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Current therapies for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) and interferon (IFN), but their relative efficacy as monotherapy or in combination has not been examined systematically for HBsAg loss (functional cure). Hence, we systematically reviewed the evidence for HBsAg loss in CHB patients treated with IFN, NA or the combination. We searched PubMed, EMBASE and abstracts from EASL, Asia Pacific Association for study of the Liver and American Association for the Study of Liver Disease for randomized controlled trials of CHB patients, comparing NA, IFN or the combination. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by NA genetic barrier, cirrhosis, type of combination therapy, HBeAg, treatment naivety, IFN dosage/duration and outcome duration. Sensitivity analysis was performed for selected strata, and HBsAg loss was measured at the end-of-study (EOS), end-of-treatment (EOT) or end-of-follow-up (EOF). Effects were reported as risk differences (RD) with 95% confidence intervals (CI) using a random-effects model. Forty-five studies were included, all with low risk of bias. For HBsAg loss at EOS, when comparing combination vs IFN, RD = 1%, 95%CI-1%, 2%; combination vs NA, RD = 5%, 95%CI 3%,7%; IFN vs NA, RD = 3%, 95%CI 2%,5%. Subgroup analysis showed a significant effect of standard IFN dose vs nonstandard; IFN duration ≥48 weeks vs <48 weeks, and loss of efficacy >2 years of follow-up. Similar findings were seen in HBsAg seroconversion, but only three studies reported HBsAg seroreversion. In conclusion, IFN monotherapy/combination had a small but significant increase in HBsAg loss over NA, associated with standard dose of IFN and ≥48 weeks of therapy, although this effect faded over time., (© 2020 John Wiley & Sons Ltd.)

Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines + standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow-up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = 0.01, 95% CI -0.05 to 0.07, and when comparing therapeutic vaccines + standard of care vs standard of care, RD = 0.03, 95% CI -0.03 to 0.09. For HBVDNA reduction at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = -0.03, 95% CI -0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD = 0.15, 95% CI 0.02-0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow-up for therapeutic vaccines + standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection., (© 2019 John Wiley & Sons Ltd.)

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype., (© 2018 John Wiley & Sons Ltd.)

Background and Aim: The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied., Methods: We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation., Results: Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment., Conclusions: The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Human amniotic epithelial cells (hAECs) have been touted as an ideal stem cell candidate, being ethically neutral, immunologically naïve, plentiful in origin, and retaining plasticity in its fetal stage. We hypothesized that by applying natural physiological signals of the developing liver, hAECs can be coaxed into becoming functional immunopermissive hepatocyte-like cells. These cells would have tremendous potential for allogenic cellular transplantation in the treatment of chronic liver insufficiency., Methods: hAECs were obtained from term placentas and subjected to hepatic trans-differentiation. Hepatic differentiated cells were analyzed with immunophenotyping, electron microscopy, reverse transcription-polymerase chain reaction as well as characterized for hepatic metabolic function. In vivo efficacy was tested using intrasplenic transplantation into non-obese diabetic (NOD) Scid Gamma mice with thioacetamide-induced chronic liver failure and analyzed for engraftment and improvement in liver indices., Results: With hepatic differentiation, hAECs assumed a hepatocytic polygonal morphology with upregulation of transcription factors responsible for liver specification. These hepatic differentiated-hAECs (HD-AECs) demonstrated bile canaliculi formation, secreted albumin, eliminated indo-cyanine green, uptook low-density lipoprotein, and inducible CYP3A4 and CYP2C9 enzymatic activities. Transplantation of HD-AECs and de novo hAECs in mice model of cirrhosis showed successful in vivo engraftment and differentiation into functional hepatocytes positive for human-specific albumin. HD-AEC cells that had undergone hepatic differentiation showed the greatest improvement in albumin function while preserving human leukocyte antigen-G expression postdifferentiation., Conclusion: hAECs were able to differentiate into functional hepatocyte-like cells both in vivo and in vitro. They showed therapeutic efficacy after transplantation in mice model of cirrhosis, offering an exciting source of cells for generation of functionally useful hepatocytes., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: Although pancreatic stent insertion is recommended for the prevention of post-procedure pancreatitis during endoscopic papillectomy, insertion of the stent after the procedure can be technically difficult. The aim of the present study was to determine the feasibility and safety of inserting a newly developed insulated pancreatic stent before endoscopic papillectomy., Methods: We conducted a prospective pilot study involving 11 consecutive patients with adenomas of the major duodenal papilla. After a 5F polytetrafluoroethylene-insulated pancreatic stent was inserted through the tumor, the stent and tumor were simultaneously grasped with a snare. After resection of the tumor with the stent in place, the tumor was incised perpendicularly along the edge of the stent for retrieval of the specimen., Results: In all patients, the insulated pancreatic stents were successfully inserted before endoscopic papillectomy and were resistant to electrical current; retrieval of the specimen was technically feasible and successful without stent migration. There were no stent-related complications, but five papillectomy-related complications (including mild bleeding [n = 4] and late papillary stenosis [n = 1]) occurred without any episodes of acute pancreatitis or perforation., Conclusions: Pre-resection stenting with a polytetrafluoroethylene-insulated stent in patients with adenomas of the major duodenal papilla is a feasible and useful technique to prevent pancreatitis.

Chronic hepatitis B is the main risk factor for hepatocellular carcinoma (HCC) in Asia. The most important preventive strategy's adoption of the universal hepatitis B vaccination program is now in its third decade. There is a clear reduction in both chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen "carriage") but also in childhood HCC in Taiwan. An outstanding concern is variability in vaccine coverage between countries. For patients with chronic hepatitis B, serum HBV DNA levels have emerged as the key risk factor for development of HCC. The initial treatment for chronic hepatitis B was interferon. One randomized control trial, and several case-control or cohort studies have shown benefits for preventing HCC, particularly in cirrhotic patients who responded to therapy. With nucleos(t)ide analogs, the most important study has been the Asian Cirrhosis Lamivudine multicenter randomized controlled trial. This showed that lamivudine can reduce disease progression in HBV-related cirrhosis, including an approximately 50% decrease in HCC incidence. Such efficacy was achieved despite emergence of drug resistance in approximately 50% of cases. Case-control studies have suggested that hepatitis B cases without cirrhosis may also benefit. In conclusion, it is now possible to prevent HBV-related HCC. The most effective method is hepatitis B vaccination, which prevents chronic HBV infection and chronic liver disease resulting therefrom. Interferon therapy appears to confer benefit but the evidence is weaker. First-generation oral antiviral (lamivudine) reduces HCC risk, particularly in cirrhotics. Long-term outcome data with newer, more potent HBV antivirals that have a higher genetic barrier to drug resistance are eagerly awaited.

Health-related quality of life (HRQoL) is an important aspect of the overall management of hepatitis B virus (HBV) infection. The major challenge is to find a valid and reliable disease-specific HRQoL instrument designed specifically for measuring health status in hepatitis B patient. Consequently, this study was undertaken to adapt culturally the Hepatitis Quality of Life Questionnaire (HQLQ) and assess its suitability for use in English-speaking hepatitis B virus-infected (HBV) patients in Singapore. Two patient focus groups were conducted to facilitate the cultural adaptation of the HQLQ. Reliability was assessed using Cronbach's alpha coefficients and intraclass correlation coefficients. Item-to-scale correlation was assessed using Spearman's rank correlations (rho) between scale scores and their constituent items. Convergent and divergent construct validities were tested in three and two a priori hypotheses, respectively, and the correlations were assessed using Spearman's rank correlation coefficients (rho). The culturally adapted questionnaire was tested in 298 HBV patients. The test-retest reliability was supported with 10 of the 12 scales showing acceptable correlation coefficients (i.e. alpha>0.7). Item-to-scale correlations were good with most items highly correlated with their hypothesized scales. Convergent and divergent construct validities were supported by the presence of hypothesized correlations between the HQLQ and the EQ-5D domains (eight of 10 sub-hypotheses for convergent construct validity and all hypotheses for divergent construct validity were fulfilled). In conclusion, our results showed that the culturally adapted HQLQ has good validity and reliability, making it a potentially useful outcome measure in the evaluation of HBV patients in Singapore.

Hepatitis B virus (HBV) infection is the most common cause of chronic viral liver disease in Singapore. Nevertheless, very little data exist on the financial burden of HBV infection to the society as a whole. The aim of this study was therefore to assess the direct and indirect cost of HBV infection in a cost-of-illness analysis. The combined data from the direct and indirect cost with the estimated prevalence for different disease stages of HBV infection would represent the annual financial burden of HBV infection to the Singaporean society as a whole. The estimated total annual cost of chronic HBV infection and its associated complications in Singapore was US$279 million (range US$34-941 million when allowing various assumptions as tested by the sensitivity analyses), with 58% or US$161 million attributable to direct cost. Based on the base-case estimation, total direct cost alone is equivalent to 12% of the national healthcare expenditure for 2003. The total cost incurred by chronic hepatitis B patients represents the biggest cost component, followed by decompensated cirrhosis (DC) patients. The ratio of direct to indirect costs based on the base-case estimation increased with disease severity, with the highest ratio obtained for the post-liver transplants (40.2:1), followed by hepatocellular carcinoma (7.4:1) and DC patients (2.7:1). The results of this study suggest that the management of HBV infection poses more than a medical challenge as it is a sizeable economic burden from both the payer and societal perspectives.

Background and Aim: Primary biliary cirrhosis (PBC) is infrequent in Asians. Among Asian patients with PBC, information on natural course is scarce. The aim of this study was to study the clinical course and prognosticators among Asians with PBC., Methods: During 1990-2005, patients diagnosed with PBC at the National University Hospital, Singapore, constituted the retrospective cohort. Their demographic characteristics were evaluated. To evaluate the prognostic factors and natural course, two outcome measures were assessed: hepatic decompensation and death or liver transplant. Multivariate analysis was undertaken to identify factors associated with hepatic decompensation and terminal event (death or liver transplantation)., Results: Thirty-four PBC patients aged 56.8 +/- 1.8 years (mean +/- SEM) of whom 32 (94%) were women were included. Thirty-two (94%) of them were of Chinese origin. At presentation, 18 (53%) were symptomatic in the form of jaundice (n = 9, 26.5%), pruritus (n = 6, 17.6%) and fatigue (n = 5, 14.7%). During 4.80 +/- 0.7 (range 0.02-15.03) years follow up, 6/16 (37.5%) asymptomatic patients developed symptoms. After 5 years, 17.6% (n = 6) and 8.8% (n = 3) had hepatic decompensation and terminal event, respectively. Sicca syndrome was present in 26% (n = 9) of patients. Multivariate analysis revealed that serum bilirubin level at presentation was the sole determinant of decompensation. Rate of change of laboratory indices did not predict either event., Conclusion: In Singapore, Chinese women constitute most of the PBC patients. Elevated serum bilirubin level at presentation was the sole predictive marker associated with dismal outcome.

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.

A major area of research in transplantation medicine is the potential application of stem cells in liver regeneration. This would require well-defined and efficient protocols for directing the differentiation of stem cells into the hepatic lineage, followed by their selective purification and proliferation in vitro. The development of such protocols would reduce the likelihood of spontaneous differentiation of stem cells into divergent lineages upon transplantation, as well as reduce the risk of teratoma formation in the case of embryonic stem cells. Additionally, such protocols could provide useful in vitro models for studying hepatogenesis and liver metabolism. The development of pharmokinetic and cytotoxicity/genotoxicity screening tests for newly developed biomaterials and drugs, could also utilize protocols developed for the hepatic differentiation of stem cells. Hence, this review critically examines the various strategies that could be employed to direct the differentiation of stem cells into the hepatic lineage in vitro.

Background and Aims: This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV)., Methods: Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here., Results: The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2-5 x upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study., Conclusions: Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine.

The Asia-Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia-Pacific countries. Hepatitis B is a major health concern in the Asia-Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia-Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia-Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia-Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.

The techniques of Western blotting and the monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to detect antibodies to platelet glycoproteins in 43 samples of serum from 23 anti-HIV positive haemophiliacs (8 with severe thrombocytopenia, 6 with moderate thrombocytopenia, and 9 with a normal platelet count), six anti-HIV negative haemophiliacs and ten controls. Antibodies were present in the majority of anti-HIV positive patients' sera even before the onset of thrombocytopenia. Thrombocytopenia was associated with an increase in the incidence of antibodies to GPIIIa and GPIb, whereas the antigen most frequently recognized in patients without thrombocytopenia was GPIIb. Anti-GPIIb and/or GPIIIa reactivity was also seen in three out of the six anti-HIV negative patients. There was no correlation between the absolute platelet count and the detection of antibodies in either assay. Effective therapy for thrombocytopenia with zidovudine, interferon or splenectomy did not influence the presence of antibody. Eight of nine patients with AIDS were negative in the MAIPA assay, consistent with their depressed immune status. It is concluded that the production of antibodies to platelet membrane glycoprotein in anti-HIV positive haemophiliacs is influenced by factors other than HIV. The presence of such antibodies is independent of the platelet count and is therefore unlikely to play a causative role in HIV-related thrombocytopenia.

Twenty haemophiliacs (17 CDC group IV and 3 CDC group II) were treated with zidovudine for a median of 37 weeks (range 10-66). Eight (40%) tolerated zidovudine without a dose change. Two patients died and five patients (29%) developed opportunist infections. Haematological toxicity occurred in ten CDC IV patients (59%) but only one case of sepsis occurred in 101 episodes of documented granulocytopenia. Thrombocytopenia responded to treatment with zidovudine in four of five patients. It is concluded that zidovudine is beneficial for symptomatic haemophiliacs and although the haematological toxicity is high, it is mostly asymptomatic, reversible and well tolerated. Two of the three CDC II patients treated with zidovudine progressed to CDC IV, but had low initial T4 lymphocyte counts and were P24 antigen positive.

HIV associated thrombocytopenia occurs in 5-10% of asymptomatic individuals, and 25-45% of people with AIDS. A variety of treatments are available but the inherited bleeding disorder in addition to the thrombocytopenia makes management in haemophiliacs a special problem. The management of this double coagulopathy is described in seven patients. IV gammaglobulin and steroids were useful only in the short term; zidovudine produced a good response, could be taken orally, had anti-HIV activity and was well tolerated in asymptomatic HIV positive patients. Interferon was an alternative when zidovudine was ineffective or produced intolerable side-effects. Splenectomy was considered only after failure of other treatments because of the increased risks of bleeding.