Chao-Wei Hsu

Off‐therapy durability of response to entecavir therapy in hepatitis B e antigen‐negative chronic hepatitis B patients

The optimal duration of nucelos(t)ide analog (Nuc) treatment in hepatitis B e antigen (HBeAg)‐negative patients with chronic hepatitis B virus (HBV) infection is unknown. The Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend that treatment can be discontinued if undetectable HBV‐DNA has been documented on three occasions ≥6 months apart. This study aimed to test this stopping rule in HBeAg‐negative chronic hepatitis B (CHB) patients treated with entecavir (ETV). Ninety‐five patients (39 cirrhosis) were treated with ETV for a median of 721 (395‐1,762) days before stopping therapy and were then monitored with serum HBV DNA and alanine aminotransferase (ALT) at least every 3 months. Within 1 year after stopping ETV therapy, “clinical relapse” (an episode of ALT elevation >2 × upper limit of normal plus HBV‐DNA >2,000 IU/mL) occurred in 43 (45.3%) of the 95 patients. Of the 39 cirrhosis patients, 17 (43.6%) relapsed and one (2.6%) developed decompensation. The median duration until relapse was 230 days (74.4% >6 months). Logistic regression analysis showed that baseline HBV‐DNA ≤2 × 105 IU/mL was the only significant independent factor for sustained response. The 1‐year relapse rate was 29% in patients with a baseline HBV DNA ≤2 × 105 IU/mL versus 53% in those with HBV DNA >2 × 105 IU/mL (P = 0.027). For the latter, consolidation therapy >64 weeks reduced the relapse rate to 33.3% in patients without cirrhosis. Conclusion: With an overall 1‐year relapse rate of 45% and 29% in those with a baseline serum HBV DNA ≤2 × 105 IU/mL, the APASL stopping rule for HBeAg‐negative CHB patients with proper off‐therapy monitoring is adequate even in patients with cirrhosis. Consolidation therapy >64 weeks seems more appropriate for those with higher baseline HBV DNA. (Hepatology 2013; 58:1888–1896)

Splenic infarction complicated by splenic artery occlusion after N-butyl-2-cyanoacrylate injection for gastric varices: case report

27:956-62. 6. Baruzzi AC, Gadelha ME, Cirenza C, Knobel E. Retroesophageal hematoma with severe dysphagia after streptokinase for the treatment of the axillosubclavian vein thrombosis [Portuguese with English abstract]. Arq Bras Cardiol 1997;69:125-7. 7. Weinrauch LA, Tam SKC, Tanzer JLh, Loewenstein MS, Shortsleeve MJ. Odynophagia in a woman with known coronary artery disease and ischemia on electrocardiogram. Tex Heart Inst J 1999;26:318-21. Queen Elizabeth Hospital NHS Trust, London, United Kingdom

Emergence of the rtA181T/sW172* mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B

BackgroundDevelopment of the hepatitis B virus (HBV) rtA181T/sW172* mutant could occur during prolonged lamivudine (LAM) therapy, conferring cross resistance to adefovir. Recent studies demonstrated an increased oncogenic potential of this mutant in NIH3T3 cells. In this study, we aimed to investigate the clinical significance of this finding.MethodsSerum samples from 123 LAM-resistant chronic hepatitis B patients were submitted for virological assays. A highly sensitive amplification created restriction enzyme site (ACRES) method was devised to detect small amounts of the rtA181T mutant in the serum. Virological factors including HBV-DNA level, genotype, precore G1896A, BCP A1762T/G1764A, rtM204I/V, rtA181T and pre-S internal deletion mutations as well as clinical variables including subsequent use of rescue drugs were submitted for outcome analysis.ResultsBy use of the highly sensitive ACRES method, the rtA181T mutant was detectable in 10 of the 123 LAM-resistant patients. During the mean follow-up period of 26.2 ± 16.4 months (range 2 to 108 months), 3 of the 10 (30.0%) rtA181T-positive patients and 2 of the 113 (1.8%) rtA181T-negative patients developed hepatocellular carcinoma (HCC). Kaplan-Meier analysis indicated that the presence of rtA181T mutation (P < 0.001), age > 50 years (P = 0.001), and liver cirrhosis (P < 0.001) were significantly associated with subsequent occurrence of HCC. All 5 HCC patients belonged to the older age and cirrhosis groups.ConclusionsEmergence of the rtA181T/sW172* mutant in LAM-resistant patients increased the risk of HCC development in the subsequent courses of antiviral therapy.

Withdrawal of lamivudine in HBeAg-positive chronic hepatitis B patients after achieving effective maintained virological suppression.

BACKGROUND A recommendation was made by the ACT-HBV Asia-Pacific Steering Committee regarding the withdrawal of lamivudine in chronic hepatitis B patients after achieving effective maintained virological suppression. The outcome of patients following this therapeutic guideline has not been clearly investigated. OBJECTIVE In this study, we examined the outcome of patients adherent to the lamivudine withdrawal guideline. STUDY DESIGN Seventy-one chronic hepatitis B patients achieving seroconversion of hepatitis B e antigen (HBeAg) as well as effective maintained virological suppression during lamivudine therapy were included. Lamivudine was withdrawn provided that undetectable HBV-DNA had been documented on two separate occasions at least 6 months apart. The patients were followed for a median period of 15 months (range, 6-72 months). The effect of pre-therapeutic clinical and virological factors on time to relapse was analyzed. RESULTS Of the 71 patients, 19 (27%) relapsed, of whom 5 showed reappearance of HBeAg and 14 had HBeAg-negative hepatitis. Cox proportional hazard model showed pre-therapeutic HBV-DNA level was the only predictor for time-to-relapse (hazard ratio=1.023, 95% confidence interval=1.004-1.043, P=0.020). Categorical analysis showed that 15/34 (44.1%) and 4/37 (10.8%) patients with pretreatment HBV-DNA levels >10(8) and <or=10(8)copies/mL, respectively, relapsed during follow-ups. The accumulative relapse rates were significantly different between the two groups of patients (Kaplan-Meier method, P=0.003). CONCLUSIONS In patients with pretreatment HBV-DNA levels <or=10(8)copies/mL, lamivudine could be withdrawn after achieving effective maintained virological suppression. Relapse of HBeAg-negative hepatitis remained a major problem.

Peginterferon Is Superior to Nucleos(t)ide Analogues for Prevention of Hepatocellular Carcinoma in Chronic Hepatitis B

BACKGROUND Clinical factors associated with hepatocellular carcinoma (HCC) have been extensively studied in antiviral treatment-naive patients with chronic hepatitis B virus (HBV) infection but not in treatment-experienced patients. Owing to the wide availability of antiviral agents that effectively suppress HBV replication, we investigated HCC risk factors in treatment-experienced patients. METHODS In a cohort of 330 patients who underwent pretherapeutic liver biopsy, we analyzed the HCC incidence in relationship to clinical parameters. Ultra-deep sequencing of the viral genome was performed on 11 entecavir-treated and pegylated interferon (peginterferon)-treated patients. RESULTS Initial univariate/multivariate explorations indicated that cirrhosis and antiviral treatment were independently associated with HCC occurrence. The peginterferon-experienced patients had a lower HCC incidence than the nucleos(t)ide analogue-treated patients (P = .011). The peginterferon and entecavir monotherapy groups also differed in HCC incidence (P = .018). Results of analysis of baseline-matched subgroups concurred with cohort analysis (P = .009 for comparison of peginterferon-experienced vs nucleotide analogue-treated patients; P = .022 for comparison of peginterferon- vs entecavir-treated patients). Viral loads of entecavir-treated patients were constantly suppressed to levels lower than those of peginterferon-treated patients (P < .001). Oncogenic surface antigen truncation mutations were detected in entecavir-treated patients with HCC but not in peginterferon-treated patients (P = .015). CONCLUSIONS Treatment by peginterferon was associated with a lower HCC incidence than nucleos(t)ide-analogue treatment in chronic HBV infection.

Decrease of Serum Angiotensin Converting Enzyme Levels Upon Telbivudine Treatment for Chronic Hepatitis B Virus Infection and Negative Correlations Between the Enzyme Levels and Estimated Glumerular Filtration Rates

Background: During antiviral therapy for chronic hepatitis B, renal function impairment could be a critical concern when oral nucleot(s)ide analogues were used. Paradoxically, long-term telbivudine treatment was associated with an increase of estimated glomerular filtration rate (eGFR) through unknown mechanisms. Objectives: We aimed to investigate changes in serum protein abundances associated with renal function in response to antiviral treatments. Materials and Methods: Primarily, a transcriptomic assay was performed to identify differentially expressed genes in peripheral blood cells caused by the telbivudine treatment. Two genes coding angiotensin converting enzyme (ACE) and complement factor H (CFH) were screened from 14 candidate renal function-related genes. ACE and CFH production were further investigated using enzyme-linked immunoassays. Results: Verification studies showed no significant change of serum CFH levels, but there was a significant reduction of serum ACE levels by continuous telbivudine treatment for 330.00 ± 0.85 days (34 patients; paired t-test, P = 0.022). Serum HBV DNA and ALT levels also decreased (P = 0.008 and < 0.001, respectively). A significant increase in eGFR was found (33 patients, paired t-test, P = 0.002) at 708.64 ± 31.63 days. Patients’ eGFRs were negatively correlated with serum ACE levels (r = -0.375, P = 0.002) but not with serum HBV DNA and ALT levels (P = 0.241 and 0.088 respectively). Significant decreases of the ACE levels were also observed upon entecavir treatment (20 patients; paired t-test, P = 0.020) at 412.88 ± 36.92 days. No significant correlation was found between serum ACE levels and eGFRs (r = -0.239, P = 0.138) in entecavir-treated patients. Conclusions: We discovered a consistent reduction of serum ACE levels by two oral antiviral monotherapies, entecavir and telbivudine. Serum ACE levels were negatively correlated with eGFRs in telbivudine treated patients.

Significant renoprotective effect of telbivudine during preemptive antiviral therapy in advanced liver cancer patients receiving cisplatin-based chemotherapy: a case–control study

Abstract Objective. Cisplatin is a known nephrotoxic agent requiring vigorous hydration before use. However, aggressive hydration could be life-threatening. Therefore, in cirrhotic patients with advanced hepatocellular carcinoma (HCC) under cisplatin-based chemotherapy, the risk of nephrotoxicity increased. Because previous studies showed that long-term telbivudine treatment improved renal function in chronic hepatitis B virus (HBV) infected patients, we conducted a case–control study to evaluate the clinical outcome of telbivudine preemptive therapy in HBV-related advanced HCC patients treated by combination chemotherapy comprising 5-fluorouracil, mitoxantrone and cisplatin (FMP). Material and methods. From June 2007 to March 2012, 60 patients with HBV-related advanced HCC, all receiving the same FMP chemotherapy protocol, were enrolled. Of them, 20 did not receive any antiviral therapy, whereas the remaining 40 patients (sex and age matched) received telbivudine preemptive therapy. Results. Progressive decrease of aminotransferase levels (p < 0.05) and progressive increase of viral clearance rates (p < 0.001) were found in telbivudine-treated group. No drug resistance developed during the course of treatment. When compared with non-antiviral-treated patients, a significantly higher post-therapeutic estimated glomerular filtration rate (eGFR) was found in the telbivudine-treated group (p < 0.001). In patients with initial eGFR >100 ml/min (n = 34), the median overall survival was significantly longer in the telbivudine-treated group (12.1 vs. 4.9 months; p = 0.042). Conclusion. Preemptive use of telbivudine significantly prevented eGFR deterioration caused by cisplatin-based chemotherapy in HBV-related advanced HCC. In patients with initially sufficient eGFR level, telbivudine treatment was associated with a longer overall survival.

A Circulating MicroRNA Signature Capable of Assessing the Risk of Hepatocellular Carcinoma in Cirrhotic Patients

With the availability of potent antiviral therapies, complete suppression of hepatitis B virus (HBV) replication and total eradication of hepatitis C virus (HCV) can now be achieved. Despite these advances, hepatocellular carcinoma (HCC) still develops in a substantial proportion of cirrhotic patients, suggesting that host factors remain critical. Dysregulation of miRNAs is noted in many cancers, and circulating miRNAs can be readily assayed. In this study, we aimed to develop a circulating miRNA signature to assess the risk of HCC in cirrhotic patients. We first discovered that HBV- and HCV-related cirrhotic patients had distinguishable circulating miRNA profiles. A cohort of 330 cirrhotic patients was then compared against a cohort of 42 early HCC patients with complete remission. A score comprising 5 miRNAs and a binary etiology variable was established that was capable of differentiating between these two groups (AUC = 72.5%, P < 0.001). The 330 cirrhotic patients were further stratified into high- and low-risk groups, and all patients were longitudinally followed for 752 (11–891) days. Of them, 19 patients developed HCC. The high-risk group had significantly higher cumulative HCC incidence (P = 0.038). In summary, a circulating miRNA-based score was developed that is capable of assessing HCC risks in cirrhotic patients.

Segregation of signaling proteins as prognostic predictors for local recurrence and distant metastasis in hepatocellular carcinoma.

Postoperative recurrence of hepatocellular carcinoma (HCC) is presented as local recurrence (LR) or extrahepatic metastasis (EHM). Recent studies indicated that EHM requires additional cellular alterations. This study aimed to examine the clinical and molecular prognostic predictors of these two events. HCC patients (289) [training cohort (n=160) and verification cohort (n=129)] receiving surgical resection of hepatomas were included. The expression levels of six signaling molecules were quantitatively assessed for prognostic analysis. Clustering analysis revealed similar expression profiles between cancer (T) and non-cancer (N) liver tissues in the same individuals. Univariate analysis showed that phosphorylated mammalian target of rapamycin (mTOR)-T was associated with LR-free survival (P=0.002), whereas extracellular signal-related kinase (ERK2)-T (P=0.005), AKT-T (P=0.001) and glycogen synthase kinase (GSK)-T/N ratio (P=0.008) were associated with EHM-free survival. When clinical predictors were added for multivariate analysis, only prolonged prothrombin time (P=0.003) and tumor number (P=0.031) was independently associated with LR-free survival, whereas age (P=0.019), creatinine levels (P=0.001) and AKT-T (P=0.004) were associated with EHM-free survival. These factors were further examined in the verification cohort. In conclusion, postoperative LR and EHM in HCC were associated with separable sets of clinical and molecular predictors.

On-treatment mortality predictors in chronic hepatitis B patients experiencing severe acute exacerbation: a prospective observational study

BackgroundSevere acute exacerbation in chronic hepatitis B could lead to mortality in some patients unless timely liver transplantation is performed. The baseline bilirubin level has been reported to be an important prognostic factor for mortality. Here we conducted a prospective observational study to examine the clinical performance of this predictor.MethodTwenty-one consecutive chronic hepatitis B patients experiencing severe acute exacerbation were treated with either telbivudine or entecavir. The clinical characteristics at baseline and week-2 were documented and correlated with mortality.ResultsOf the 21 patients included, 9 had baseline bilirubin >10 mg/dL. Four of these 9 patients (44.4%) eventually died, whereas all other patients survived. During the initial 2-week period, the change of bilirubin was −1.2 mg/dl in the survivors, but was +8.05 mg/dl in the mortalities (P = 0.009). When this on-treatment factor was combined, 5 of the 21 patients had baseline bilirubin > 10 mg/dL plus an increase of bilirubin level at week-2. Of these 5 patients, 4 (80%) died. Thus, by combining the baseline and on-treatment bilirubin levels, a positive predictive value of 80% and a negative predictive value of 100% could be achieved. Other significant on-treatment mortality predictors (at week-2) included higher international normalized ratio of prothrombin time (2.75 vs. 1.3, P = 0.004), higher model for end-stage liver disease score (30 vs. 17, P = 0.006), lower alpha-fetoprotein level (36.3 vs. 459.6 ng/mL, P = 0.039), and more rapid deterioration of the estimated glomerular filtration rate (eGFR) (P = 0.008). Interestingly, during the course, deterioration of eGFR was statistically significant in entecavir-treated (P = 0.028), but not in telbivudine-treated patients. Additionally, the patients treated with telbivudine had significant increase in serum alpha-fetoprotein (27.9 to 191.9 ng/ml, P = 0.046) in the first 2 weeks, whereas the corresponding feature was not found in those treated with entecavir (P = 0.139).ConclusionsIn this prospective observational study, we discovered that the baseline and on-treatment bilirubin levels should be combined to achieve a better predictive value. Telbivudine might have a renoprotective effect in addition to its efficacy in viral suppression in patients with severe acute exacerbation.