experienced HBV-DNA elevation, those who maintained detectable, but low, HBV-DNA levels, and those who maintained undetectable HBV-DNA levels, respectively. The 5-year cumulative HCC incidence rate was 5.9% for patients who started AVT; longer AVT duration and longer complete virological response (<12 IU/mL) duration was associated with lower HCC risk. CONCLUSION: Compensated cirrhosis patients with detectable, but low, viral load were not at low risk for HCC, and AVT was associated with lower HCC risk, suggesting that prompt AVT should be considered for these patients.

Combination treatment of trans-arterial chemo-embolisation, radiotherapy and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumour thrombosis: Interim analysis of prospective phase II trial.

Objectives This study evaluated the objective response to and toxicity of trans-arterial chemo-embolisation (TACE) followed by radiotherapy and hyperthermia (CERT) in hepatocellular carcinoma patients with portal vein tumour thrombosis. Methods The study design was a single-centre prospective phase II trial. Patients were first treated with TACE, with the first hyperthermia session 1 week later. Respiration-gated radiotherapy (RT) was delivered in 10 fractions of 3-5 Gy after another week. Six sessions of hyperthermia were delivered twice a week according to an energy escalation protocol. Response evaluation was planned at 1 month after RT completion using the modified Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Interim analysis was conducted on patients enrolled from October 2013 to November 2014. During this period, 46 patients (90.2%) who received at least one hyperthermia session were eligible and enrolled. Median follow-up was 6.7 months (range 2.0-15.0 months). Complete response was observed in 10 (21.7%) patients and partial response in 27 (47.8%). Most toxicities were grade I or II. One death was related to severe pneumonia of unknown cause in the left lung and one patient could not complete planned treatment because of continuous elevation of bilirubin after TACE. Late, asymptomatic gastroduodenal toxicities were noticed in 13 (28.3%) patients. Conclusion Preliminary evaluation of CERT showed a promising response rate with acceptable toxicities.

Sorafenib therapy for hepatocellular carcinoma with extrahepatic spread: treatment outcome and prognostic factors.

BACKGROUND & AIMS: Sorafenib is recommended as the treatment of choice for hepatocellular carcinoma (HCC) with extrahepatic spread (EHS). However, early discontinuation of sorafenib treatment is not uncommon because of adverse events, deterioration of liver function and/or performance. This study aimed to investigate the treatment outcome and prognostic factors of sorafenib treatment in HCC patients with EHS in which sorafenib was administered for at least 8 weeks. METHODS: From May 2007 to December 2012, a total of 254 HCC patients with EHS were treated with sorafenib monotherapy for at least 8 weeks. The treatment outcome, risk factors for disease progression, and overall survival were retrospectively analyzed. RESULTS: The median duration of radiologic progression and overall survival after sorafenib was 2.5 and 9.6 months, respectively. Prognostic factors for radiologic progression were intrahepatic tumor with macrovascular invasion (MVI) (hazard ratio (HR) 2.38, p<0.001), intrahepatic tumor without MVI (HR 2.37, p<0.001), age <60 years (HR 1.44, p=0.008), peritoneal involvement (HR 1.57, p=0.03), and underlying hepatitis B (HR 1.46, p=0.05). Prognostic factors for overall survival were lack of disease control with sorafenib (HR 2.98, p<0.001), intrahepatic tumor with MVI (HR 2.23, p<0.001), intrahepatic tumor without MVI (HR 1.70, p=0.003), Child-Pugh class B (HR 1.90, p=0.009), serum AFP ⩾200ng/ml (HR 1.45, p=0.009), and ALT ⩾40U/L (HR 1.34, p=0.041). In patients with chronic hepatitis B, the use of antiviral treatment was associated with favorable overall survival after sorafenib therapy (HR 0.64, p=0.003). CONCLUSION: Sorafenib prolonged survival in HCC patients with EHS who achieved disease control. Intrahepatic tumor is a poor prognostic factor for both disease progression and overall survival in HCC patients with EHS treated with sorafenib.

Association between serum osteocalcin levels and non-alcoholic fatty liver disease in women.

BACKGROUND AND AIMS: Osteocalcin was found to have a significant role in insulin resistance. Insulin resistance is considered a pathophysiological mechanism of nonalcoholic fatty liver disease (NAFLD). However, the relationship between serum osteocalcin level and NAFLD is not well known. METHODS: A total of 7,067 women undergoing abdominal ultrasonography, bone mineral density, and serum osteocalcin level measurement were analyzed. RESULTS: Serum osteocalcin level was independently associated with menopausal status, bone mineral density, calcium, phosphate, alkaline phosphatase, fasting blood glucose, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, γ-glutamyltransferase, and NAFLD. When women were grouped according to their menopausal status and bone mineral density, the serum osteocalcin level showed an independent inverse association with NAFLD in premenopausal women without osteopenia or osteoporosis (n = 2,941) [odd ratio (OR): 0.94, 95% confidence interval (CI): 0.91-0.96, p < 0.001] and postmenopausal women without osteopenia or osteoporosis (n = 2,155) (OR: 0.96, 95% CI: 0.95-0.98, p < 0.001), however, not in premenopausal (n = 308) or postmenopausal women (n = 1,663) with osteopenia or osteoporosis. CONCLUSIONS: The serum osteocalcin level was an independent factor associated with NAFLD, especially for women with normal bone mineral density. © 2015 S. Karger AG, Basel.

Stopping Preemptive Antiviral Therapy for Hepatitis B Virus Can Be Considered for Patients with Favorable Predictors.

BACKGROUND: Preemptive antiviral therapy is recommended for chronic hepatitis B virus (HBV)-infected patients receiving cytotoxic chemotherapy. However, little data are available for the stopping therapy. AIMS: We evaluated clinical outcome and predictors of off-treatment virological response of patients who discontinued therapy. METHODS: Ninety-five adult patients who discontinued therapy were enrolled. They were analyzed for sustained off-treatment virological response, defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy. RESULTS: Sustained off-treatment virological response was seen in 52 patients (54.7%). The baseline HBV DNA level was an independent factor associated with sustained off-treatment virological response, and the rate was 72.1 and 23.5% for those with HBV DNA < 2000 IU/ml and ≥ 2000 IU/ml, respectively (P < 0.001). The duration of consolidation treatment showed marginal association with sustained off-treatment virological response [odd ratio (95% confidence interval) 1.20 (0.98-1.47), P = 0.069] for those with baseline HBV DNA < 2000 IU/ml, but not for those with ≥ 2000 IU/ml. The sustained off-treatment virological response rate was 54.5, 71.4, 73.9, and 100% for consolidation treatment duration of <3, 3-6, 6-12, and ≥ 12 months, respectively, among those with baseline HBV DNA < 2000 IU/ml. CONCLUSIONS: The baseline HBV DNA level was indicator for sustained off-treatment virological response after stopping preemptive antiviral therapy. Consolidation treatment duration showed association with sustained off-treatment virological response only for those with low baseline HBV DNA levels.

Serum alpha-fetoprotein may have a significant role in the surveillance of hepatocellular carcinoma in hepatitis B endemic areas.

BACKGROUND/AIMS: The role of serum alpha-fetoprotein (AFP) determination in hepatocellular carcinoma (HCC) surveillance is controversial. METHODS: We reviewed a total of 132 patients (mean age 57.8 ± 9.6, males = 101 (76%); HBsAg positive = 109 (82.6%); cirrhosis = 94 (71.2%)) who were diagnosed with HCC during regular surveillance test with ultrasound (US) and AFP. RESULTS: The primary mode of tumor detection was US only in 51.5%, US and AFP in 22.0%, AFP only in 19.7%, and incidental in 6.8% of patients. US detected 68.5% of tumor diagnosed at early stage, which was significantly lower than tumor beyond-early stage (85.0%, p = 0.048). AFP doubling (an increase in AFP level more than double from a prior surveillance) was more frequently observed in HBV-related HCC (47.7%) than HCV-related HCC (11.8%, p = 0.009). The AFP increased sensitivity by 19.7% for all patients; 28.0% for HBV-related early stage HCC patients. CONCLUSIONS: This result suggest that serum AFP measurements may have a significant role in increasing sensitivity in HCC surveillance, especially for detecting early stage HBV-related HCC.

Hepatocellular Carcinoma Risk of Compensated Cirrhosis Patients with Elevated HBV DNA Levels according to Serum Aminotransferase Levels.

Sometimes, hepatitis B virus (HBV)-related cirrhotic patients with normal aminotransferase levels are closely followed-up for the elevation of aminotransferase levels instead of prompt antiviral therapy (AVT). We analyzed the long-term hepatocellular carcinoma (HCC) risk according to the aminotransferase levels in a retrospective cohort of 1,468 treatment-naïve, HBV-related, compensated cirrhosis patients with elevated HBV DNA levels (≥ 2,000 IU/mL). Based on aminotransferase levels, patients were categorized into normal (< 40 U/L, n = 364) and elevated group (≥ 40 U/L, n = 1,104). During a median of 5.3 yr of follow-up (range: 1.0-8.2 yr), HCC developed in 296 (20%) patients. The 5-yr cumulative HCC incidence rate was higher in patients with elevated aminotransferase level, but was not low in normal aminotransferase level (17% vs. 14%, P = 0.004). During the follow-up, 270/364 (74%) patients with normal aminotransferase levels experienced elevation of aminotransferase levels, and AVT was initiated in 1,258 (86%) patients. Less patients with normal aminotransferase levels received AVT (70% vs. 91%, P < 0.001) and median time to start AVT was longer (17.9 vs. 2.4 months, P < 0.001). AVT duration was an independent factor associated with HCC, and median duration of AVT was shorter (4.0 vs. 2.6 yr, P < 0.001) in patients with normal aminotransferase levels. The HCC risk of compensated cirrhosis patients with normal aminotransferase level is not low, and AVT duration is associated with lowered HCC risk, indicating that prompt AVT should be strongly considered even for those with normal aminotransferase levels.

Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease.

BACKGROUND: It is generally stated that oral antiviral therapy in patients with chronic hepatitis B (CHB) decreases the risk of developing hepatocellular carcinoma (HCC). Although oral nucleos(t)ide analogues (NUCs) may induce a state similar to inactive stage CHB, the long-term risk for HCC in patients treated with NUCs compared with inactive CHB is unclear. METHODS: A total of 1378 patients who were treatment naïve and started NUC therapy and 1014 patients with inactive stage CHB who were HBeAg-negative and continuously had hepatitis B DNA <2000 IU/mL during follow-up were enrolled. The NUC group was divided into two groups by continuous viral suppression: NUC complete responder (CR) group and NUC incomplete responder (IR) group. Cumulative HCC incidence rates were compared between the groups. RESULTS: The risk of developing HCC was significantly higher in the NUC CR group compared with the inactive CHB group, regardless of the presence of baseline liver cirrhosis (p<0.001). Risk factors associated with the development of HCC were treatment groups (p<0.001), age (p<0.001), sex (p<0.001) and the presence of liver cirrhosis at baseline (p=0.005). Of the NUC group, the cumulative incidence of HCC in the NUC IR group was significantly higher compared with the NUC CR group (p=0.028). CONCLUSIONS: The use of potent oral antiviral therapy can effectively suppress HBV replication in patients with CHB. However, the risk of HCC development in patients treated with oral antiviral agent is still significantly higher than patients with inactive stage CHB.

Differences between hepatocellular carcinoma and hepatitis B virus infection in patients with and without cirrhosis.

BACKGROUND: In patients with hepatitis B virus (HBV) infections, differences in hepatocellular carcinoma (HCC) between those with liver cirrhosis and those without cirrhosis have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between noncirrhotic and cirrhotic patients and to determine prognostic factors for tumor recurrence after hepatectomy in patients with HBV and HCC. METHODS: Between 2005 and 2010, 441 curative hepatectomies for HCC in patients with cirrhosis and 454 for HCC in patients without cirrhosis were performed. RESULTS: Cirrhotic patients had lower platelet counts, protein induced by vitamin K antagonist-II (PIVKA-II) levels, and tumor size than noncirrhotic patients. HCC differentiation in noncirrhotic patients was poorer than in cirrhotic patients. The 1-, 2-, and 3-year disease-free survival rates were 72.0, 65.6, and 61.0% in noncirrhotic patients, and 68.6, 56.5, and 51.5% in cirrhotic patients, respectively (P = 0.013). However, the 1-, 2-, and 3-year overall survival rates were 92.4, 85.5, and 81.7% in noncirrhotic patients, and 91.9, 86.1, and 82.4% in cirrhotic patients, respectively (P = 0.683). Risk factors for tumor recurrence in each group varied in multivariate analyses. Increased age, high platelet counts, microvascular invasion, serosal invasion, and intrahepatic metastasis predisposed to tumor recurrence in noncirrhotic patients, but elevated PIVKA-II and alkaline phosphatase levels, low serum albumin levels, portal vein invasion, intrahepatic metastasis, and tumor size were predisposing factors for recurrence in cirrhotic patients. CONCLUSIONS: The clinicopathologic characteristics and risk factors for tumor recurrence in cirrhotic and noncirrhotic HCC patients with HBV infection differ.

HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma.

BACKGROUND: Recent studies have shown that high hepatitis B virus (HBV) load is associated with increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). The aim of our study was to investigate the predictive role of HBV DNA and hepatitis B surface antigen (HBsAg) levels in early and late recurrence of HCC after curative resection in patients with HBV-related HCC. METHODS: From January 2008 to December 2010, a total of 248 patients underwent curative resection for HBV-related early-stage HCC (solitary tumor; < 5 cm in diameter or multinodular tumor; number of tumors ≤ 3 and diameter < 3 cm). We analyzed the predictive factors including HBV DNA and HBsAg levels for early recurrence (within 2 years) and late recurrence (after 2 years) of HCC after curative resection. RESULTS: The median follow-up duration was 33.3 months. Cumulative recurrence rates after resection at 1, 3, and 5 years were 16.6, 34.0, and 46.7 %, respectively. The multivariate analysis showed that risk factors for early recurrence were the presence of microvascular invasion (hazard ratio [HR] 3.86; p < 0.001), preoperative HBV DNA levels ≥ 20,000 IU/mL (HR 2.77; p < 0.001), and des-γ-carboxy prothrombin level ≥ 40 mAU/mL (HR 1.76; p = 0.045). Although, the risk factors for late recurrence by multivariate analysis were preoperative HBsAg levels ≥ 4,000 IU/mL (HR 2.80; p = 0.023) and age at resection ≥ 50 years (HR 3.22; p = 0.032). CONCLUSION: The HBV DNA levels were associated with early recurrence, whereas HBsAg levels were associated with late recurrence after curative resection in HBV-related HCC.

The feasibility of combined transcatheter arterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is regarded as the standard treatment of care in Barcelona Clinic Liver Cancer (BCLC) stage C patients. However, the modest overall survival (OS) and disease control rate warrants for a better treatment modality. This study aimed to investigate the feasibility of combined transarterial chemoembolization and radiotherapy (TACE+RT) in comparison with sorafenib for advanced hepatocellular carcinoma (HCC). METHODS AND MATERIALS: From 2007 to 2011, a total of 116 patients with locally advanced HCC were retrospectively enrolled. Sixty-seven patients treated with TACE+RT were compared with 49 patients treated with sorafenib. Propensity score matching generated a matched cohort composed of 27 patients from each group. OS was the primary endpoint for the analysis. RESULTS: At baseline, the sorafenib group had a tendency for a tumour size ≥10 cm, presence of lymph node metastasis and main portal vein tumour thrombosis compared to the TACE+RT group. The OS in the TACE+RT group was significantly longer compared to the sorafenib group (14.1 months vs. 3.3 months, P < 0.001). In the propensity score-matched cohort, baseline characteristics did not differ between the two groups. The TACE+RT group showed prolonged OS compared to the sorafenib group (6.7 months vs. 3.1 months, P < 0.001). Multivariate analysis revealed that TACE+RT was the only independent prognostic factor associated with survival in the propensity score-matched cohort (HR = 0.172, P < 0.001). CONCLUSIONS: The OS of TACE+RT was longer compared to sorafenib treatment in locally advanced HCC patients without distant metastasis. Further prospective studies are warranted to confirm these findings.