Nancy Leung

A one year trial of Lamivudine for chronic hepatitis B

BACKGROUND AND METHODSnIn preliminary trials, lamivudine, an oral nucleoside analogue, has shown promise for the treatment of chronic hepatitis B. We conducted a one-year, double-blind trial of lamivudine in 358 Chinese patients with chronic hepatitis B. The patients were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143), or placebo (73) orally once daily. The patients underwent liver biopsies before entering the study and after completing the assigned treatment regimen. The primary end point was a reduction of at least two points in the Knodell necroinflammatory score.nnnRESULTSnHepatic necroinflammatory activity improved by two points or more in 56 percent of the patients receiving 100 mg of lamivudine, 49 percent of those receiving 25 mg of lamivudine, and 25 percent of those receiving placebo (P<0.001 and P=0.001, respectively, for the comparisons of lamivudine treatment with placebo). Necroinflammatory activity worsened in 7 percent of the patients receiving 100 mg of lamivudine, 8 percent of those receiving 25 mg, and 26 percent of those receiving placebo. The 100-mg dose of lamivudine was associated with a reduced progression of fibrosis (P=0.01 for the comparison with placebo) and with the highest rate of hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) (16 percent), the greatest suppression of HBV DNA (98 percent reduction at week 52 as compared with the base-line value), and the highest rate of sustained normalization of alanine aminotransferase levels (72 percent). Ninety-six percent of the patients completed the study. The incidence of adverse events was similar in all groups, and there were few serious events.nnnCONCLUSIONSnIn a one-year study, lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B. A daily dose of 100 mg was more effective than a daily dose of 25 mg.

2-Year GLOBE Trial Results: Telbivudine Is Superior to Lamivudine in Patients With Chronic Hepatitis B

BACKGROUND & AIMSnThe GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B.nnnMETHODSnHepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level).nnnRESULTSnThe therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes.nnnCONCLUSIONSnTelbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update

Background/Aims: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update.

A randomized, controlled trial of combination therapy for chronic hepatitis B : Comparing pegylated interferon-α2b and lamivudine with lamivudine alone

Context Few studies have evaluated combination therapies for chronic hepatitis B. Contribution In this single-center, open-label trial, 100 patients with hepatitis B e antigenpositive chronic hepatitis B and moderately elevated alanine aminotransferase levels were randomly assigned to a staggered regimen of pegylated interferon-2b for 32 weeks plus lamivudine for 52 weeks or lamivudine monotherapy. Patients receiving combination therapy more often had virologic responses and less often developed lamivudine-resistant mutants than those receiving monotherapy. Transient influenza-like symptoms, alopecia, and local erythematous reactions were more common with combination therapy. Cautions Patients assigned to combination therapy received treatment for 8 weeks longer than those assigned to monotherapy. The Editors Chronic hepatitis B virus (HBV) infection affects more than 300 million people globally (1). Patients who have HBV infection with positivity for hepatitis B e antigen (HBeAg) and persistently active disease have increased risks for progressive disease leading to liver cirrhosis and hepatocellular carcinoma (2). Conventional interferon treatment with injections given up to 3 times per week for 12 to 24 weeks may lead to HBeAg seroconversion in 33% of treated patients compared with 12% of untreated controls (3). The treatment response to conventional interferon treatment among Asian patients seems less satisfactory (4, 5). Pegylated interferon-2b is synthesized by bonding recombinant interferon-2b to polyethylene glycol and is given once weekly rather than 3 times weekly (6). The antiviral efficacy of pegylated interferon-2b for treating chronic hepatitis C is superior to that of conventional interferon (7, 8), but few studies have evaluated pegylated interferon in patients with chronic hepatitis B. Lamivudine is an oral nucleoside analogue that effectively suppresses HBV replication (9, 10). Studies suggest that only 16% to 18% of patients treated with lamivudine for 1 year develop HBeAg seroconversion (9-11). Extending lamivudine treatment for up to 4 years is associated with development of drug-resistant viral mutants in about 70% of patients (12). The durability of HBeAg seroconversion is estimated to be 46% to 64% up to 3 years after the cessation of lamivudine treatment (13-15). Successful elimination of HBV depends on a durable immune clearance of the existing pool of intrahepatic HBV, particularly the closed covalent circular DNA (16). Combining an immunomodulator (such as interferon) and an antiviral agent (such as lamivudine) is an appealing approach for treating chronic hepatitis B. However, past studies in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B showed conflicting results about the superiority of combination therapy over lamivudine monotherapy (11, 17-20). We evaluated whether the combination of pegylated interferon-2b and lamivudine improves antiviral efficacy and increases HBeAg seroconversion rates more than lamivudine monotherapy in patients with HBeAg-positive chronic hepatitis B and moderately elevated alanine aminotransferase (ALT) levels. Since extending interferon treatment from 16 to 32 weeks is associated with higher rates of HBeAg seroconversion (21), combination therapy includes pegylated interferon-2b given for 32 weeks. Methods Patients We recruited consecutive patients 18 to 65 years of age with chronic hepatitis B from the Hepatitis Clinic of the Prince of Wales Hospital, Hong Kong, China, a secondary referral center serving around 1 million people. All patients had been positive for hepatitis B surface antigen (HBsAg) for at least 6 months, were HBeAg-positive, and had a serum HBV DNA level of at least 500000 copies/mL and an ALT level that was 1.3 to 5 times the upper limit of normal. We excluded patients who had decompensated liver disease or a history of interferon or antiviral agent use. Other exclusion criteria were co-infection with hepatitis C virus, hepatitis D virus, or HIV; history of hepatocellular carcinoma; other causes of liver disease, including autoimmune hepatitis; Wilson disease; hemochromatosis and 1-antitrypsin deficiency; serious medical or psychiatric illness; concurrent use of corticosteroid or immunosuppressive agents; and pregnancy. We conducted the study in accordance with the guidelines of the Declaration of Helsinki. The ethics committee of The Chinese University of Hong Kong approved the protocol, and all patients gave witnessed, written informed consent. Study Design The study was a phase III, open-label, randomized trial. Within 4 weeks of screening for eligibility criteria, patients were randomly assigned to either combination therapy with pegylated interferon-2b (PegIntron, Shering-Plough Corp., Kenilworth, New Jersey) and lamivudine (Zeffix, GlaxoSmithKline, Middlesex, United Kingdom) or lamivudine monotherapy in a ratio of 1:1. We based study group assignment on a computer-generated list, and research staff who were not involved in patient management placed the random numbers in opaque envelopes. A research nurse prescribed study drugs after receiving the information about treatment allocation at the baseline visit. Figure 1 shows the study design. Pegylated interferon-2b was given as a subcutaneous injection at a dosage of 1.5 g/kg of body weight per week for patients who weighed less than 65 kg or 100 g per week for patients who weighed more than 65 kg for 32 weeks (6). Lamivudine was administered as 100 mg orally daily for 52 weeks in both groups of patients. In patients receiving combination therapy, pegylated interferon-2b was administered 8 weeks before lamivudine was administered. Then both treatments were given in combination for 24 weeks, followed by lamivudine monotherapy for a further 28 weeks. Patients in the combination group were asked to return at weeks 1, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52, and 60 (end of treatment). Patients in the lamivudine monotherapy group received lamivudine for 52 weeks and were asked to return for follow-up at weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52 (end of treatment). We followed patients in both groups every 8 weeks in the post-treatment period for 24 more weeks. We gave open-label lamivudine treatment to patients who experienced severe post-treatment relapse of chronic hepatitis B (defined as an ALT level > 10 times the upper limit of normal and HBV DNA level > 500000 copies/mL). Figure 1. Study design. Safety The investigators interviewed patients for symptomatic adverse effects and closely monitored laboratory tests at each follow-up visit. They recorded symptoms and events that patients reported spontaneously, symptoms and events elicited in response to open-ended questions, and adverse effects observed at the follow-up visits. They assessed all adverse events on the likelihood of causality by the study drug or drugs. They assessed the severity of adverse events according to a preset table and classified the event as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4). The dosage of pegylated interferon was reduced, as necessary, according to the severity of the adverse events. The dosage was reduced from 100 g per week (or 1.5 g/kg per week if body weight < 65 kg) to 50 g per week (or 1.0 g/kg per week if body weight < 65 kg) for grade 3 adverse events (or sometimes grade 2 adverse events at the discretion of the investigator). The dosage could be further reduced to 25 g per week (or 0.5 g/kg per week if body weight < 65 kg) if the adverse recurred despite initial dosage reduction. Pegylated interferon therapy was stopped in case of grade 4 adverse events. Patients receiving combination treatment were allowed to continue lamivudine if investigators thought that the adverse effect was related to pegylated interferon use. Lamivudine therapy was stopped if the adverse event persisted despite cessation of pegylated interferon therapy. We tested serum for HBV DNA levels, HBeAg, and antibody to HBeAg (at baseline, then 8 weekly until the end of treatment, and weeks 8, 16, and 24 after treatment) and HBsAg and antibody to HBsAg (at baseline, end of treatment, and 24 weeks after treatment). We determined the presence of lamivudine-resistant mutations in the serum sample at the end of treatment. Liver biopsy was performed within 4 weeks before treatment began and at the end of treatment. Laboratory Assays Serologic Assays We tested for HBsAg and antibodies to hepatitis C virus, hepatitis D virus, and HIV by using commercially available enzyme-linked immunosorbant assay kits (Abbott GmBH Diagnostika, Wiesbaden-Delkenheim, Germany). We measured HBeAg and antibody to HBeAg by using an enzyme-linked immunosorbant assay (Sanofi Diagnostics, Pasteur, France). Virologic Assays We based our sample size calculations and initial screening for eligibility on the DNA cross-linking assay (NAXCOR XLnt, NAXCOR, Menlo Park, California), which has a lower limit of detection of 500000 copies/mL for quantification of HBV DNA (22). Since the TaqMan real-time polymerase chain reaction assay (Applied Biosystem, Foster City, California) became available in our laboratory, we used this assay to measure HBV DNA levels at baseline and in all follow-up visits (23, 24). The range of HBV DNA detection was from 102 to 109 copies/mL; the correlation coefficient of the standard curve was routinely greater than 0.990. We performed HBV genotyping by restriction fragment length polymorphism in a residual serum sample taken from each patient at their initial visit (25, 26). We determined the presence of lamivudine-resistant mutants by using the INNO-LiPA HBV DR line probe assay (Innogenetics N.V., Ghent, Belgium) according to the instruction of the manufacturer (27). End Points We defined virologic response as HBeAg seroconversion (that is, loss of HBeAg), detection of antibody to HBeAg, and HBV DNA level less than 500000 copies/mL and biochemical response as normalization of

Early Hepatitis B Virus DNA Reduction in Hepatitis B e Antigen-Positive Patients with Chronic Hepatitis B : A Randomized International Study of Entecavir Versus Adefovir

This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside‐naïve adults with chronic hepatitis B (CHB). Sixty‐nine nucleoside‐naïve CHB patients with baseline HBV DNA of 108 copies/mL or more were randomized 1:1 to open‐label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (−6.23 log10 copies/mL versus −4.42 log10 copies/mL, respectively; mean difference −1.58 log10 copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV−ADV difference estimate: −0.66 log10 copies/mL; 95% CI [−0.30, −0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir‐treated than adefovir‐treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV‐treated versus 15 (47%) ADV‐treated patients had HBV DNA of 105 copies/mL or more. Both antivirals were well tolerated. Conclusion: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside‐naïve HBeAg‐positive patients with CHB. (HEPATOLOGY 2009;49:72‐79.)

Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: A randomized, open‐label study

A randomized, open‐label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child‐Turcotte‐Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log10 copies/mL [95% confidence interval −2.30, −1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two‐thirds of subjects in both groups showed improvement/stabilization in Child‐Turcotte‐Pugh status. Model for End‐Stage Liver Disease score change at week 48 was −2.6 for entecavir and −1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. Conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine. (HEPATOLOGY 2011;)

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.)

Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection.

Co-chairs: GW McCaughan, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia M Omata, Tokyo University Hospital, Tokyo, Japan Faculty Members: D Amarapurkar, Bombay Hospital, Mumbai, India S Bowden, Victorian Infectious Diseases Reference Laboratories, Melbourne, Australia WC Chow, Singapore General Hospital, Singapore A Chutaputti, Pramongkutklao Hospital, Bangkok, Thailand G Dore, National Center in HIV Epidemiology and Clinical Research, Sydney, Australia E Gane, NZ Liver Transplant Unit, Auckland, New Zealand R Guan, Mount Elizabeth Medical Center, Singapore SS Hamid, The Aga Khan University, Karachi, Pakistan W Hardikar, Royal Children’s Hospital, Melbourne, Australia CK Hui, Queen Mary Hospital, University of Hong Kong, Hong Kong, China W Jafri, The Aga Khan University, Karachi, Pakistan J-D Jia, Beijing Friendship Hospital, Capital Medical University, Beijing, China M-Y Lai, National Taiwan University Hospital, Taiwan L Wei, Peking University Peoples Hospital, Beijing, China N Leung, The Chinese University of Hong Kong, Hong Kong, China T Piratvisuth, Prince of Songkla University, Hat Yai, Thailand S Sarin, GB Pant Hospital, Delhi, India J Sollano, University Santo Tomas Hospital, Manilla, Philippines R Tateishi, University of Tokyo Hospital, Tokyo Japan

Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation.

Goals To determine the 2-year survival and prognostic indicators of hepatitis B virus–related cirrhosis after the onset of hepatic decompensation. Background Chronic hepatitis B (CHB) patients with cirrhosis and resultant hepatic decompensation have reduced survival. However, the natural history of these patients has not been well characterized in previous studies. Better understanding of survival and prognostic indicators is essential in management of these patients, especially in determining who should be candidates for orthotopic liver transplantation. Study This is a retrospective longitudinal study of 96 patients with CHB-related cirrhosis after the onset of hepatic decompensation. The overall survival was ascertained, and clinical and laboratory variables were analyzed. Significant prognostic indicators for survival at 2 years were determined using univariate and multivariate analyses with Cox regression model. Results The overall survival was 80% at 2 years after onset of decompensation. With univariate and multivariate analyses, hepatic encephalopathy and hypoalbuminemia less than 2.8 g/dL were significant prognostic indicators of poor survival probability. The hazard ratios were 5.22 (95% confidence interval, 1.67–16.3) and 8.57 (95% confidence interval, 1.94–37.8), respectively. Patients with hypoalbuminemia less than 2.8 g/dL had a 2-year survival of only 62%. Conclusions Our study showed that of CHB patients who developed the first episode of hepatic decompensation, those with hepatic encephalopathy or significant hypoalbuminemia or both have worse prognoses. They should be considered potential candidates for liver transplantation.

How should we manage patients with non-alcoholic fatty liver disease in 2007?

Evidence‐based management guidelines for non‐alcoholic fatty liver disease (NAFLD) are lacking in the Asia–Pacific region or elsewhere. This review reports the results of a systematic literature search and expert opinions. The Asia–Pacific Working Party on NAFLD (APWP‐NAFLD) has generated practical recommendations on management of NAFLD in this region. NAFLD should be suspected when there are metabolic risk factors and/or characteristic changes on hepatic ultrasonography. Diagnosis by ultrasonography, assessment of liver function and complications, exclusion of other liver diseases and screening for metabolic syndrome comprise initial assessment. Liver biopsy should be considered when there is diagnostic uncertainty, for patients at risk of advanced fibrosis, for those enrolled in clinical trials and at laparoscopy for another purpose. Lifestyle measures such as dietary restrictions and increased physical activity (aerobic exercise) should be encouraged, although the best management strategy to achieve this has yet to be defined. Complications of metabolic syndrome should be screened for regularly. Use of statins to treat hypercholesterolemia is safe and recommended; frequent alanine aminotransferase (ALT) monitoring is not required. Obese patients who do not respond to lifestyle measures should be referred to centers specializing in obesity management; consideration should be given to bariatric surgery or gastric ballooning. The role of pharmacotherapy remains investigational and is not recommended for routine clinical practice. Non‐alcoholic fatty liver disease should be recognized as part of the metabolic syndrome and managed in a multidisciplinary approach that addresses liver disease in the context of risk factors for diabetes and premature cardiovascular disease. Lifestyle changes are the first line and mainstay of management.