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Background & Aims: Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy., Methods: Cirrhosis was induced in NOD Scid gamma mice with 4 months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI., Results: 8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastasis developed in 3 cirrhotic PDX lines and was associated with early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P = .027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P ≤ .03)., Conclusions: A clinically relevant cirrhotic PDX model preserves tumor angiogenesis and allows prediction of response to multikinase inhibitors for personalized therapy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. We report an immune-permissive murine model of liver cirrhosis with full clinical correlates of decompensated liver disease, and allows testing efficacy of stem cell transplantation. Liver cirrhosis was induced in Nod-scid gamma(NSG) mice with oral thioacetamide(TA) and compared to controls over 12 months. 4 month TA treated cirrhotic mice were then transplanted intrasplenically with 2million human fetal liver progenitor cells(HFH) and compared with cirrhotic controls 2 months after transplantation. NSG-TA mice developed shrunken and nodular livers with histological evidence of fibrosis as compared to controls. This was associated with evidence of worsening decompensated liver disease, with jaundice, hypoalbuminemia, coagulopathy, and encephalopathy in NSG-TA mice. Transplantation of HFH resulted in improvement in both fibrosis and markers of decompensated liver disease. We have demonstrated that NSG-TA mice can recapitulate the full clinical picture of structural and functional cirrhosis, both of which can be improved by transplantation of human fetal liver cells. This model serves as a valuable tool for validation of in vivo liver stem cell transplantation and opens up opportunities for studying the mechanism how stem cells reverse fibrosis.

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes., Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed., Findings: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment., Interpretation: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis., Funding: Gilead Sciences., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Chronic hepatitis B virus (HBV) infection is the main etiologic risk factor for hepatocellular carcinoma (HCC). Early studies indicated that the increase of omega-6-derived oxylipins may be involved in the pathogenesis of HBV-related HCC, yet their changes during the distinct clinical phases of chronic HBV infection remain unclear. To fill this gap, in this study we investigated the omega-6-derived oxylipin profiles in patients with three major clinical stages of chronic HBV infection (chronic hepatitis B, liver cirrhosis, and HCC)., Methods: Eighteen omega-6-derived oxylipins were quantified in serum samples of 34 patients with chronic hepatitis B, 46 patients with HBV-related liver cirrhosis, 38 patients with HBV-related HCC, and 50 healthy controls using liquid chromatography tandem mass spectrometry., Results: Seven oxylipins were found to be altered in patients with HBV-related liver diseases, including 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME), 12,13-DiHOME, 14,15-dihydroxyeicosatrienoic acid (14,15-DiHETrE), 13-hydroxyoctadecadienoic acid (13-HODE), 12-hydroxyeicosatetraenoic acid (12-HETE), 11-HETE, and thromboxane B 2 (TXB 2 ). Of these, three oxylipins derived from the cytochrome P450 (CYP450) pathways including 9,10-DiHOME, 12,13-DiHOME, and 14,15-DiHETrE were found to be associated with the levels of α-fetoprotein (AFP), a tumor marker. In combination with AFP, age, and gender, a combination of these seven differential oxylipins could significantly enhance the prediction of HBV-related liver diseases, particularly for liver cirrhosis (p < 0.05)., Conclusion: This study for the first time shows the correlations between CYP450-derived oxylipins and the progression of chronic HBV infection, and sheds a new light on the surveillance of HBV-related live diseases using oxylipins.

Background/aims: Comparison of the accuracy of magnetic resonance elastography (MRE) and diffusion weighted imaging (DWI) for the diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB)., Methods: In this retrospective analysis, we investigated 63 patients with CHB and liver fibrosis. DWI was performed with both breath-hold (DWI-BH) and free-breathing (DWI-FB) sequences (b=0, 500). The mean liver stiffness and apparent diffusion coefficient (ADC) were calculated by drawing regions of interest maps. Fibrosis staging according to the METAVIR system was independently performed by an experienced pathologist. A receiver operating curve (ROC) analysis was conducted to determine the accuracy of MRE, DWI-BH and DWI-FB in the detection and stratification of liver fibrosis. The performance of the detection of significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) was also evaluated by comparing areas under the ROC., Results: There was a moderate and significantly negative correlation between the ADC values and liver stiffness. The accuracies for the detection of ≥F2/≥F3/F4 stage fibrosis with DWI-FB, DWI-BH and MRE were 0.84/0.76/0.72, 0.72/0.83/0.79 and 0.99/0.99/0.98, respectively. The performance of MRE was significantly better than DWI-FB and DWI-BH. There were no significant differences between the performance of DWI-FB and DWI-BH., Conclusions: MRE is more accurate than DWI for the detection and stratification of liver fibrosis in CHB.

Hepatic fibrosis is a common pathway leading to liver cirrhosis, which is the end result of any injury to the liver. Accurate assessment of the degree of fibrosis is important clinically, especially when treatments aimed at reversing fibrosis are being evolved. Despite the fact that liver biopsy (LB) has been considered the "gold standard" of assessment of hepatic fibrosis, LB is not favored by patients or physicians owing to its invasiveness, limitations, sampling errors, etc. Therefore, many alternative approaches to assess liver fibrosis are gaining more popularity and have assumed great importance, and many data on such approaches are being generated. The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on liver fibrosis in 2007, with a mandate to develop consensus guidelines on various aspects of liver fibrosis relevant to disease patterns and clinical practice in the Asia-Pacific region. The first consensus guidelines of the APASL recommendations on hepatic fibrosis were published in 2009. Due to advances in the field, we present herein the APASL 2016 updated version on invasive and non-invasive assessment of hepatic fibrosis. The process for the development of these consensus guidelines involved review of all available published literature by a core group of experts who subsequently proposed consensus statements followed by discussion of the contentious issues and unanimous approval of the consensus statements. The Oxford System of the evidence-based approach was adopted for developing the consensus statements using the level of evidence from one (highest) to five (lowest) and grade of recommendation from A (strongest) to D (weakest). The topics covered in the guidelines include invasive methods (LB and hepatic venous pressure gradient measurements), blood tests, conventional radiological methods, elastography techniques and cost-effectiveness of hepatic fibrosis assessment methods, in addition to fibrosis assessment in special and rare situations.

Background & Aims: While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients., Methods: Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up., Results: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy., Conclusions: APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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.)

Aim: To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia., Methods: The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on-treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response., Results: 150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules., Conclusion: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

Objectives: This study aimed to evaluate the risk of development of hepatocellular carcinoma (HCC) according to underlying liver status and virological response (VR) to entecavir (ETV) in chronic hepatitis B patients with cirrhosis. Procollagen III N-terminal peptide (PIIINP) concentration during ETV treatment and its association with HCC development were also evaluated., Methods: A total of 306 patients with clinically diagnosed liver cirrhosis were treated with ETV for ≥12 months and were subsequently followed up for the occurrence of HCC (median follow-up duration: 37.0 months). Patients who developed HCC within 12 months were excluded. VR was defined as a hepatitis B virus DNA level <20 IU/ml at 12 months after ETV treatment., Results: A total of 209 patients (68.3%) had compensated cirrhosis, and the remaining patients (31.7%) had decompensated cirrhosis. The 5-year cumulative incidence of HCC was 26.8%. A multivariate Cox regression analysis identified the following independent risk factors for developing HCC in all the patients: age >50 years (hazard ratio (HR)=8.41; 95% confidence interval (CI)=3.86-18.28; P=0.000), male sex (HR=4.24; 95% CI=1.83-9.81; P=0.001), high serum PIIINP level at 12 months (HR=1.07; 95% CI=1.02-1.13; P=0.007), and no VR at 12 months (HR=2.10; 95% CI=1.02-4.33; P=0.043). The subgroup analyses showed that no VR at 12 months is a significant risk factor for developing HCC in the patients with decompensated cirrhosis (HR=7.74; 95% CI=1.34-44.78; P=0.022) but not in those with compensated cirrhosis (P=0.749)., Conclusions: The antiviral treatment with ETV did not completely eliminate the risk of developing HCC in our patients with cirrhosis. However, VR to ETV was associated with a low probability that the patients with decompensated cirrhosis would develop HCC.

Objectives: We measured the accuracy of magnetic resonance elastography (MRE) for the detection and staging of liver fibrosis in chronic hepatitis B (CHB) and compared it with serum fibrosis markers., Methods: Prospective comparison of MRE and routine serum fibrosis markers, namely serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), ALT/AST ratio (AAR), AST to platelet ratio index (APRI) and prothrombin index (PI), was performed in 63 consecutive CHB patients who underwent MRE and histological confirmation of liver fibrosis within a 6-month interval. Diagnostic performance of MRE and serum markers for staging fibrosis (≥F1), significant fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis (F4) was compared., Results: The study group comprised 63 patients (19 female; mean age ± SD, 50 ± 11.9 years). MRE (ρ = 0.94, P < 0.0001), APRI (ρ = 0.42, P = 0.0006), PI (ρ = 0.42, P = 0.0006) and AST (ρ = 0.28, P = 0.028) results correlated significantly with fibrosis stage. MRE was significantly more accurate than serum fibrosis markers for the detection of significant fibrosis (0.99 vs. 0.55-0.73) and cirrhosis (0.98 vs. 0.53-0.77). Sensitivity, specificity, positive predictive and negative predictive values for MRE for significant fibrosis and cirrhosis were 97.4 %, 100 %, 100 % and 96 %, and 100 %, 95.2 %, 91.3 % and 100 %, respectively., Conclusion: MRE is an accurate non-invasive technique for the detection and staging of liver fibrosis in CHB., Key Points: • Magnetic resonance elastography is accurate for liver fibrosis detection and staging. • MR elastography is more accurate than serum tests for staging liver fibrosis. • MR elastography can potentially replace liver biopsy in chronic hepatitis B.

Goals: To determine the clinical outcome of chronic hepatitis B cirrhotics on antiviral therapy., Background: The long-term outcome of hepatitis B cirrhotics on therapy remains to be characterized., Methods: A large clinic cohort of chronic hepatitis B cirrhotic patients were enrolled in a treatment program of lamivudine ± adefovir therapy. Patients were analyzed for clinical outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), and progression in Child-Pugh score, Model for End-stage Liver Disease score, and mortality were assessed. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression., Results: Of 143 chronic hepatitis B cirrhotics, 19.6% had decompensated cirrhosis. At 5 years, the mean survival was 83.6%, development of ascites, HCC, encephalopathy, and deterioration in Child-Pugh score were 7.0%, 15.9%, 10.8%, and 16.9%, respectively. The overall progression of liver-related complications was 32.8% at 5 years. Multivariate analysis showed that ascites, albumin ≤28 g/L, Child-Pugh score ≥7.9, Model for End-stage Liver Disease score ≥10.9 were significantly associated with liver-related complications. Low albumin and low hepatitis B virus DNA were independent factors for liver-associated mortality. Lamivudine resistance did not affect mortality or liver disease progression. When stratified by Child-Pugh status, the mean survival of those with Child C cirrhosis was worse than Child A and B cirrhosis (P<0.001, log-rank test). Early deaths (≤12 mo) were due to liver failure or sepsis, whereas deaths ≥12 mo were mainly due to HCC., Conclusion: Decompensated chronic hepatitis B cirrhotics may suffer early mortality despite antiviral treatment, and therefore should be considered for early liver transplantation.

Background/aims: The usefulness of liver stiffness measurement (LSM) for monitoring changes in fibrosis and inflammation in chronic hepatitis B (CHB) patients receiving antiviral therapy is unknown. The aim of this study was to evaluate changes in liver stiffness and correlate them with changes in serological markers and histology in CHB patients receiving entecavir., Methodology: The study included 38 patients with CHB and 24 cirrhotic patients with CHB. All patients received entecavir for over 12 months. Liver stiffness was measured by transient elastography at baseline and after 48wks of therapy. Liver biopsy was performed on 15 patients at baseline and during therapy., Results: Among 62 treated patients, 51 (82.2%) achieved HBV DNA <50 copies/mL and 43 (69%) achieved alanine aminotransferase (ALT) normalization at 48wks. The median liver stiffness value at baseline was 15.1 kPa (5.6-75.0) and decreased significantly to 8.8kPa (3.0-33.8) after 48wks. A decrease in liver stiffness value during therapy correlated significantly with decreases in albumin (r=-0.357, p=0.004), bilirubin (r=0.342, p=0.007), ALT (r=0.319, p=0.012), and aspartate aminotransferase (AST) (r=0.353, p=0.005) concentrations. Decreases in liver stiffness values correlated significantly with improvement in necroinflammatory scores., Conclusion: We suggest that LSM can reflect the changes of necroinflammation in patients with chronic hepatitis B receiving antiviral therapy.

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.

Background & Aims: Tumor and viral antigens are expressed by hepatocellular carcinoma (HCC) in patients with chronic hepatitis B, but little is known about the immunodominance and function of tumor- and virus-specific CD8+ T cells in these patients., Methods: HLA-A2-restricted T-cell responses to 16 tumor antigens and hepatitis B virus (HBV) proteins were tested using 49 previously described epitopes. Cells from 30 HLA-A2+, HBV-infected patients (10 with HCC, 10 with HBV cirrhosis, and 10 HBV but no cirrhosis) were analyzed, after expansion, by enzyme-linked immunosorbent spot (ELISPOT). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 production, as well as expression of the degranulation marker CD107a on tumor-specific CD8+ T cells, were evaluated., Results: Cells from all groups had tumor-specific responses. The tumor antigens NY-ESO-1 and SSX-2 were most frequently targeted and were immunogenic in the HLA-A2 subtypes that are characteristic of Asian ethnicity. Tumor-specific T cells had low affinities; T cells from non-HCC patients were polyfunctional (IFN-gamma+, TNF-alpha+, CD107a+) and those from HCC patients displayed an exhausted phenotype (IFN-gamma+, CD107a+). Programmed Death 1 (PD-1) was expressed at higher levels on T cells from tumor and liver than peripheral blood from HCC patients and might contribute to T-cell exhaustion. Blocking PD-1/PD-L1 increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function., Conclusions: Patients with or without HCC have a quantitative and functional hierarchy of tumor-specific T cells. HLA-A2-restricted T cells from HCC patients target NY-ESO-1, but exist in an exhausted state that might require additional activation to restore function.

Aim: We set to determine factors that determine clinical severity after the development of resistance., Methods: Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups: 13/35 (37%) were non-cirrhotics with normal pre-treatment ALT (Group IA), 12/35 (34%) were non-cirrhotics with elevated pre-treatment ALT (Group IB), and 10/35 (29%) were cirrhotics (Group II). Patients were followed for a median of 98 wk (range 26-220) after the emergence of genotypic resistance., Results: Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients (75%) developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score (in the cirrhotic group) were predictive of clinical resistance and correlated with peak ALT levels and CPT score., Conclusion: The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death (30%) with the development of lamivudine resistance.

Background/aims: An ideal noninvasive diagnostic test for hepatic fibrosis should be simple, inexpensive, and accurate. We aimed to find the simple marker for predicting hepatic fibrosis and to compare the accuracy of AST, platelet, AST/ALT ratio and AST to platelet ratio index (APRI) in chronic hepatitis B patients without clinical evidence of cirrhosis., Methods: A total of one hundred and twenty-six chronic hepatitis B patients who underwent liver biopsy at the Ajou University Hospital from August 1998 to December 2003 were enrolled. Hepatic fibrosis was assessed using the Ludwig classification. Significant fibrosis was defined as fibrosis score of 3 or more. The AST/ALT ratio and APRI were calculated and correlations with hepatic fibrosis were analyzed., Results: APRI showed a significant correlation (r=0.501, p=0.000) with hepatic fibrosis, and was superior to AST, AST/ALT ratio and platelet in predicting fibrosis. Patients with significant fibrosis (fibrosis stage 3, 4) can be identified to have APRI = 1 with sensitivity 71.2% and specificity 70.3%. The sensitivity and specificity of an APRI = 1.5 for cirrhosis (stage 4) were 83.3% and 75.0%., Conclusions: Simple index using AST and platelet value can predict the presence of significant fibrosis and cirrhosis in chronic hepatitis B patients without clinical evidence of cirrhosis.