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.

Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study.

BACKGROUND: We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis. METHODS: This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored. RESULTS: In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151-2.401]; 0.985 [0.978-0.993]; 4.240 [1.783-10.084]; and 3.345 [1.457-7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230-216.289]; and 5.676 [1.273-25.300], respectively; Ps < 0.05). CONCLUSIONS: PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.

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.

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.

Long-term clinical outcomes in patients with autoimmune hepatitis according to treatment response in Asian country.

BACKGROUND & AIMS: As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. METHODS: A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver-related adverse outcomes including liver-related death, liver transplantation and hepatocellular carcinoma were evaluated. RESULTS: With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non-remission. With a median follow-up duration of 6.6 years, the risk of liver-related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non-response. The cumulative risk of liver-related adverse outcomes was the highest in patients with non-response (8.51/100 person-years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver-related adverse outcomes. CONCLUSIONS: Patients with CBR within 1 year after treatment initiation had the lowest risk of liver-related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long-term outcomes.

High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B.

OBJECTIVE: High serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality. DESIGN: This historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, <19 IU/mL; males, <30 IU/mL) were compared with those of 1497 immune-active (IA)-phase patients (ALT ≥80 IU/mL) treated with nucleos(t)ide analogues. RESULTS: The IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; p<0.001) were significantly higher in the IT group than the IA group. In multivariable analyses, the IT group showed a significantly higher risk of HCC (HR 2.54; 95% CI 1.54 to 4.18) and death/transplantation (HR 3.38; 95% CI 1.85 to 6.16) than the IA group, which was consistently identified through inverse probability treatment weighting, propensity score-matched and competing risks analyses. CONCLUSIONS: Untreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.

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).

Telbivudine versus entecavir in patients with undetectable hepatitis B virus DNA: a randomized trial.

BACKGROUND: Telbivudine has been suggested to induce hepatitis B surface antigen (HBsAg) decline to the similar degree as pegylated interferon. We aimed to investigate whether telbivudine could further decrease HBsAg titer in patients who maintain undetectable serum hepatitis B virus (HBV) DNA after initial entecavir treatment. METHODS: In this open-label trial, patients who had serum HBsAg and HBV DNA levels ≥1,000 IU/mL and <60 IU/mL, respectively, following entecavir (0.5 mg/day) treatment for HBeAg-positive chronic hepatitis B were randomized to either switch treatment to telbivudine (600 mg/day, n = 47) or continue entecavir (n = 50) for 48 weeks. RESULTS: The baseline characteristics were comparable between groups including HBsAg levels (median, 3.41 log10 IU/mL). All patients had undetectable HBV DNA and normal alanine aminotransferase level. At week 48, the mean change in serum HBsAg levels was not significantly different between the telbivudine and entecavir groups (-0.03 log10 IU/mL vs. -0.05 log10 IU/mL; P = 0.57). No patient experienced HBsAg seroclearance or HBsAg decline >0.5 log10 IU/mL. Eleven patients (23.4%) in the telbivudine group, but none in the entecavir group, experienced virologic breakthrough (P < 0.001). Seven patients (14.9%) exhibited genotypic resistance mutations (M204I +/- L180M) during the virologic breakthrough. CONCLUSION: Sequential therapy with entecavir followed by telbivudine resulted in a high rate of virologic breakthrough and drug-resistance without any beneficial effect on HBsAg decline. These results do not support the use of low genetic barrier drugs as a switch treatment strategy in patients who achieve virologic response with high genetic barrier drugs. TRIAL REGISTRATION: NCT01595685 (date of trial registration: May 8, 2012).

Tumor Volume Doubling Time as a Dynamic Prognostic Marker for Patients with Hepatocellular Carcinoma.

BACKGROUND AND AIMS: To evaluate the clinical value of tumor growth rate in hepatocellular carcinoma (HCC) patients, we investigated the growth rate of HCC by calculating the tumor volume doubling time (TVDT) and its impact on survival and recurrence. METHODS: A retrospective cohort study of 269 HCC patients who underwent two or more pretreatment imaging studies of computed tomography or magnetic resonance imaging was performed. Tumor growth rate and TVDT were calculated by comparing tumor volumes between imaging studies. Clinical parameters independently related to a TVDT of <2 months were evaluated. After dividing patients into slow-growing (159 patients with TVDT >2 months) and rapid-growing (110 patients with TVDT <2 months) groups, we compared the groups in terms of their survival and recurrence outcomes. The response to transarterial chemoembolization (TACE) was evaluated according to TVDT. RESULTS: The median tumor growth rate and TVDT were 37.5%/month and 2.37 months, respectively. By logistic regression analyses, a high Child-Pugh score, small initial tumor diameter, gross vascular invasion, and tumor multiplicity were found to be independently associated with a TVDT of <2 months (P < 0.05). Patients in the rapid-growing group had lower survival rates and higher recurrence rates (P < 0.05). The response to TACE was worse in the rapid-growing group (P < 0.05). CONCLUSIONS: A fast HCC growth rate is associated with poor liver function and aggressive tumor biology. HCC patients with shorter TVDTs exhibit poorer survival and recurrence outcomes as well as a poor response to TACE.

Correction to: Tumor Volume Doubling Time as a Dynamic Prognostic Marker for Patients with Hepatocellular Carcinoma.

The original version of this article unfortunately contained an error in corresponding author e-mail. It was submitted and published as kimkim70@amc.seoul.kr instead of kimkm70@amc.seoul.kr.

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.

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.

Comprehensive outcomes of on- and off-antiviral prophylaxis in hepatitis B patients undergoing cancer chemotherapy: A competing risks analysis.

Although antiviral prophylaxis is essential in hepatitis B patients in the context of cancer chemotherapy, there is little evidence-based consensus regarding the appropriate prevention strategy depending on the underlying type of cancer and viral status. This retrospective study included a comprehensive cohort of 302 hepatitis B surface antigen-positive patients with various cancers undergoing chemotherapy and antiviral prophylaxis. The rates of hepatitis B virus (HBV) reactivation during antiviral therapy (>1 log10 IU/mL increase or positive conversion of serum HBV DNA) and relapse when off antivirals ([re]appearance of HBV DNA >2,000 IU/ml with related alanine aminotransferase elevation) were evaluated, together with the associated risk factors, in a competing risks analysis where cancer death was considered as the competing event. During antiviral prophylaxis, HBV was reactivated in six patients (1.9%), who had leukemia (n = 4) or lymphoma (n = 2) and were treated with lamivudine (n = 4) or entecavir (n = 2). The incidence rate of HBV relapse in 127 off-prophylaxis patients was 21.3% during a median post-antiviral period of 11.7 months. Lymphoma, pre-prophylactic HBV DNA ≥2,000 IU/ml, and age ≥50 years were independent predictors of off-treatment HBV relapse (adjusted hazard ratios 5.25, 3.07, and 0.34, respectively; Ps < 0.05). Antiviral and anticancer drugs, duration of consolidation on antiviral prophylaxis, and HBeAg positivity were not independent predictors. In conclusion, hepatitis B flare-ups are not rare in patients receiving cancer chemotherapy during and after anti-HBV prophylaxis, even when potent antivirals are used. Patients with hematopoietic or lymphoid neoplasms or high viral burdens should receive prolonged and powerful HBV prophylaxis. J. Med. Virol. 88:1576-1586, 2016. © 2016 Wiley Periodicals, Inc.

Clinical characteristics and potential aetiologies of non-B non-C hepatocellular carcinoma in hepatitis B virus endemic area.

BACKGROUND & AIMS: We investigated potential aetiologies, clinical characteristics and prognosis of non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients in hepatitis B virus (HBV) endemic area, according to potential causes such as previous HBV exposure, chronic alcohol intake and metabolic syndrome. PATIENTS AND METHODS: Among 4690 HCC patients treated at Asan Medical Center between 2007 and 2009, 523 were newly diagnosed with NBNC HCC, and their medical records and survival data were analyzed retrospectively. RESULTS: Among 321 NBNC HCC patients whose hepatitis B core antibody (anti-HBc) test results were available, 81.0%, 37.1% and 15.5% had anti-HBc positivity, chronic alcohol intake and metabolic syndrome respectively. One-hundred and fifty-two patients (47.4%) had previous exposure to HBV without chronic alcohol intake or metabolic syndrome. Hepatitis B surface antibody (anti-HBs) was positive in 48.0% of the 523 NBNC HCC patients, which was much lower than that in general Korean population, and 52.3% of anti-HBc-positive NBNC HCC patients were negative for anti-HBs. Anti-HBc-negative alcoholic patients presented with more advanced cirrhosis with Child-Pugh class B/C liver function than anti-HBc-positive patients (P = 0.002). In multivariate analysis, baseline liver function, alpha-foetoprotein levels and tumour stage were significant prognostic factors and aetiology did not affect patient survival. CONCLUSIONS: Prior HBV infection could be a potential aetiology in over 40% of NBNC HCC patients in HBV endemic area. Positivity for anti-HBc and negativity for anti-HBs may be a serologic surrogate marker for occult HBV infection in these area. The prognosis of NBNC HCC was determined by tumour stage and underlying liver function.

Prevalence and prediction of coronary artery disease in patients with liver cirrhosis: a registry-based matched case-control study.

BACKGROUND: There is conflict regarding the prevalence of coronary artery disease (CAD) in patients with liver cirrhosis. This study aimed to investigate the prevalence of silent CAD in comparison with the general population, and to identify the relevant risk factors in patients with liver cirrhosis. METHODS AND RESULTS: This retrospective study included 1045 prospectively registered consecutive patients with liver cirrhosis without any history of chest pain or CAD, who underwent computerized coronary angiography as a pretransplant workup. These were matched with 6283 controls with healthy livers, based on propensity scores according to established cardiovascular risk factors. Obstructive CAD was defined as ≥50% luminal narrowing in any artery. A matched analysis of 853 pairs showed that the proportion of subjects with obstructive CAD did not differ significantly between the cirrhotic and control groups (7.2% versus 7.9%, P=0.646), in agreement with the outcome of multivariate analysis for its predictors, with an adjusted odds ratio for liver cirrhosis of 1.06 (P=0.690). Nonobstructive CAD was more prevalent in the matched cirrhotic cases (30.6% versus 23.4%, P=0.001). In the pooled cirrhotic cohort, older age, male sex, hypertension, diabetes mellitus, and alcoholic cirrhosis were independently associated with obstructive CAD (adjusted odds ratios, 1.07, 2.74, 1.69, 2.37, and 2.17, respectively; P<0.05 for all), whereas liver function and coagulation parameters were not. CONCLUSIONS: Asymptomatic cirrhotic patients and nonhepatic subjects are similar in terms of the prevalence of occult obstructive CAD. Traditional cardiovascular risk factors are related to critical coronary stenosis in cirrhotic patients, and thus may be helpful indicators for more careful preoperative evaluation of coronary risk.

Optimal methods for measuring eligibility for liver transplant in hepatocellular carcinoma patients undergoing transarterial chemoembolization.

BACKGROUND & AIMS: We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT). METHODS: 271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time-dependent receiver operating characteristic curves (AUC) estimation. RESULTS: Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to-seven model. Higher AUC values were observed with the size method only in the up-to-seven model (p<0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method (p<0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method (p=0.017). CONCLUSIONS: The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion.

A Patient-Based Nomogram for Predicting Overall Survival after Radiofrequency Ablation for Hepatocellular Carcinoma.

PURPOSE: To develop a prognostic nomogram based on specific patient and tumor factors capable of estimating individual survival outcomes after radiofrequency (RF) ablation as a primary therapy for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study included 893 patients who were initially treated with curative RF ablation for HCC; patients were temporally divided into derivation (n = 607) and validation (n = 286) cohorts. A multivariate Cox proportional hazards model for overall survival was developed and validated. The discriminatory accuracy of the model was compared with the preexisting Cancer of the Liver Italian Program (CLIP) system and the Tokyo score previously proposed for percutaneous therapy for HCC by analyzing receiver operating characteristic (ROC) curves. RESULTS: A nomogram was generated for 3-year survival, incorporating largest tumor diameter and number of tumors, serum albumin and creatinine, platelet count, prothrombin time, and serum α-fetoprotein on a logarithmic scale. It had good calibration and discrimination abilities with a C-index of 0.74. The validation results also showed that the nomogram performed well in terms of goodness-of-fit and discrimination (C-index, 0.72). Analysis of ROC curves in the validation cohort indicated that the model had better predictive power than CLIP and Tokyo scores (C-indexes, 0.54 and 0.66, respectively). CONCLUSIONS: This prognostic tool quantifying per-patient expected survival after RF ablation can be used in daily clinical decision making with regard to patients with HCC deemed suitable for radical ablation and is probably more reliable than existing guidelines.

Comparison of chemoembolization with and without radiation therapy and sorafenib for advanced hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

PURPOSE: To compare efficacy of transarterial chemoembolization with and without radiation therapy (RT) versus sorafenib for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: This single-center retrospective study involved 557 patients with HCC with PVTT who initially received chemoembolization (1997-2002; n = 295), chemoembolization and RT (2003-2008; n = 196), or sorafenib (2009-2012; n = 66) according to eligibility criteria among an initial population of 617. The three groups were divided into three pairs (chemoembolization vs chemoembolization/RT, chemoembolization vs sorafenib, and chemoembolization/RT vs sorafenib), and time to progression (TTP) and overall survival (OS) were compared by propensity-score analyses. RESULTS: The chemoembolization/RT group had longer median TTP and OS than the chemoembolization-alone and sorafenib groups (P < .001). Multivariate Cox analysis revealed that chemoembolization/RT treatment was an independent predictor of favorable TTP and OS. In the matched cohort, median TTP and OS were significantly longer in the chemoembolization/RT group than the chemoembolization-alone group (102 pairs; TTP, 8.7 mo vs 3.6 mo [P < .001]; OS, 11.4 mo vs 7.4 mo [P = .023]) or the sorafenib group (30 pairs; TTP, 5.1 mo vs 1.6 mo [P < .001]; OS, 8.2 mo vs 3.2 mo [P < .001]), in agreement with the inverse probability of treatment weighted (IPTW) outcomes. In matching analyses, the chemoembolization-alone group had longer median TTP and OS than the sorafenib group (46 pairs; TTP, 3.4 mo vs 1.8 mo [P < .001]; OS, 5.9 mo vs 4.4 mo [P = .003]). There was no significant difference in terms of OS with the IPTW approach (P = .108), but there was one in terms of TTP (P < .001). CONCLUSIONS: Within the limitation of a retrospective study, the present data indicate that transarterial chemoembolization combined with RT could be considered as an alternative to the standard sorafenib in the treatment of patients with advanced-stage HCC with PVTT.

Nomograms for Predicting Outcomes after Chemoembolization in Patients with Nonmetastatic Hepatocellular Carcinoma.

PURPOSE: To construct prognostic nomograms capable of estimating individual probabilities of tumor progression and overall survival (OS) at specific time points during serial transarterial chemoembolization for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The study included 1,181 consecutive patients with nonmetastatic HCC undergoing repeated transarterial chemoembolization at a single tertiary referral center. Patients were assigned to 2 cohorts according to the first transarterial chemoembolization date: derivation (2004-2006; n = 854) and validation (2007; n = 327) sets. Multivariate Cox proportional hazards models were developed based on covariates derived before transarterial chemoembolization and assessed for their association with 5-year OS and 3-year progression-free survival (PFS). The accuracy of the models was internally and externally validated. RESULTS: The 5-year OS of the derivation set was 25.4%, and 3-year PFS was 20.8%. Nomograms for OS and PFS were built into the derivation set incorporating the following factors: log [tumor volume] calculated as 4/3 × 3.14 × (maximum radius of tumor in cm(3)); tumor number; tumor type (nodular or infiltrative); Child-Pugh class (A or B); (model for end-stage liver disease score/10)(-2); log [α-fetoprotein]; and portal vein invasion. The models had good discrimination and calibration abilities with C-indexes of 0.80 (5-y survival) and 0.77 (3-y progression). The results of external validation confirmed that these models performed well in terms of discrimination and goodness-of-fit (C-indexes 0.77 for 5-y survival and 0.73 for 3-y progression). CONCLUSION: Nomograms quantifying the survival and progression outcomes in patients treated with transarterial chemoembolization are useful clinical aids in providing personalized care.

Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: A case-control study.

BACKGROUND AND AIM: To identify factors associated with non-alcoholic fatty liver disease (NAFLD) in healthy Asian subjects. METHODS: A propensity score-matched case-control study was designed. To investigate the effects of demographic and clinical factors on the presence of NAFLD, a baseline-category logit model was used. Potential living liver donors with no hepatic steatosis (< 5%: n = 1353, group 1) were considered the baseline category, and subjects with mild (5-33%: n = 724, group 2) and moderate/severe (> 33%: n = 116, group 3) hepatic steatosis were defined as cases. Age and gender were matched between cases and controls, which resulted in 83 matched subjects in each of the three groups. The area of abdominal (visceral and subcutaneous) fat was directly measured in all subjects by unenhanced computed tomography. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyltranspeptidase, total cholesterol and triglyceride levels, and visceral fat amount were directly correlated with the grade of hepatic steatosis, and high-density lipoprotein cholesterol levels were inversely correlated with it (all P values < 0.05). In a multivariate model, visceral fat amount was significantly correlated with both mild (group 2) and moderate to severe (group 3) NAFLD, with respective odds ratios (ORs) of 1.03 relative to group 1 (Ps < 0.05). Body mass index (BMI), ALT, and subcutaneous fat were significant predictors of only moderate to severe NAFLD (ORs of 0.54, 1.20, and 1.02, respectively, for group 3 vs group 1; Ps < 0.05). CONCLUSIONS: Our results indicate that visceral adiposity makes non-obese subjects more susceptible to NAFLD, compared with subcutaneous fat and BMI.