Li-Ying Liao

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients

Background:Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.Methods:Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m−2. The primary end point was disease-control rate (DCR).Results:Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5–43.1) and 7.3 (95% CI: 4.7–9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1–17.9) and 5.8 (95% CI: 1.4–10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1–2 local and/or allergic reactions.Conclusions:ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.

Hepatitis B viral factors in HBeAg-Negative carriers with persistently normal serum alanine aminotransferase levels†

Chronic hepatitis B patients with high‐normal serum ALT (levels of 0.5‐1× upper limit of normal) are still at risk of liver disease progression. We thus investigated the correlation between serum ALT level and hepatitis B viral factors in HBeAg‐negative carriers with persistently normal serum ALT level (PNALT). Baseline clinical and virological features of 414 HBeAg‐negative carriers, including 176 (42.5%) with low‐normal ALT (levels of less than 0.5× upper limit of normal) and 238 (57.5%) with high‐normal ALT, were compared. Compared with HBV carriers with low‐normal ALT, those with high‐normal ALT were older (41 vs. 37 years, P < 0.001) and had a greater frequency of serum HBV DNA level >10 4 copies/ml (63.4% vs. 47.5%, P < 0.001) as well as a higher prevalence of basal core promoter T1762/A1764 mutant (36.5% vs. 24.2%, P = 0.01). Multivariate analysis showed that factors associated with a high‐normal serum ALT level included male sex [odds ratio (OR), 1.82; 95% confidence interval (CI), 1.10‐3.01, P = 0.019], increasing age (OR, <30 years: 1, reference; 30‐39 years: 2.43, 95% CI, 1.18‐5.03, P = 0.016; 40‐49 years: 4.22, 95% CI, 1.99‐8.93, P < 0.001; ≥50 years: 4.06, 95% CI, 1.69‐9.78, P = 0.002) and serum HBV DNA level >10 4 copies/ml (OR, 1.83; 95% CI, 1.07‐3.13, P = 0.027). Conclusion: HBeAg‐negative patients with persistently normal ALT are not a homogenous group, and those with high‐normal ALT share some of the characteristics that have been associated with adverse long‐term outcomes. (HEPATOLOGY 2007;45:1193–1198.)

Basal core‐promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen‐negative chronic hepatitis B

Background/Aims: The long‐term outcomes in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B are distinct from those in HBeAg‐positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core‐promoter mutations with the clinical and virological characteristics of patients with HBeAg‐negative chronic hepatitis B in Taiwan.

Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up†‡§

Patients dually infected with hepatitis C virus (HCV)/hepatitis B virus (HBV) have a higher risk of developing advanced liver disease or hepatocellular carcinoma compared with monoinfected patients. Yet, there is a similar rate of sustained virologic response (SVR) after peginterferon alfa‐2a and ribavirin combination therapy in these patients compared with HCV‐monoinfected patients and a high hepatitis B surface antigen (HBsAg) seroclearance rate. The durability of hepatitis C and B clearance in coinfected patients was investigated in a 5‐year follow‐up study. Patients with active HCV genotype 1, both HBV‐coinfected (n = 97) and HBV‐monoinfected (n = 110), underwent 48‐week combination therapy with peginterferon alfa‐2a plus ribavirin. In patients with active HCV genotype 2 or 3, both HBV‐coinfected (n = 64) and monoinfected (n = 50) patients underwent 24‐week combination therapy. A total of 295 (91.9%) patients completed treatment and 24 weeks posttreatment follow‐up; 264 (89.5%) patients agreed to receive additional follow‐up for up to 5 years after the end of treatment. After a median follow‐up of 4.6 ± 1.0 years, six of the 232 patients achieving SVR developed HCV RNA reappearance, including five HCV genotype 1/HBV‐coinfected patients and one HCV genotype 2/3‐monoinfected patient. Subgenomic analysis of the HCV core gene indicated that five patients developed delayed recurrence of HCV infection. Overall, the cumulative recurrence rate of HCV infection was 2.3% (0.4%/year; 95% confidence interval [CI], 0.9%‐5.5%). The cumulative HBsAg seroclearance rate was 30.0% (95% CI, 21.5%‐42.0%); with 33.1% (95% CI, 21.8%‐50.1%) in the 48‐week combination therapy group and 24.3% (95% CI, 13.7%‐42.9%) in the 24‐week therapy group. Conclusion: Peginterferon alfa‐2a and ribavirin therapy provides good HCV SVR durability and a high accumulative HBsAg seroclearance rate in patients who are coinfected with HCV and HBV. (HEPATOLOGY 2013;)

HBsAg Profiles in Patients Receiving Peginterferon Alfa-2a plus Ribavirin for the Treatment of Dual Chronic Infection with Hepatitis B and C Viruses

BACKGROUND With use of peginterferon alfa-2a and ribavirin combination therapy in patients with dual chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, 11.2% of patients achieved clearance of hepatitis B surface antigen (HBsAg) at 6 months after treatment; however, reactivation of HBV DNA was observed in 36.3%. We investigated the predictive potential of HBsAg quantification. METHODS HBsAg quantification was performed in 120 e antigen-negative patients dually infected with HBV and hepatitis C virus and treated with peginterferon alfa-2a/ribavirin for 48 weeks (HCV genotype 1; n = 74) or 24 weeks (HCV genotype 2/3; n = 46). HBsAg was quantified at baseline, week 4, week 12, end of treatment, and 24 weeks after treatment. RESULTS The baseline median serum HBsAg level was 120 IU/mL and decreased gradually during treatment. Low baseline HBsAg was significantly associated with HBsAg clearance (40% for HBsAg level 20 IU/mL vs 2.2% for HBsAg level >20 IU/mL; P < .05). A decrease in HBsAg level from baseline to week 12 of 50% was associated with a reduced likelihood of HBV DNA reactivation in patients with baseline undetectable serum HBV DNA (positive predictive value, 89.5%). CONCLUSIONS HBsAg quantification appears to be a useful indicator of posttreatment outcome in patients dually infected with HBV and hepatitis C virus.

Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B.

Background. Mutations in the precore stop codon (G1896A) and the basal core promoter (A1762T and G1764A) are frequently found in hepatitis B envelope antigen (HBeAg)-negative chronic hepatitis B. However, the clinical significance of these mutations remains controversial. We therefore investigated the influence of hepatitis B virus (HBV) genotypes, as well as precore/basal core promoter mutants, on the clinical and virological features of patients with HBeAg-negative chronic hepatitis B. Methods. Serum samples from 37 patients with HBeAg-negative chronic hepatitis B were collected for serological and molecular assays. The precore and basal core promoter regions were amplified by polymerase chain reaction and the amplicons were directly sequenced and analyzed. HBV geno-type was determined by polymerase chain reaction-restriction fragment length polymorphism. Results. Most of the patients had detectable serum HBV DNA, and genotypes B and C were the predominant strains. The overall prevalence of the precore stop codon mutant and basal core promoter mutant was 67% and 60%, respectively. The baseline clinical and virological features of patients with genotype B and genotype C infection were comparable. However, in the patients with precore/basal core promoter dual mutations there was a significantly lower proportion of individuals with a high detectable serum HBV DNA level (>100 pg/ml) than in the patients with either the precore stop codon mutation alone or the basal core promoter mutation alone (P = 0.04 by the logistic regression test for the trend). Conclusions. Our data suggest a high prevalence of precore stop codon and basal core promoter mutation in Taiwanese patients with HBeAg-negative chronic hepatitis B, and the influence of the basal core promoter mutation on HBV replication is modulated by the emergence of the precore stop codon mutation.

Interferon α‐2b with and without ribavirin in the treatment of hepatitis B e antigen–positive chronic hepatitis B: A randomized study

To study whether interferon (IFN) α and ribavirin combination therapy has a beneficial effect for hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B, we enrolled 119 such patients in a randomized study. Fifty‐nine patients received 5 million units of IFN‐α2b daily for 4 weeks followed by 5 million units three times a week for 28 weeks, plus 1,200 mg ribavirin daily. Sixty patients received the same dosage of IFN plus placebo. They were followed up for 24 weeks posttreatment, and 105 patients (88%) completed the entire course of 56 weeks. By intention‐to‐treat analysis, the rate of combined response (serum hepatitis B virus [HBV] DNA <2.5 pg/mL and HBeAg seroconversion) was 17% versus 25% between the IFN/ribavirin and IFN/placebo group, respectively, at the end of treatment (P = .35) and 25% vs. 20% at the end of follow‐up (P = .32). Using quantitative real‐time polymerase chain reaction assay, the log(10) reduction of serum HBV DNA was 1.05 ± 1.72 (mean ± SD) versus 1.29 ± 1.91 between the two groups at the end of treatment (P = .49) and was 2.15 ± 2.15 versus 1.21 ± 2.48 at the end of follow‐up (P = .04). Prolonged observations in 83 patients suggested that the combined response was 29% (n = 17) versus 20% (n = 12) at 48 weeks after the end of treatment, respectively (P = .17). The safety profile was similar, except that the IFN/ribavirin group had a higher risk of anemia (15% vs. 0%; P = .002). In conclusion, for the treatment of HBeAg‐positive chronic hepatitis B, adding ribavirin does not seem to increase the efficacy of IFN. (HEPATOLOGY 2006;43:742–749.)

Eight-year nationwide survival analysis in relatives of patients with hepatocellular carcinoma: Role of viral infection

Abstract Background: Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8‐year period to understand the risk and cause of HCC in relatives of patients with HCC.

Evolution of hepatitis B virus precore/basal core promoter gene in HBeAg-positive chronic hepatitis B patients receiving lamivudine therapy.

Aim: Lamivudine is effective in hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B, but the relapse rate after cessation of treatment is high. The evolution of viral genome may contribute to the viral replication under antiviral pressure of lamivudine. We therefore determined the evolution of hepatitis B virus (HBV) precore/basal core promoter and polymerase genes in HBeAg‐positive chronic hepatitis B patient during lamivudine therapy.

Intra-arterial carbon dioxide-enhanced ultrasonogram of hepatocellular carcinoma treated by transcatheter arterial embolization and percutaneous ethanol injection therapy

The purpose of this study was to investigate the value of carbon dioxide‐enhanced ultrasonography (CO2‐US) in the evaluation of viable hepatocellular carcinomas (HCC) which were treated by transcatheter arterial embolization (TAE), percutaneous ethanol injection (PEI), or a combination treatment (TAE and PEI). Forty‐one patients with 66 HCC were included in the study. They underwent CO2‐US and angiography were performed in all tumours after they were treated by TAE, PEI or a combination treatment. Forty‐six tumours were positively enhanced by CO2‐US and 40 of them were positive by angiography. These 46 tumours were proved to be viable tumours either by biopsy or by follow‐up studies. The positive predictive value was 100% for CO2‐US and 87.8% in angiography. Twenty tumours were negative by CO2‐US and these were also negative by angiography. Carbon dioxide‐enhanced ultrasonography is a more reliable method for detecting the viable portion of the treated HCC compared with conventional angiography.