Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC.

BACKGROUND AND AIM: Plasma-exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. METHODS: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. RESULTS: ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS-matched cohort (n = 208, [ALS-119; PE-94, FPSA-25)], SMT-89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42-24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5-11.1), and lower liver-failure-related deaths as compared to FPSA and SMT (P < .05). PE cleared inflammatory cytokines, damage-associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) compared to non-responders. PE was associated with lesser adverse effects as compared to FPSA. CONCLUSIONS: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma-exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.

Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission.

The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.

Correction to: Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The article Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update, written by [Shiv Sarin], was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 06, 2019 without open access.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

Open-label phase 1b pilot study to assess the antiviral efficacy of simvastatin combined with sertraline in chronic hepatitis C patients.

BACKGROUND: 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors inhibit HCV replication in vitro. The combination of sertraline and simvastatin has synergistic antiviral activity in vitro, but there are no prior in vivo studies. Our aims were to prospectively assess the antiviral efficacy and safety of this drug combination in chronic hepatitis C (CHC) patients. METHODS: A total of 15 CHC adults (including 1 control subject) that were treatment-naive or prior partial responders/relapsers to standard-of-care therapy were enrolled at four centres (2 in Singapore and 2 in the US). Patients received simvastatin 40 mg once daily and sertraline 50 mg once daily for 7 days, and then 80 mg once daily and 100 mg once daily, respectively, for another 21 days with a 14-day follow-up. RESULTS: Of the 15 CHC patients, 13 completed the study. Subjects were mostly Caucasian (8/15), mean age 49.1 ±9 years and the genotype distribution was 1=10, 2=2 and 3=3. No subject discontinued dosing due to adverse events. Mean HCV RNA change from baseline was from -0.005 to -0.236 log(10) IU/ml across study intervals. Three subjects had transient >1 log(10) HCV RNA declines. No subject achieved >2 log(10) HCV RNA decline. CONCLUSIONS: The combination of sertraline and simvastatin is well-tolerated over the short-term, but has no significant antiviral or anti-inflammatory response in CHC patients. This may reflect in vivo differences in synergy between statin and/or selective serotonin reuptake inhibitors and incomplete inhibition of membrane protein prenylation with statin therapy.

Role of the miR-106b-25 microRNA cluster in hepatocellular carcinoma.

MicroRNAs are tiny RNA molecules which serve as important post-transcriptional regulators of gene expression. Dysregulated expression of microRNAs has been observed in human cancers, indicating that microRNAs may function as oncogenes or as tumor suppressors. To date, the microRNAs encoded by the oncogenic miR-17-92 cluster, and its paralog the miR-106b-25 cluster, are among those which are differentially expressed in human cancers. In this study, we examined and confirmed the over-expression of these clusters in hepatocellular carcinoma and in hepatoma-derived cells. At least 50% of the tumor samples showed a greater than two-fold increase in the expression for miR-18 and for the miR-106b-25 cluster when compared with the corresponding paired non-tumor samples. Knock-down studies for the miR-106b-25 cluster, which includes miR-106b, miR-93 and miR-25, showed that the expression of the cluster is necessary for cell proliferation and for anchorage-independent growth. In tumors with high expression of this cluster, reduced expression of the BH3-only protein Bim, a miR-25 target, was observed. We further identified the transcription factor E2F1 as a target gene for miR-106b and miR-93 and it is likely that one of the roles of the miR-106b-25 cluster is to prevent excessively high E2F1 expression, which may then cause apoptosis. We conclude that there is aberrant expression of microRNAs encoded by the oncogenic miR-17-92 cluster and the miR-106b-25 cluster in hepatocellular carcinoma. The consistent overexpression of the miR-106b-25 cluster and its role in cell proliferation and anchorage-independent growth points to the oncogenic potential of this cluster.

Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B.

BACKGROUND/AIMS: In the GLOBE trial, telbivudine treatment was identified as a significant, independent predictor of better outcomes at 2 years. We analyzed all telbivudine recipients in this trial to determine the predictors of optimal outcomes. METHODS: The intent-to-treat population comprised 458 HBeAg-positive and 222 HBeAg-negative telbivudine-treated patients. Multivariate logistic regression analyses were employed to evaluate baseline and/or early on-treatment variables. RESULTS: Baseline HBV DNA<9 log(10)copies/mL, or ALT levels > or = 2x above normal were strong pretreatment predictors for HBeAg-positive, but not for HBeAg-negative patients. However, non-detectable serum HBV DNA at treatment week 24 (TW24) was the strongest predictor for better outcomes for both groups. A combination of pretreatment characteristics plus TW24 response identified subgroups with the best outcomes: (1) HBeAg-positive patients with baseline HBV DNA<9 log(10)copies/mL, ALT > or = 2x above normal and non-detectable HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 89%, HBeAg seroconversion in 52%, telbivudine resistance in 1.8%; and (2) HBeAg-negative patients with baseline HBV DNA<7 log(10)copies/mL and non-detectable serum HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 91%, telbivudine resistance in 2.3%. CONCLUSION: During telbivudine treatment, non-detectable serum HBV DNA at treatment week 24 is the strongest predictor for optimal outcomes at 2 years.

Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.

UNLABELLED: Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log(10) copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 x upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log(10) copies/mL and -50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. CONCLUSION: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement.

Report of an international workshop: Roadmap for management of patients receiving oral therapy for chronic hepatitis B.

An international group of experienced hepatologists and virologists conducted a single-day workshop to review the management of patients with chronic hepatitis B receiving treatment with oral nucleosides or nucleotides. Guidelines regarding on-treatment management and available published data on the importance of serum hepatitis B virus (HBV) DNA as a marker of outcomes were reviewed. On-treatment monitoring strategies to define early virologic responses that might be predictive of better outcomes and a reduced risk of viral resistance were proposed for further study. This treatment plan, labeled the roadmap concept, recommends monitoring of serum HBV DNA levels to identify outcomes of therapy. Primary treatment failure was defined as a reduction of serum HBV DNA levels by less than 1 log10 IU/mL from baseline at week 12. Measurement of the HBV DNA level at week 24 was considered essential to characterize virologic responses as complete, partial, or inadequate. Complete virologic response was defined as negative HBV DNA by a sensitive assay (<60 IU/mL or <300 copies/mL); partial virologic response was defined as HBV DNA levels less than 2000 IU/mL (4 log10 copies/mL), and inadequate virologic response was defined as HBV DNA levels of 2000 IU/mL or greater (4 log10 copies/mL). Strategies are proposed for managing patients in each of these categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug. Future studies of the use of the roadmap concept in improving outcomes of chronic hepatitis B are warranted.

A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore.

GOALS: To estimate and compare the direct medical cost in the management of chronic hepatitis B (CHB) infection and its complications from the perspective of public health organizations in Hong Kong and Singapore. BACKGROUND: Hong Kong and Singapore are endemic hepatitis B virus areas with about 10% and 5%, respectively, of the population estimated as hepatitis B virus infected. STUDY: The medical histories of 660 patients with CHB who received medical services over 5 years from three major public hospitals in Hong Kong and Singapore were studied retrospectively. Costs were analyzed according to the five disease states and estimated in Hong Kong dollars (HKD) and Singapore dollars (SGD). RESULTS: In both Hong Kong and Singapore, the per-patient total annual cost increased with the severity of the disease. CHB cost HKD 6318 (US 810 dollars) in Hong Kong and SGD 718.15 (US 410.37 dollars) in Singapore. Compensated cirrhosis cost HKD 10,304 (US 1321 dollars) in Hong Kong and SGD 1,175.34 (US 671.62 dollars) in Singapore. Decompensated cirrhosis cost HKD 58,428 (US 7490 dollars) in Hong Kong and SGD 15,389.84 (US 8794.19 dollars) in Singapore. Hepatocellular carcinoma cost HKD 121,822 (US 15,618 dollars) in Hong Kong and SGD 12314.04 (US 7036.59 dollars) in Singapore. Each case of liver transplant was estimated to cost HKD 514,498 (US 65,961 dollars) in Hong Kong and SGD 86,369.28 (US 49,353.87 dollars) in Singapore. CHB in Hong Kong accounted for about 4% of the healthcare expenditure. CONCLUSION: This study confirms that CHB and its liver disease complications are a significant economic burden to the healthcare budgets of Hong Kong and Singapore, and indicates that effective therapy that arrests or reverses the progression of liver disease would be highly cost-effective.