Chee-Kin Hui

A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common cause of cancer death throughout the world. The majority of patients are not suitable for curative resection either because of the advanced stage of the disease at the time of presentation or because of underlying cirrhosis. Transcatheter intraarterial lipiodol chemoembolization (TACE) has been reported to be one of the most effective palliative measures for HCC. However, its severe side effects continue to make its use controversial.

Natural history and disease progression in Chinese chronic hepatitis B patients in immune‐tolerant phase

In view of the findings that high hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is associated with increased risk of chronic hepatitis B (CHB)–related complications, disease progression in CHB patients in the immune‐tolerant phase is uncertain. We evaluated disease progression in 57 immune‐tolerant CHB patients with high HBV DNA. Each subject underwent an initial liver biopsy. In those who remained in the immune‐tolerant phase, a follow‐up liver biopsy was performed after 5 years of follow‐up. Patients who developed elevated serum alanine aminotransferase (ALT) levels were discontinued from the study after a follow‐up liver biopsy. Disease progression was defined as a 1‐point increase in fibrosis stage. Initial liver biopsies showed the median fibrosis stage of the study patients was 1 (range 0–1). By the end of follow‐up, 9 of the 57 patients (15.8%) had developed elevated serum ALT. In those who remained in the immune‐tolerant phase, follow‐up fibrosis stage was comparable with the initial fibrosis stage (P = 0.58). However, disease progression was greater in patients who developed elevated serum ALT when compared with those who remained in the immune‐tolerant phase (5 of 9 vs. 3 of 48, respectively, P = 0.001). The median rate of fibrosis progression of patients who remained in the immune‐tolerant phase was lower than that of patients with high serum ALT (0 U/year [range −0.40–0.20 U/year] versus 0.21 U/year [range 0–1.11 U/year], respectively, P = 0.04). Conclusion: CHB patients in the immune‐tolerant phase have mild disease. In those who remained in the immune‐tolerant phase in the present study, disease progression was minimal. However, immune‐tolerant patients who progressed to the immune clearance phase often faced disease progression. (HEPATOLOGY 2007.)

Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy

Background: The hepatic outcome of hepatitis B surface antigen (HBsAg) positive patients undergoing chemotherapy after withdrawal of pre-emptive lamivudine is unknown. Aims: To examine the occurrence of hepatitis B virus (HBV) reactivation after withdrawal of pre-emptive lamivudine. Methods: Pre-emptive lamivudine was started one week before initiation of chemotherapy in 46 consecutive HBsAg positive patients and continued for the entire duration of chemotherapy. Pre-emptive lamivudine was stopped at a median 3.1 (range 3.0–3.4) months after completion of chemotherapy. Patients were longitudinally followed up after withdrawal of pre-emptive lamivudine. Results: Median time of follow up after withdrawal of lamivudine was 25.7 (range 5.7–75.7) months. Eleven of the 46 patients (23.9%) developed HBV reactivation after withdrawal of pre-emptive lamivudine. Eight of the 16 patients with high pre-chemotherapy HBV DNA (⩾104 copies/ml) compared with three of the 30 patients with low pre-chemotherapy HBV DNA (<104 copies/ml) developed HBV reactivation (50.0% v 10.0%, respectively; p<0.001). Hepatitis B e antigen positive patients were also more likely to develop HBV reactivation (5/11 (45.5%) v 6/35 (17.1%), respectively; p = 0.041). A high pre-chemotherapy HBV DNA (⩾104 copies/ml) was the most important risk factor for HBV reactivation after withdrawal of pre-emptive lamivudine on Cox proportional hazards analysis (relative risk 16.13, (95% confidence interval 2.99-87.01; p = 0.001). Conclusions: HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation.

Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin†

Enhancer of zeste homolog 2 (EZH2) has been shown to be overexpressed in hepatocellular (HCC). We investigated the potential role of EZH2 in HCC tumorigenesis and examined the usefulness of RNA interference (RNAi) targeting EZH2 as a form of HCC treatment. Lentivirus‐mediated RNAi was employed to knock‐down EZH2 expression in human hepatoma cells to study the function of EZH2 in tumorigenesis and evaluate the treatment efficacy. Lentivirus‐mediated RNAi effectively reduced EZH2 expression. Suppression of EZH2 in HCC cells significantly reduced their growth rate in vitro and markedly diminished their tumorigenicity in vivo. Moreover, in a mice model of established large‐sized HCC, we showed that intratumor injection of lentiviral (Lenti)‐shRNA (short hairpin RNA) or siRNA (small interfering RNA) targeting EZH2 produced significant tumor regression. To understand its molecular mechanism of action, we employed proteomic profiling technique and found that stathmin 1 is the downstream target of EZH2, as Lenti‐shEZH2 treatment decreased stathmin protein expression, and ectopic overexpression of stathmin prevented Lenti‐shEZH2 mediated tumor growth inhibition. Conclusion: Results from our study suggested for the first time that EZH2 plays a key role in HCC tumorigenesis, and is a novel therapeutic target for HCC. (HEPATOLOGY 2007;46:200–208.)

A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase

BACKGROUND Detectable serum hepatitis C virus (HCV) RNA in HCV patients with persistently normal alanine transaminase (PNALT) has been found to be associated with significant liver damage. AIMS The primary outcome of this study was to compare the histological progression of fibrosis in patients with PNALT and elevated alanine transaminase (ALT). METHODS Forty patients with PNALT (Group 1) and 41 patients with elevated ALT (Group 2) were recruited into this study. Only patients with fibrosis of F0 to F2 were recruited into this study. RESULTS The median time to second liver biopsies was 6.3 (range 2.0-11.1) years. Nine patients (22.5%) in Group 1 and 17 patients (41.5%) from Group 2 had progression of fibrosis. There was a trend towards a significantly higher cumulative probability of fibrosis progression in Group 2 (P=0.06). In patients with an initial F0 to F1 fibrosis, there was a significant difference in cumulative probability of fibrosis progression between Groups 1 and 2 (22.6% (7/31) vs. 43.3% (13/31), respectively, P=0.02). CONCLUSIONS Anti-HCV patients with PNALT with an initial fibrosis of F0 or F1 were less likely to develop progression of fibrosis than those with elevated ALT, although patients with PNALT may have histologically and clinically progressive disease.

Quantitation of covalently closed circular hepatitis B virus DNA in chronic hepatitis B patients

This study examined a signal amplification assay, the Invader assay, for the quantitation of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in liver biopsies and sera. DNA was extracted from liver biopsy and serum samples were collected from 16 hepatitis B e antigen (HBeAg)‐positive and 36 antibody‐to‐HBeAg‐positive (anti–HBe‐positive) chronic hepatitis B patients. The amount of total HBV DNA and cccDNA was measured using the Invader assay. Anti–HBe‐positive patients had lower median total intrahepatic HBV DNA (P < .001) and intrahepatic cccDNA levels (P = .001) than HBeAg‐positive patients. Intrahepatic cccDNA correlated positively with the total intrahepatic HBV DNA (r = 0.950, P < .001). However, the proportion of intrahepatic HBV DNA in the form of cccDNA was inversely related to the amount of total intrahepatic HBV DNA (r = −0.822, P < .001). A small amount of cccDNA was detected in 39 of 52 (75%) serum samples. Anti‐HBe‐positive patients had lower median serum cccDNA levels than HBeAg‐positive patients (P = .002). Serum HBV DNA correlated positively with intrahepatic total HBV DNA (r = 0.778, P < .001) and intrahepatic cccDNA (r = 0.481, P = .002). In conclusion, the Invader assay is a reliable assay for the quantitation of cccDNA. Serum and intrahepatic total HBV DNA and cccDNA levels become lower as the disease progresses from HBeAg‐positive to anti–HBe‐positive phase, with cccDNA becoming the predominant form of intrahepatic HBV DNA. (HEPATOLOGY 2004;40:727–737.)

Relationship between the Development of Precore and Core Promoter Mutations and Hepatitis B e Antigen Seroconversion in Patients with Chronic Hepatitis B Virus

Chinese patients with chronic hepatitis B virus (332 with and 44 without cirrhosis-related complications) were studied. Fifty percent of patients <30 years old had precore mutations. The prevalence of precore mutations among hepatitis B e antigen (HBeAg)-positive patients, although lower than that among anti-HBe-positive patients (P=.031), was already high (44.2%). Median HBV DNA level in anti-HBe-positive patients was 1.5 x 10(6)-1.55 x 10(6) copies/mL, irrespective of the presence or absence of precore mutations. There was no difference in the prevalence of precore mutations between patients with and without complications (P, not significant). However the prevalence of core promoter mutations was higher among patients with complications than among those without complications (90.5% vs. 69.3%, respectively; P=.003). In conclusion, precore mutations occurred in a large proportion of Chinese patients with chronic hepatitis B virus before HBeAg seroconversion. The development of complications was not related to precore mutations but was probably due to the persistence of significant viremia after HBeAg seroconversion.

96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B

BACKGROUND/AIMS In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METHODS Thirty treatment-nai ve, HBeAg-positive patients were randomized to combination ADV plus FTC (n=14) or ADV plus placebo monotherapy (n=16) for 96 weeks. HBV DNA was measured by polymerase chain reaction. Treatment was stopped in those with HBeAg seroconversion. RESULTS The median decrease in HBV DNA at week 96 was higher in the combination group (-5.30 vs. -3.98 log(10)copies/ml, p=0.05). More patients in the combination group had normalization of alanine aminotransaminase and HBV DNA<300 copies/ml at week 96 when compared with the monotherapy group [11 of the 14 patients (78.6%) vs. 6 of the 16 patients (37.5%), p=0.03]. However, HBeAg seroconversion at week 96 was similar in the 2 groups [2/14 (14.3%) vs. 4/16 (25.0%), p=NS]. No ADV or FTC resistance was detected at week 96. In those with HBeAg seroconversion, 50.0% had post-treatment relapse. CONCLUSIONS Combination ADV plus FTC resulted in more potent suppression of HBV DNA over 96 weeks of therapy.

Interferon and Ribavirin Therapy for Chronic Hepatitis C Virus Genotype 6: A Comparison with Genotype 1

Because there is a lack of data on the treatment outcome of patients who carry hepatitis C virus (HCV) genotype 6, we conducted a prospective study, to compare the effect of interferon and ribavirin therapy in HCV genotypes 1 and 6, of patients with seropositive anti-HCV, persistently elevated alanine transaminase levels, and detectable HCV RNA. Patients were treated with subcutaneous recombinant interferon alpha-2b and ribavirin for 12 months. Of 40 patients, 16 had genotype 6, and 24 had genotype 1. An end-of-treatment response was detected in 12 (75%) patients with genotype 6 and in 10 (41.6%) patients with genotype 1 (P=.05). A sustained virological response (SVR) was present in 10 (62.5%) patients with genotype 6 and in 7 (29.2%) patients with genotype 1 (P=.04). Genotype 6 has a better response than genotype 1 and is associated with a higher SVR.

Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients

Recently, controversies have arisen about whether hepatitis B e antigen (HBeAg) seroconversion can result in regression of fibrosis, thus improving the clinical outcome of Chinese patients with chronic hepatitis B. In this study, we determined if spontaneous HBeAg seroconversion is associated with regression of fibrosis in Chinese chronic hepatitis B patients. We evaluated the histology of liver samples from 128 HBeAg‐positive treatment‐naive Chinese patients who had undergone 2 liver biopsies over the years. Regression of fibrosis was defined as a decrease in fibrosis stage of at least 1 point. Sustained disease remission was defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 104 copies/ml at follow‐up liver biopsy. The mean duration (± standard error of the mean) between the initial and follow‐up liver biopsies was 43.9 ± 3.4 months. Regression of fibrosis was higher in patients with sustained disease remission (5 of 13 [38.5%] versus 22 of 115 [19.1%], P < 0.00005), patients who were younger (20‐29 years old) at initial liver biopsy (17of 54 [31.5%] versus 10 of 74 [13.5%], P = 0.0004), and patients with genotype B (17of 43 [39.5%] versus 10 of 85 [11.8%], P = 0.004). On multivariate analysis, sustained disease remission (relative risk [RR] 3.00, 95% confidence interval [95% CI] 1.29‐7.01, P = 0.01) and being 20‐29 years old at initial liver biopsy (RR 2.94, 95% CI 1.01‐8.62, P = 0.04) were independently associated with regression of fibrosis. The rate of fibrosis progression was lower in patients with sustained disease remission than in those who remained HBeAg positive (median 0 fibrosis units/year, range −2.00 to −0.70 fibrosis units/year, versus median 0.51 fibrosis units/year, range 0 to +2.03 fibrosis units/year, P = 0.02). Conclusion: Spontaneous sustained remission of disease is associated not only with little progression of fibrosis but also with regression of fibrosis. (HEPATOLOGY 2007.)