Byung Chul Yoo

Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: Analysis of prognostic factors

BACKGROUND & AIMS The aim was to assess 10-year outcomes of radiofrequency ablation as a first-line therapy of early-stage hepatocellular carcinoma with an analysis of prognostic factors. METHODS From April 1999 to April 2011, 1305 patients (male:female=993:312; mean age, 58.4 years) with 1502 early-stage hepatocellular carcinomas (mean size, 2.2 cm) were treated with percutaneous radiofrequency ablation as a first-line option. Follow-up period ranged from 0.4 to 146.6 months (median, 33.4 months). We assessed the 10-year follow-up results of recurrences and survival with the analyses of prognostic factors. RESULTS Recurrences occurred in 795 patients (1-17 times), which were managed with various therapeutic modalities. The cumulative local tumor progression rates were 27.0% and 36.9% at 5 and 10 years, respectively, for which the only significant risk factor was large tumor size (B=0.584, p=0.001). Cumulative intrahepatic distant and extrahepatic recurrence rates were 73.1% and 88.5%, and 19.1% and 38.2% at 5 and 10 years, respectively. Corresponding overall survival rates were 59.7% and 32.3%, respectively. Poor survival was associated with old age (B=0.043, p=0.010), Child-Pugh class B (B=-1.054, p<0.001), absence of antiviral therapy during follow-up (B=-0.699, p=0.034), and presence of extrahepatic recurrence (B=0.971, p=0.007). CONCLUSIONS Ten-year survival outcomes after percutaneous radiofrequency ablation as a first-line therapy of hepatocellular carcinoma were excellent despite frequent tumor recurrences. Overall survival was influenced by age, Child-Pugh class, antiviral therapy, or extrahepatic recurrence.

A phase II dose‐escalating trial of clevudine in patients with chronic hepatitis B

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti‐hepatitis B virus (HBV) activity in vitro. A multicenter dose‐escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 × 106 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty‐two patients were enrolled (5, 10, 10, and 7 patients in the 10‐, 50‐, 100‐, and 200‐mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 in the 10‐, 50‐, 100‐, and 200‐mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose‐limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100‐mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV‐infected patients and support further clinical study. (HEPATOLOGY 2004;40:140–148.)

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Clevudine is highly efficacious in hepatitis B e antigen‐negative chronic hepatitis B with durable off‐therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (e‐CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were −4.25 and −0.48 log10 copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log10 reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well‐maintained during the post‐treatment follow‐up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. Conclusion: A 24‐week clevudine therapy was well‐tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e‐CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission. (HEPATOLOGY 2007.)

Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea

BACKGROUND/AIMS The aims of this study were to determine the frequency of precore/core promoter mutations and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Korea. METHODS Patients with chronic hepatitis B virus (HBV) infection were tested for HBeAg, anti-HBe, liver profile and HBV-DNA by a branched DNA (bDNA) assay. Serum HBV-DNA was amplified by a polymerase chain reaction and the precore/core promoter sequence was determined. RESULTS Among the 413 consecutive HBeAg-negative patients, 19.6% were bDNA-positive. Evidence of liver disease was found in 90.1% of bDNA-positive and 41.7% of bDNA-negative patients. Overall, 17.7% of HBeAg-negative patients had e-CHB. Precore mutation (A1896) was detected in 93.7% of HBeAg-negative bDNA-positive and 93.9% of HBeAg-negative bDNA-negative patients. In 59 HBeAg-positive patients, 78% had wild-type and 22% had a mixture of wild-type and A1896 mutant. Core promoter TA mutation was detected in 89.9% of HBeAg-negative bDNA-positive patients, 89.8% of HBeAg-negative bDNA-negative patients, and 74.6% of HBeAg-positive patients. No correlation was found between the presence of precore/core promoter mutations and HBV-DNA levels or disease severity. CONCLUSIONS In Korean patients infected with HBV genotype C, precore mutation occurred almost invariably along with HBeAg seroconversion and core promoter TA mutation was frequent irrespective of viral replication levels or disease severity.

Balloon-Occluded Retrograde Transvenous Obliteration of Gastric Varices: Outcomes and Complications in 49 Patients

OBJECTIVE Our aim was to evaluate the clinical outcomes, techniques, and complications of balloon-occluded retrograde transvenous obliteration for treating gastric varices with spontaneous gastrosystemic shunts. MATERIALS AND METHODS From November 2002 through October 2005, 49 consecutive patients with gastric varices were treated by balloon-occluded retrograde transvenous obliteration. The sclerosant was injected through the outflow veins during balloon occlusion. Immediate postprocedural CT scans were obtained to evaluate the procedural details. Recurrence and rebleeding of gastric varices and worsening of esophageal varices were evaluated by endoscopic examination and CT. The survival rates and prognostic factors after the procedure were also assessed. RESULTS There were six procedural failures and two procedure-related deaths. Disappearance or marked shrinkage of the treated gastric varices with no recurrent gastric variceal bleeding was noted in 39 patients (79.6% clinical success rate). Approximately two thirds of our patients experienced worsening of esophageal varices during the median follow-up period of 457 days. The cumulative survival rates at 1 year and 3 years after balloon-occluded retrograde transvenous obliteration were 83.1% and 65.7%, respectively. The prognostic factors associated with survival were the preprocedural Child-Pugh classification and the total bilirubin level. The survival rates and procedural outcomes for the patients with severely compromised liver function were poor. CONCLUSION Balloon-occluded retrograde transvenous obliteration is an effective treatment for the obliteration of gastric varices. However, application of this procedure to severely compromised patients should be considered carefully.

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.

A 12‐week clevudine therapy showed potent and durable antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a nucleoside analog with an unnatural β‐L configuration. In a phase I/II clinical trial, once daily doses ranging from 10 to 200 mg for 28 days were well tolerated, and produced significant antiviral activity. The present study was conducted to assess the degree and durability of the antiviral response to 12 weeks of clevudine treatment, and to investigate its safety and tolerability. A total of 98 patients with HBeAg‐positive chronic hepatitis B were randomized to placebo (n = 32), 30‐mg clevudine (n = 32), and 50‐mg clevudine (n = 34) groups. Patients were followed up after 12 weeks of treatment for a further 24 weeks off‐therapy. Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log10 copies/mL in the placebo, 30‐mg clevudine, and 50‐mg clevudine groups, respectively (P < .0001). Posttreatment antiviral activities were sustained, with 3.32 and 2.99 log10 reductions at week 12 off‐therapy and 2.28 and 1.40 log10 reductions at week 24 off‐therapies in the 30‐ and 50‐mg clevudine groups, respectively. Median serum alanine aminotransferase (ALT) levels decreased markedly from baseline during clevudine treatment and were maintained below the upper limit of normal throughout the 24 weeks off‐therapy in the two clevudine‐treated groups. The incidences of adverse events and treatment‐emergent grade 3 or 4 laboratory abnormalities were similar for the three groups. In conclusion, clevudine showed potent antiviral activity during therapy and induced a sustained posttreatment antiviral effect for 6 months after a 12‐week treatment period, and this was associated with a sustained normalization of ALT levels. (HEPATOLOGY 2006;43:982–988.)

UGT1A7 haplotype is associated with an increased risk of hepatocellular carcinoma in hepatitis B carriers

The UGT1A7 gene encodes UDP‐glucuronosyltransferase, a key enzyme catalyzing the glucuronidation of various carcinogens. In this study, we investigated the association between haplotypes of the whole UGT1A7 gene and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. Sequence analysis of exon1 and the promoter region of the UGT1A7 gene was carried out to determine haplotype profiles for 244 patients with hepatocellular carcinoma, 223 hepatitis B carriers, and 314 healthy control subjects. Hepatitis B carriers with haplotypes other than haplotype 1 (Ht1; CTCTCGTG at –341, –57, 33, 387, 391, 392, 622, and 756) had a significantly greater risk of developing HCC with odds ratios (OR) of 1.67 (95% confidence interval [CI]; 1.11–2.52) for Ht1/others and 1.85 (95% CI; 1.09–3.14) for others/others. In multivariate logistic regression analysis including age and haplotypes from Ht1 to Ht4, the presence of Ht2 (CGAGAACG) or Ht4 (CTCGAATG) was associated with HCC risk (OR = 1.45 [95% CI; 1.03–2.03] and 4.95 [95% CI; 1.75–13.98], respectively). The results of this study show that the UGT1A7 haplotype is a suitable susceptibility marker for the development of HCC in hepatitis B carriers. (Cancer Sci 2008; 99: 340–344)

Ultrasonographically Detected Non-Alcoholic Fatty Liver Disease Is an Independent Predictor for Identifying Patients With Insulin Resistance in Non-Obese, Non-Diabetic Middle-Aged Asian Adults

OBJECTIVES:We assessed the association among ultrasonographically detected non-alcoholic fatty liver disease (US-NAFLD), metabolic syndrome (MetS), and insulin resistance (IR) in non-obese, non-diabetic middle-aged adults, to find out whether US-NAFLD is independently associated with IR in this population.METHODS:A total of 5,878 non-obese (body mass index, ≥18.5 and <25), non-diabetic individuals were analyzed. IR was estimated with the homeostasis model assessment index (HOMA2–IR) and defined when HOMA2–IR ≥1.5. MetS was defined by the Adult Treatment Panel III (ATP III) criteria.RESULTS:MetS was present in 381 (6.5%) participants, IR was present in 801 (13.6%) participants, and US-NAFLD was present in 1,611 (27.4%) participants. The increase in the prevalence of US-NAFLD closely followed the increase in the number of metabolic components diagnosed according to the ATP III criteria (15.2%, 28.5%, 48.0%, 65.7%, 71.4%, and 100% for 0, 1, 2, 3, 4, and 5 metabolic components, respectively, P<0.001). US-NAFLD showed a significantly higher odds ratio (OR) for IR, regardless of the number of metabolic components (OR (95% confidence interval) of 3.48 (2.45–4.94), 3.63 (2.74–4.82), 3.19 (2.29–4.44), and 2.43 (1.43–3.81) for 0, 1, 2, and ≥3 metabolic components, respectively, P<0.001 for all values). MetS showed a low sensitivity (0.22) for the identification of individuals with IR, and either US-NAFLD alone (0.60) or US-NAFLD with MetS (0.66) improved sensitivity with acceptable trade-off in specificity.CONCLUSIONS:US-NAFLD was an independent predictor for IR, irrespective of the number of metabolic components of MetS in the non-obese, non-diabetic middle-aged Asian adults. US-NAFLD could identify individuals with IR that cannot be identified by MetS in this population.