Hepatitis: Fung J

Yuen MF, Fung J, Wong DK, Lai CL. · Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. · Lancet Infect Dis. · Pubmed #19324298 No free full text.

Abstract: Emergence of drug resistance in antiviral therapy for chronic hepatitis B negates treatment benefits. There is a lower chance for emergence of resistance for drugs with rapid and potent viral suppression and a high genetic barrier for resistant mutations. Measurement of viral load at 24 weeks' treatment to aid decision making is mandatory for patients receiving drugs that are associated with a higher resistance rate. Combination treatment with drugs that belong to different groups is associated with a lower chance of resistance. To ensure better control of viral replication in patients with drug resistance, the addition of another drug without an overlapping resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. With such strategies, most patients can be maintained in clinical remission. However, because of the mechanism of viral persistence, research efforts should continue to anticipate and prevent the emergence of multidrug-resistant strains.

Fung J, Lai CL, Yuen MF. · The University of Hong Kong, Queen Mary Hospital, Department of Medicine, Pokfulam Road, Hong Kong. · Expert Opin Investig Drugs. · Pubmed #18808318 No free full text.

Abstract: Hepatitis B virus is a significant cause of liver cirrhosis and hepatocellular carcinoma in patients with chronic infection. Higher levels of viral load are associated with increased risk of developing liver-related complications. The current available oral therapies suppress viral replication through their action on the hepatitis B virus polymerase. As treatment with oral nucleoside/nucleotide analogues is associated with the development of drug-resistant mutations, there is continuing research for newer and more potent antiviral agents to reduce the chance of drug resistance. LB80380, a prodrug, is an oral nucleotide analogue that inhibits viral replication by incorporation into the viral DNA. Antiviral activity against wild-type virus and virus with drug-resistant mutations was demonstrated in Phase II trials, with significant reduction of viral load in patients treated with LB80380. LB80380 was also shown to be safe and well tolerated.

Anonymous00331, Demetris AJ, Adeyi O, Bellamy CO, Clouston A, Charlotte F, Czaja A, Daskal I, El-Monayeri MS, Fontes P, Fung J, Gridelli B, Guido M, Haga H, Hart J, Honsova E, Hubscher S, Itoh T, Jhala N, Jungmann P, Khettry U, Lassman C, Ligato S, Lunz JG, Marcos A, Minervini MI, Mölne J, Nalesnik M, Nasser I, Neil D, Ochoa E, Pappo O, Randhawa P, Reinholt FP, Ruiz P, Sebagh M, Spada M, Sonzogni A, Tsamandas AC, Wernerson A, Wu T, Yilmaz F. · No affiliation provided · Hepatology. · Pubmed #16871565 No free full text.

Abstract: Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.

Fung J, Eghtesad B, Patel-Tom K, DeVera M, Chapman H, Ragni M. · Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA. · Liver Transpl. · Pubmed #15382219 links to  free full text

Abstract: 1. Liver transplantation for human immunodeficiency virus (HIV)-positive patients with end-stage liver disease in the era of highly active retroviral therapy has proven to be an effective treatment. The concerns of HIV progression have not been borne out by the growing worldwide experience. 2. CD4 counts are stable and HIV viral load is controllable with medication following liver transplantation. 3. Hepatitis C virus (HCV) coinfection in HIV-positive recipients is universal, but the severity of recurrence does not appear to be different from that in HIV-negative patients with HCV liver disease. 4. Complex pharmacokinetic interactions between the calcineurin inhibitors used for immunosuppression along with protease inhibitors are present, but management directed at recognizing the need for monitoring levels does not appear to increase the risk of toxicity. 5. The degree of immunosuppression from iatrogenic drug therapy and HIV does not lead to increased risk of infectious complications.

Yuen MF, Seto WK, Chow DH, Tsui K, Wong DK, Ngai VW, Wong BC, Fung J, Yuen JC, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. · Antivir Ther. · Pubmed #18240869 No free full text.

Abstract: BACKGROUND: Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease. METHODS: One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually. RESULTS: Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls (P = 0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC (P = 0.024) and a greater HBV DNA reduction (P = 0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation. CONCLUSIONS: Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.

Yuen MF, Sablon E, Libbrecht E, Van De Velde H, Wong DK, Fung J, Wong BC, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. · Antivir Ther. · Pubmed #17310822 No free full text.

Abstract: BACKGROUND: Comprehensive study on viral factors predicting treatment responsiveness to lamivudine is lacking. AIMS: To define the significance of various viral factors and changes of viral population with lamivudine treatment. Patients and methods: Hepatitis B virus (HBV) DNA levels at baseline, week 24, 52 and year 3 were measured in 80 patients on continuous lamivudine therapy for 3 years. Genotypes, core promoter/precore mutations, YMDD mutations, polymorphic sequence of polymerase gene (rt91 I/L, rt256S/C) were determined at baseline, week 12, 24 and 52. YMDD mutations were also determined at year 3. RESULTS: High alanine aminotransferase levels and presence of core promoter/ precore mutations at baseline were associated with higher chance of achieving HBV DNA <1,000 copies/ml (good response) and higher rate of hepatitis Be antigen (HBeAg) seroconversion at week 52. Achieving HBV DNA levels <1,000 copies/mi at week 24 as well as baseline core promoter/precore mutations were associated with higher chance of achieving good response, higher rate of HBeAg seroconversion and lower rate of YMDD mutations at year 3. Lamivudine reversed core promoter mutations to wild type in 25% of patients. All 5 patients with rt256C had poor HBV DNA response, persistent HBeAg and YMDD mutations by year 3. There was no difference in treatment response between patients with genotype B and C. CONCLUSIONS: Achieving HBV DNA levels <1,000 copies/ml at 24 week is the best target for short- and long-term treatment efficacy. Core promoter and precore mutations were associated with better treatment outcome, and rt256C polymorphism in the polymerase gene with poor response.

Wong DK, Yuen MF, Ngai VW, Fung J, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. · Antivir Ther. · Pubmed #17302253 No free full text.

Abstract: Entecavir and lamivudine are potent nucleoside analogues that can suppress hepatitis B virus (HBV) replication. However, the effects of these two antiviral agents on intrahepatic total HBV DNA and covalently closed circular DNA (cccDNA) are not known. In this study, we aimed to assess the effect of 48 weeks of entecavir/lamivudine therapy on intrahepatic total HBV DNA and cccDNA levels. Forty chronic hepatitis B patients, participating in two Phase III entecavir trials at our centre, were randomized to receive 48 weeks of either 0.5 mg once daily of entecavir (n = 21) or 100 mg once daily of lamivudine (n = 19). Their serological, virological and biochemical responses, as well as intrahepatic HBV DNA levels were monitored. There was no significant difference between entecavir and lamivudine therapy in terms of post-treatment serological, virological and biochemical responses. Both nucleoside analogues reduced serum viral load, intrahepatic total HBV DNA, and cccDNA by about 4.8 logs, 2 logs, and 1 log respectively. An increase in the proportion of intrahepatic HBV DNA in the form of cccDNA was seen after 48 weeks of therapy. In conclusion, both entecavir and lamivudine can successfully reduce intrahepatic HBV DNA and cccDNA. CccDNA becomes the dominant form of HBV DNA during viral suppression and is possibly responsible for viral rebound after short-term antiviral therapy.

Jain A, Vekatramanan R, Yelochan B, Kashyap R, Marcos A, Fung J. · Strong Memorial Hospital, Department of Surgery, Transplant Division, University of Rochester, Rochester, New York 14642, USA. · Transplant Proc. · Pubmed #16213346 No free full text.

Abstract: Hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LTx) in the United States. Ribavirin with pegylated interferon is the only treatment option for HCV recurrence in post-LTx patients. In clinical practice, for more than 50% of patients, ribavirin dose needs to be modified. AIM: The aim of this study was to examine the role of ribavirin level and its relevance in the management of post-LTx patients in terms of renal dysfunction, efficacy, toxicity, and potential drug interactions. PATIENTS AND METHODS: Thirty-four blood samples were available from 22 post-LTx patients. Ribavirin concentrations in plasma (all samples) and whole blood concentrations (16 samples) were examined. The dose of ribavirin ranged from 400 mg/d to 1000 mg/d, but concentrations were normalized to 800 mg/d. RESULTS: There was a wide variation in plasma concentration of ribavirin, ranging from 1.8 to 122.1 mg/mL. The concentrations were similar in whole blood and plasma. Dose-normalized concentration with creatinine clearance below 70 mL/min were significantly higher when compared with creatinine clearance above 70 mL/min (P = .015). Eleven patients required erythropoietin; their mean ribavirin dosage was higher but mean ribavirin concentration was lower compared to the 11 patients who did not require erythropoietin factor. There was no difference in mean ribavirin concentration in patients who cleared the virus (n = 7) compared and who did not clear the virus (n = 9). Three patients were on nucleoside reverse transcriptase inhibitors (NRTI) had significantly higher concentration (mean 87.1 microg/mL) compared to those who did not receive NRTI (mean 34.4 microg/mL, P = .00) CONCLUSION: Ribavirin concentration in plasma and whole blood were similar, with a wide variation. Patients with impaired renal function and those who were on NRTI had significantly higher concentrations of ribavirin. The ribavirin concentrations did not predict either the clearance of HCV RNA or the need for erythropoitin factor.

Yuen MF, Tanaka Y, Fong DY, Fung J, Wong DK, Yuen JC, But DY, Chan AO, Wong BC, Mizokami M, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. · J Hepatol. · Pubmed #18977053 No free full text.

Abstract: BACKGROUND/AIMS: To determine whether gender, age, hepatitis B virus genotype, core promoter and precore mutations, HBeAg/ anti-HBe status, HBV DNA, ALT levels and cirrhosis on presentation were independent risk factors and derive a novel risk score for the development of HCC. METHODS: CHB patients (820) were followed up (mean duration 76.8 months) for the occurrence of HCC. RESULTS: The 5- and 10-year prevalence of HCC were 4.4% and 6.3%, respectively. Cox regression analysis showed that male gender (p = 0.025, RR 2.98), increasing age (p < 0.001, RR 1.07), higher HBV DNA levels (p = 0.02, RR 1.28), core promoter mutations (p = 0.007, RR 3.66), and presence of cirrhosis (p < 0.001, RR 7.31) were independent risks for the development of HCC. A risk score was derived and validated with sensitivity > 84% and specificity > 76% to predict the 5- and 10- year risks for the development of HCC. The AUC for the 5- and 10-year prediction were 0.88 and 0.89, respectively. CONCLUSIONS: The risk score, based on age, gender, HBV DNA levels, core promoter mutations and cirrhosis, can estimate the chance of development of HCC in 5 and 10 years after presentation. It can be used to identify high-risk CHB patients for treatment and screening of HCC.

But DY, Lai CL, Lim WL, Fung J, Wong DK, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. · Vaccine. · Pubmed #18835318 No free full text.

Abstract: Long-term immunogenicity and efficacy of HBVvaccination with different regimens of HBV vaccines (A: 2-dose recombinant vs. B: 3-dose recombinant vs. C: 3-dose plasma-derived vaccines) without booster dose were examined in 318 Chinese children. Geometric mean titer (GMTs) of anti-HBs of group A subjects was significantly lower than that of groups B and C subjects at years 1, 5, 10 and 15. At year 22, the proportion of subjects with anti-HBs > or = 10 mlU/mL for groups A, B and C were 35.3%, 76.5% and 52.4%, respectively (p < 0.05 between groups A and B) in 55 subjects. In the 22 years study period, none was found to be HBsAg positive, and 72 subjects had > or = 1 episodes of anamnestic response. In conclusion, the 3-dose regimens have a better long-term immunogenicity. In terms of protection against HBV infection, the 2-dose and 3-dose vaccines had equal efficacies.

Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, Lau K, Yuen JC, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. · Gastroenterology. · Pubmed #18722377 No free full text.

Abstract: BACKGROUND & AIMS: Our aims were to study the virologic, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance. METHODS: We determined the age of HBsAg seroclearance that is associated with a lower risk for hepatocellular carcinoma (HCC) in 298 CHB patients (median follow-up, 108 months). The following virologic and histologic features were also determined: liver stiffness (n = 229), liver histology, serum HBV DNA levels over time (n = 265), intrahepatic HBV DNA with covalently closed circular DNA (cccDNA) levels, and messenger RNA (mRNA) expression. RESULTS: The median age of HBsAg seroclearance was 49.6 years. Seven (2.4%) patients developed HCC. Cumulative risk for HCC was higher in patients with HBsAg seroclearance at ages >or=50 years compared with those with HBsAg seroclearance at ages <50 (P = .004) years. Of these 2 groups of patients, 29.5% and 7.9%, respectively, had significant fibrosis by liver stiffness measurement (P = .001), and 15.4% of patients had mild histologic fibrosis. Intrahepatic total HBV DNA and cccDNA were detected in 100% and 79.3% of patients, respectively. All patients had undetectable surface and precore/pregenomic RNA transcripts. One (9.1%) patient had X mRNA expression. Serum HBV DNA were detectable in 13.4%, 6.1%, and 3.7% of patients within 1 year and 5-10 and >10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels. CONCLUSIONS: HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age <50 years was associated with a lower risk for the development of HCC.

Ma NF, Lau SH, Hu L, Xie D, Wu J, Yang J, Wang Y, Wu MC, Fung J, Bai X, Tzang CH, Fu L, Yang M, Su YA, Guan XY. · State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, 651 East Dongfeng Road, Guangzhou, China. · Clin Cancer Res. · Pubmed #18698024 No free full text.

Abstract: PURPOSE: X protein (HBx), a product of hepatitis B virus, has been closely associated with the development of hepatocellular carcinoma (HCC). Based on observations that the COOH-terminal truncated HBx was frequently detected in HCC, the aim of this study is to evaluate the function of COOH-terminal truncated HBx in hepatocarcinogenesis. EXPERIMENTAL DESIGN: Expression pattern of HBx was analyzed by immunohistochemistry on tissue microarray containing 194 pairs of HCCs and their matched nontumor liver tissues. MIHA and HepG2 cells transfected with full-length (X2) and COOH-terminal truncated HBx (X1) were tested for their ability to grow in soft agar and form tumors in vivo. Proliferation and apoptosis were assessed using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assays, respectively. To gain additional insight, the expression profile of HepG2-X2 and HepG2-X1 were compared using cDNA microarray. RESULTS: COOH-terminal truncated HBx was frequently detected in HCCs (79.3%, n = 111), and our in vitro and in vivo studies showed that the truncated rather than the full-length HBx could effectively transform immortalized liver cell line MIHA. Interestingly, expression profiling revealed differential expression of key genes implicated in the control of cell cycle and apoptosis. CONCLUSIONS: These findings strongly suggest that the COOH-terminal truncated HBx plays a critical role in the HCC carcinogenesis via the activation of cell proliferation.

Fung J, Lai CL, Hung I, Young J, Cheng C, Wong D, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China. · J Infect Dis. · Pubmed #18657036 No free full text.

Abstract: BACKGROUND: To date, no study has evaluated pegylated interferon for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6. We aimed to determine the efficacy of pegylated interferon plus ribavirin for treating infection with genotype 6 versus genotype 1. METHODS: Forty-two patients chronically infected with HCV (for genotype 1, n = 21; for genotype 6, n = 21) were treated with pegylated interferon alpha-2a (n = 20) or alpha-2b (n = 22) combined with oral ribavirin for 48 weeks. RESULTS: There was no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%; P > .05) and end-of-treatment response (71% vs. 81%; ). Patients infected with genotype 6 had a higher rate of sustained virological response (SVR) than did patients infected with genotype 1 (86% vs. 52%; P = .019). The overall adverse-effects profile was similar in both genotype groups. There was no significant difference in the rate of SVR between patients receiving pegylated interferon alpha-2a and those receiving alpha-2b. Multivariate analysis showed that genotype was the only significant factor associated with SVR (P = .039). CONCLUSIONS: Treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. Further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.

Fung J, Lai CL, Yuen MF. · Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. · J Gastroenterol Hepatol. · Pubmed #18637060 No free full text.

Abstract: The main goals of chronic hepatitis B treatment should be the long-term suppression of viral replication to minimize disease progression and the risk for the development of hepatocellular carcinoma. Treatment end-points, depending on surrogate markers alone, in particular hepatitis B e-antigen seroconversion, may not be ideal for patients who acquire the disease early in life. Currently-available drugs include interferons and oral nucleoside/nucleotide analogs. Although interferon therapy provides a finite treatment period, a significant proportion of patients may not respond, and long-term outcome is inconclusive. Long-term efficacy has been demonstrated for both lamivudine and adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide analogs with a high genetic barrier and potent antiviral activity, such as entecavir, should be used to reduce the chance of developing drug-resistant mutations. Drugs with a low genetic barrier, including lamivudine and telbivudine, should be used in conjunction with early testing for antiviral response. This can predict favorable outcomes in the long term. The early detection of drug-resistant mutations should prompt clinicians to either add or switch to another agent with a different drug-resistance profile. There are currently no treatment models in the use of combination or sequential therapy in treatment-naïve patients. To date, long-term treatment appears to be the most effective option. Despite recent advances made with better understanding on the natural history of chronic hepatitis B infection and with newer antiviral drugs available, challenges remain with respect to treatment criteria, treatment end-points, and duration of treatment.

Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. · Am J Gastroenterol. · Pubmed #18616655 No free full text.

Abstract: BACKGROUND/AIMS: To identify the risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection. METHODS: Seventy-two patients who underwent liver resection for HBV-related HCC were recruited. Demographic, biochemical, tumor, and viral factors at the time of resection were evaluated by univariate and multivariate analyses to identify risk factors associated with recurrence after resection. RESULTS: The median follow-up period was 18.9 months and the median age was 53 yr, with male-to-female ratio of 59:13. Age >60 yr, tumor size >5 cm, poorly differentiated tumor, lymphovascular permeation, the presence of microsatellite lesions, alpha-fetoprotein (AFP) level >1,000 ng/mL and HBV viral load >2,000 IU/mL (4 log(10) copies/mL) at the time of tumor resection, HBV genotype C, core promoter mutations, and patients with no antiviral treatment after tumor resection were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV viral load >2,000 IU/mL (4 log(10) copies/mL) (P= 0.001, odds ratio [OR] 22.3), AFP >1,000 ng/mL (P= 0.02, OR 7.4), tumor size >5 cm (P= 0.02, OR 5.1), and age >60 yr (P= 0.01, OR 4) at the time of tumor resection remained to be the independent risk factors. CONCLUSIONS: Viral load of >2,000 IU/mL (4 log(10) copies/mL) is the most important correctable risk factor for HCC recurrence after resection. Whether antiviral therapy in these patients can decrease tumor recurrence requires further investigations.

Fung J, Lai CL, Fong DY, Yuen JC, Wong DK, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong. · Liver Int. · Pubmed #18482268 No free full text.

Abstract: Abstract Aim: To correlate liver stiffness with demographical factors and routine liver biochemistry and to assess the predictive value of these as potential markers of fibrosis. Methods: Transient elastography was performed in 1268 chronic hepatitis B (CHB) patients. According to a previous validated study for CHB, liver stiffness of >8.1 and >10.3 kPa were used as cut-off values for defining severe fibrosis and cirrhosis respectively. Results: Liver stiffness correlated positively with bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin, alpha-fetoprotein (AFP) and HBV DNA levels and negatively with albumin and platelet levels (P<0.05 for all correlations). From 13 parameters (age, sex, platelet, AST, ALT, GGT, AFP, albumin, globulin, bilirubin, ALP, HBV DNA and hepatitis B e-antigen), four best parameters (AST, platelet, GGT and AFP) were used to derive a liver stiffness model. Using log (index)=1.44+0.1490(GGT)+0.3308 log (AST)-0.5846 log (platelets)+0.1148 log (AFP+1) to predict both severe fibrosis and cirrhosis had area under the receiver operating characteristics curve of 0.85. Conclusion: Routine liver biochemistry correlated well with liver stiffness in Asian CHB patients. A model using simple serum markers can predict liver stiffness, and further studies are required to validate the usefulness of these simple tests as non-invasive markers of fibrosis in CHB.

Fung J, Lai CL, But D, Wong D, Cheung TK, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. · Am J Gastroenterol. · Pubmed #18422821 No free full text.

Abstract: OBJECTIVE: To document the prevalence and factors associated with severe fibrosis and cirrhosis in a large population of Asian chronic hepatitis B (CHB) patients. METHODS: Transient elastography was performed in unselected CHB patients. Liver stiffness score of <8.1 kPa was used as a cut-off for the presence of severe fibrosis or liver cirrhosis. RESULTS: 1315 patients were recruited, of which 951 (72%) were treatment-naive. Of these, 319 (34%) had severe fibrosis, with higher prevalence seen in males compared with females (39% vs 24% respectively, p < 0.01. Severe fibrosis was seen with increasing age from 20% in patients <25 years to 81% in those >65 years. Higher prevalence of severe fibrosis was seen in HBeAg(+) patients compared to HBeAg(-) patients age >45 years (58% vs 43% respectively, p = 0.03), in patients with HBV DNA levels >or=4 log compared with <4 log copies/ml (41% vs 27% respectively, p < 0.01), and in patients with stepwise increase of ALT levels (<0.5 x ULN vs 0.5-1 x ULN vs 1-2 x ULN; 11% vs 30% vs 48% respectively, p < 0.01). After multivariate analysis, gender, age and ALT levels were significant factors associated with severe fibrosis. Patients who received antiviral treatment had lower ALT, stiffness score and prevalence of cirrhosis compared to treatment-naive patients [25 vs 35 U/L (p < 0.01), 6.2 vs 6.7 kPa (p = 0.031) and 14% vs 22% (p = 0.008) respectively]. CONCLUSION: The overall prevalence of severe fibrosis in CHB patients was 34% with higher rates seen in older age groups, males, and in patients with higher ALT levels.

Yuen MF, Fong DY, Wong DK, Yuen JC, Fung J, Lai CL. · Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. · Hepatology. · Pubmed #18027877 No free full text.

Abstract: The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)-positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. Conclusion: The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target.

Wong DK, Tanaka Y, Lai CL, Mizokami M, Fung J, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China. · J Clin Microbiol. · Pubmed #17942661 links to  free full text

Abstract: A sensitive chemiluminescence enzyme immunoassay has been developed for hepatitis B virus (HBV) core-related antigen (HBcrAg) detection. We aimed to investigate the usefulness of HBcrAg measurement for monitoring chronic hepatitis B disease. HBcrAg levels were measured by a chemiluminescence enzyme immunoassay in 54 untreated patients and 39 patients treated with either entecavir or lamivudine. The HBcrAg concentration correlated positively with the levels of serum HBV DNA (r = 0.820), intrahepatic total HBV DNA (r = 0.700), and covalently closed circular DNA (cccDNA) (r = 0.664; for all, P values were <0.001). A higher HBcrAg concentration was associated with a greater proportion of hepatitis B core antigen immunostaining. Although the differences were not statistically significant, patients with higher Knodell necroinflammation and fibrosis scores tended to have higher serum HBcrAg concentration levels. In the treated patients, the logarithmic reduction in HBcrAg at week 48 correlated positively with the logarithmic reduction of serum HBV DNA, intrahepatic total HBV DNA, and cccDNA. Of the 31 patients with undetectable serum HBV DNA (<300 copies/ml) at the end of treatment, 20 (65%) still had detectable HBcrAg. A greater reduction in posttreatment HBcrAg concentration was associated with histological improvement and a decrease in hepatitis B core antigen immunostaining. HBcrAg concentrations of <40,000 kU/ml at baseline and <200 kU/ml at week 24 were associated with a higher chance of having undetectable HBV DNA at week 48. In conclusion, serum HBcrAg levels correlated with HBV virological markers and reflected the chronic hepatitis B disease activity in the liver.

Fung J, Yuen MF, Yuen JC, Wong DK, Lai CL. · Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. · Aliment Pharmacol Ther. · Pubmed #17635372 No free full text.

Abstract: AIM: To investigate the level of hepatitis B virus (HBV) DNA in Chinese chronic hepatitis B (CHB) patients below which hepatocellular carcinoma (HCC) is unlikely to occur. METHODS: A total of 92 CHB patients diagnosed with HCC were recruited; 184 CHB patients without HCC, matched for age, sex and HBeAg status were included as controls. HBV DNA levels were performed at the time of HCC development and at the same age time points for control group. RESULTS: The median HBV DNA level in HCC patients was 1.7 x 10(6) copies/mL compared with 2.2 x 10(5) copies/mL in controls (P = 0.006). In HCC patients, 21 (22.8%) were HBeAg(+), with no significant difference in HBV DNA levels compared with controls. Seventy-one (77%) HCC patients were HBeAg(-) with median HBV DNA level of 3.2 x 10(5) copies/mL, compared with 6.0 x 10(4) copies/mL in controls (P = 0.006). In HBeAg(-) patients, the control group had significantly greater proportion of patients having HBV DNA levels <10(5) and <10(4) copies/mL compared with HCC patients. Fifteen per cent of all HCC patients had HBV DNA levels <10(3) copies/mL. CONCLUSIONS: In HBeAg(+) patients, HBV DNA levels were high in both HCC and control patients. In HBeAg(-) patients, HCC was more likely to develop in patients with HBV DNA level >10(4) copies/mL. However, 15% of the patients with HCC had HBV DNA levels <10(3) copies/mL.

Fung KT, Fung J, Lai CL, Yuen MF. · Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong. · Eur J Gastroenterol Hepatol. · Pubmed #17625435 No free full text.

Abstract: BACKGROUND: In Hong Kong, chronic hepatitis B (CHB) is endemic with a prevalence rate of 8.8%. Data, however, on chronic hepatitis C infection and other nonviral causes of chronic liver disease (CLD) are limited. AIM: To investigate the spectrum of CLDs in Hong Kong. METHODS: Records of all patients attending the Hepatology Clinic of Queen Mary Hospital, Hong Kong, in 2004 were reviewed to identify those with CLDs and their underlying causes. RESULTS: A total of 6106 patients were found to have CLD. CHB accounted for 89.4% of the cases, followed by chronic hepatitis C infection (5.1%). Nonviral causes accounted for the remaining 5.5% [alcoholic liver disease (ALD) (1.7%), nonalcoholic fatty liver disease (1.5%), primary biliary cirrhosis (PBC) (1.3%)]. Patients with CHB and Wilson's disease were significantly younger than patients with other causes (P<0.002). More than 90% of patients with autoimmune hepatitis and PBC were women. The prevalence of CHB infection was lower in patients with PBC than the general population. Among patients with ALD, the prevalence rate was higher for chronic hepatitis C but similar for CHB, as compared with the general population. CONCLUSIONS: Despite universal HBV vaccination since 1988, CHB remains the commonest cause of CLD in Hong Kong. PBC and nonalcoholic fatty liver disease were not rare in the Chinese population, being important causes of nonviral liver disease. The prevalence of chronic viral infection among patients with PBC or ALD confirmed the findings of other published literatures.

Fung J, Lai CL, Yuen JC, Wong DK, Tanaka Y, Mizokami M, Yuen MF. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. · Antivir Ther. · Pubmed #17503746 No free full text.

Abstract: AIM: To determine differences in Chinese patients treated with adefovir (ADV) monotherapy or ADV in combination with lamivudine (3TC) after development of resistance to 3TC, with respect to biochemical improvement, HBV DNA suppression and development of subsequent ADV resistance. METHODS: All hepatitis B patients with 3TC resistance treated with ADV for 3 months or more at our centre were included, and monitored 3-6 monthly for biochemical and virological response, and development of ADV resistance. RESULTS: A total of 56 patients were included, 50% switched to ADV monotherapy and 50% received combination 3TC/ADV therapy. Median follow-up was 15.5 months. Normalization of alanine aminotransferase (ALT) occurred in 25 (89%) patients in the ADV group compared with 24 (86%) in the 3TC/ADV group (P = 0.686). Virological response (VR) was achieved in seven (35%) patients in the ADV group at 12 months compared with five (28%) in the 3TC/ADV group (P = 0.637). By 24 months, seven (64%) patients in the ADV group achieved VR compared with two (40%) in the 3TC/ADV group (P = 0.377). Cumulative probability of developing genotypic ADV resistance in the ADV group at 24 months was 18% compared with 7% in the 3TC/ADV group (P = 0.94). CONCLUSION: There was no obvious improvement in ALT normalization and virological suppression or reduction in the development of ADV-resistant mutations with 3TC/ADV therapy compared with ADV monotherapy. Further studies with longer follow-ups are required to determine whether combination 3TC/ADV therapy will reduce the emergence of ADV resistance compared with ADV monotherapy.

Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, Yuen JC, Mizokami M, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. · Gut. · Pubmed #17483190 No free full text.

Abstract: BACKGROUND/AIM: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. METHODS: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. RESULTS: Genotype C, CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA >or=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels >or=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. CONCLUSIONS: CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Yuen MF, Tam S, Fung J, Wong DK, Wong BC, Lai CL. · Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. · Aliment Pharmacol Ther. · Pubmed #17014576 No free full text.

Abstract: BACKGROUND: Safety of traditional Chinese medicine in patients with chronic hepatitis B is unknown. AIM: To study the clinical outcome of traditional Chinese medicine-induced hepatotoxicity in chronic hepatitis B patients. PATIENTS AND METHODS: All chronic hepatitis B patients in 2004 with liver dysfunction requiring hospitalization were screened prospectively for traditional Chinese medicine intake. The hepatotoxicity of individual traditional Chinese medicine elements was determined by extensive search of both English and Chinese publications. RESULTS: Of 45 chronic hepatitis B patients, the liver dysfunction in seven (15.6%) was attributable to traditional Chinese medicine. All had liver dysfunction pattern resembling those of acute exacerbation of chronic hepatitis B. Three patients had adverse outcomes (two deaths, one liver transplantation). One patient had accelerated course of cirrhosis now awaiting liver transplantation. The identified hepatotoxic components were Polygonum multiflorum Thunb, Cassia obtusifolia L, Melia toosendan Sieb., Rheum palmatum L., Scolopendra subspinipes mutilans L, Alisma orientale Juzepe, Glycyrrhiza uralensis Fisch. and Mentha haplocalyx Briq. One traditional Chinese medicine formula was adulterated with a highly hepatotoxic agent, N-nitrosofenfluramine. CONCLUSIONS: Traditional Chinese medicine-related hepatotoxicity resulted in high mortality in chronic hepatitis B patients. Prospective randomized-controlled trials with the same stringent criteria as western medicine clinical trials are required for Chinese medicines, to document their efficacies and safety before they can be advocated for the treatment of patients.

Cheung TK, Lai CL, Wong BC, Fung J, Yuen MF. · Department of Medicine, Division of Gastroenterology and Hepatology, University of Hong Kong, Queen Mary Hospital, Hong Kong. · Aliment Pharmacol Ther. · Pubmed #16907890 No free full text.

Abstract: BACKGROUND: Clinical features of hepatocellular carcinoma patients are changing because of screening. AIM: To examine the clinical features of hepatocellular carcinoma patients in Hong Kong and validity of different staging systems. METHODS: A total of 223 Chinese patients with hepatocellular carcinoma were studied. RESULTS: Seventy-eight percent of hepatocellular carcinoma patients had chronic hepatitis B (43% diagnosed by screening). Hepatitis B positivity, weight loss, jaundice, encephalopathy, alpha-fetoprotein level, portal vein thrombosis, extrahepatic metastasis, and treatment were shown to be independent factors affecting survival. Of chronic hepatitis B patients, hepatitis B virus DNA levels (P = 0.001) and portal vein thrombosis (P = 0.008) were independent factors affecting survival. Seventy-six percent of chronic hepatitis B patients with hepatocellular carcinoma were hepatitis B e antigen negative. Screening patients had hepatocellular carcinoma detected at an earlier stage and better survival (median survival: 21 vs. 4 months, P < 0.0001). All staging systems had good stratification of survival. Prognosis and median survival generated were different when compared with the US data. CONCLUSIONS: Chronic hepatitis B was the most common cause of hepatocellular carcinoma in Hong Kong. High-risk chronic hepatitis B patients should be followed irrespective of the hepatitis B e antigen status. Hepatitis B virus DNA levels at the time of diagnosis are an important survival predictor. Screening detected hepatocellular carcinoma at an earlier stage and prolonged survival. Staging systems should be validated in different populations.