George K. K. Lau

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

Hepatitis B virus surface antigen levels: A guide to sustained response to peginterferon alfa‐2a in HBeAg‐negative chronic hepatitis B

We investigated the relationship between hepatitis B virus surface antigen (HBsAg) serum level decline and posttreatment response in patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B from a large multinational study of pegylated interferon alfa‐2a (peginterferon alfa‐2a), with or without lamivudine, versus lamivudine alone. Serum HBsAg was quantified using the Architect assay (Abbott Diagnostics) at pretreatment, end of treatment (week 48), and 6 months after the end of treatment (week 72) in sera from 386 of the 537 patients who participated in the multinational study (peginterferon alfa‐2a, 127; peginterferon alfa‐2a plus lamivudine, 137; lamivudine monotherapy, 122). Pretreatment HBsAg levels varied according to genotype, with the highest levels present in patients infected with genotypes A (median, 4.11 log10 IU/mL) and D (median, 3.85 log10 IU/mL). Significant on‐treatment decline in HBsAg was observed during treatment with peginterferon alfa‐2a (alone or combined with lamivudine; mean decline at week 48, −0.71 and −0.67 log10 IU/mL, respectively, P < 0.001), but not during treatment with lamivudine alone (−0.02 log10 IU/mL). Significantly more patients treated with peginterferon alfa‐2a (21%) or peginterferon alfa‐2a plus lamivudine (17%) achieved HBsAg levels <100 IU/mL at the end of treatment compared with lamivudine (1%) (both P < 0.001 versus lamivudine). End‐of‐treatment HBsAg level correlated strongly with HBV DNA suppression to ≤400 copies/mL 6 months posttreatment. An HBsAg level <10 IU/mL at week 48 and on‐treatment decline >1 log10 IU/mL were significantly associated with sustained HBsAg clearance 3 years after treatment (both P < 0.0001). Conclusion: On‐treatment quantification of HBsAg in patients with HBeAg‐negative chronic hepatitis B treated with peginterferon alfa‐2a may help identify those likely to be cured by this therapy and optimize treatment strategies. (HEPATOLOGY 2009;49:1141–1150.)

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.

Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers.

Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment‐naïve CHB patients were recruited (HBeAg‐positive, n = 71; HBeAg‐negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg‐positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg‐negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg‐positive patients. Conclusion: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg‐positive and HBeAg‐negative CHB. HBeAg titers may fall independent of viral replication as HBeAg‐defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker. (HEPATOLOGY 2010)

Factors That Predict Response of Patients With Hepatitis B e Antigen–Positive Chronic Hepatitis B to Peginterferon-Alfa

BACKGROUND & AIMS Therapy with pegylated interferon (PEG-IFN)-alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN-alfa therapy. METHODS The study included 542 patients treated with PEG-IFN-alfa-2a (180 microg/wk, 48 wk) and 266 patients treated with PEG-IFN-alfa-2b (100 microg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 x 10(3) IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed. RESULTS HBV genotype, high levels of alanine aminotransferase (ALT; >or=2 x upper limit of normal), low levels of HBV DNA (<2.0 x 10(8) IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels. CONCLUSIONS The best candidates for a sustained response to PEG-IFN-alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.

Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.

affecting 20-30% of the general population, and recent studies indicate that fatty liver is an emerging problem in the Asia-Pacific region. 3 A comprehensive review of available data reveals that the overall prevalence of NAFLD in the Asia-Pacific region is broadly similar to that in North America, affecting between 12% and 24% of community subgroups. 4,5 The prevalence varies by age, gender, ethnicity, and locality (urban versus rural), as well as with criteria used for disease definition. 5 There is strong evidence that the prevalence of NAFLD in this region has increased substantially during the last 15 years in parallel with regional trends in over- nutrition (decreased physical activity with disproportionate food intake), central and overall obesity, type 2 diabetes mellitus (T2DM), and the metabolic syndrome. 6-8 Present trends in the obesity and diabetes pandemic indicate that a further increase in NAFLD prevalence is likely in the immediate future. 9,10

MINIMUM GRAFT SIZE FOR SUCCESSFUL LIVING DONOR LIVER TRANSPLANTATION

BACKGROUND The extension of living donor liver transplantation to adult recipients is limited by the adequacy of the size of the graft. We evaluate the effect of the graft size on the survival of the recipient in order to establish a clinical guide for the minimum requirement. METHODS The clinical records of 14 adults and 11 children (body weight 6.1-100 kg) who underwent living donor liver transplantation for chronic or acute liver failure were reviewed. The effect of the graft weight ratio (graft weight divided by standard liver weight of recipient) on graft function and survival was studied. RESULTS The graft weight ratio ranged from 31 to 203%. The overall graft and patient survival rates were 84% at a median follow-up of 29 months. The survival rate was 95% for recipients with a graft weight ratio >40%, and 40% only for those with a ratio < or =40% (P = 0.016). It was 88% (7/8) when the ratio was >100%, 100% (5/5) when the ratio was 71 to 100%, 100% (7/7) when the ratio was 41 to 70%, and 40% (2/5) only when the ratio was < or =40%. When the graft weight ratio was < or =40%, early graft dysfunction was evident and contributed to the causes of death in three patients. CONCLUSIONS Preoperative computed tomographic measurement of liver size of a living donor is essential. A graft that represented 40% or less of the recipients standard liver weight should be regarded as a marginal graft with a lower success rate.

Sustained Response of Hepatitis B e Antigen-Negative Patients 3 Years After Treatment with Peginterferon Alfa-2a

BACKGROUND & AIMS Patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treated with peginterferon alpha-2a with or without lamivudine achieve significantly higher 6-month posttreatment rates of response compared with those treated with lamivudine alone. The durability of <or=3-year posttreatment response was investigated in this study. METHODS Patients received peginterferon alpha-2a only (180 microg once weekly; n = 177), in combination with lamivudine (100 mg daily; n = 179) or lamivudine alone (n = 181) for 48 weeks. A total of 315 patients (116, 114, and 85, respectively) participated in this posttreatment observational study. RESULTS Three years after treatment, the percentage of patients with normal alanine aminotransferase (ATL) was higher for patients treated with peginterferon alpha-2a (31%) than with lamivudine (18%; P = 0.032). Similarly, 28% of patients treated with peginterferon had hepatitis B virus (HBV) DNA levels <or= 10,000 copies/mL versus 15% of patients treated with lamivudine (P = .039). Peginterferon alpha-2a treatment and high baseline ALT level were independent baseline predictors of long-term virologic response (P = .040 and P = .01, respectively). Of the patients who had been treated with a peginterferon alpha-2a-containing regimen, 8.7% cleared hepatitis B surface antigen (HBsAg; 44% of those with undetectable HBV at 3-year posttreatment follow-up) compared with none treated with lamivudine alone. CONCLUSIONS Biochemical and virologic responses were sustained for <or=3 years in approximately 25% of patients given a 48-week course of peginterferon alpha-2a, with or without lamivudine. The increased rate of HBsAg clearance in patients with HBeAg-negative chronic hepatitis B supports the use of peginterferon alpha-2a as a first-line treatment.

Virologic Monitoring of Hepatitis B Virus Therapy in Clinical Trials and Practice: Recommendations for a Standardized Approach

Treatment of chronic hepatitis B virus (HBV) infection is aimed at suppressing viral replication to the lowest possible level, and thereby to halt the progression of liver disease and prevent the onset of complications. Two categories of drugs are used in HBV therapy: the interferons, including standard interferon alfa or pegylated interferon alfa, and specific nucleoside or nucleotide HBV inhibitors that target the reverse-transcriptase function of HBV-DNA polymerase. The reported results of clinical trials have used varying definitions of efficacy, failure, and resistance based on different measures of virologic responses. This article discusses HBV virologic markers and tests, and their optimal use both for planning and reporting clinical trials and in clinical practice.

Non-alcoholic fatty liver disease in the Asia–Pacific region: Definitions and overview of proposed guidelines

Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western industrialized countries, affecting 20–40% of the general population. Large population‐based surveys in China, Japan, and Korea indicate that the prevalence of NAFLD is now 12% to 24% in population subgroups, depending on age, gender, ethnicity, and location (urban versus rural). There is strong evidence that the prevalence of NAFLD has increased recently in parallel with regional trends in obesity, type 2 diabetes, and metabolic syndrome; and that further increases are likely. The relationship between NAFLD, central obesity, diabetes, and metabolic syndrome is clearly evident in retrospective and prospective Asian studies, but the strength of association with these metabolic risk factors is only appreciated when regional definitions of anthropometry are used. Pathological definition of NAFLD, particularly its activity and the extent of liver fibrosis, requires histological examination, but liver biopsy is often not appropriate in this disorder for logistic reasons. An alternative set of operational definitions is proposed here. Clinicians need guidelines as how best to diagnose and manage NAFLD and its associated metabolic disorders in countries with scant healthcare resources. The Asia–Pacific Working Party (APWP) for NAFLD was convened to collate evidence and deliberate these issues. Draft proposals were presented and discussed at Asia–Pacific Digestive Week at Cebu, Philippines, in late November 2006, and are published separately in this issue of the Journal as an Executive Summary. The present document reviews the reasoning and evidence behind the APWP‐NAFLD proposals for definition, assessment, and management of NAFLD in the Asia–Pacific region.