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Abstract Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000–4999 mAU/mL), and 10.7% latent VK deficiency (200–999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p

Abstract Background and Aim The purpose of this study was to analyze factors associated with the overall survival (OS) of atezolizumab/bevacizumab combination therapy for advanced hepatocellular carcinoma (aHCC). We also assessed the OS of patients with ineffective therapy and those who discontinued treatment owing to adverse events (AEs). Methods This retrospective multicenter study involved 139 patients with aHCC who received atezolizumab/bevacizumab combination therapy between November 2020 and September 2022. Results The median duration of treatment was 136.5 days, and the median observation period was 316 days. The overall response rate was 40%, and the disease control rate was 78% according to mRECIST criteria. Grade ≥2 AEs occurred in 63 patients (43%) and led to treatment discontinuation in 16 patients. Multivariate analysis revealed that treatment response and occurrence of grade ≥2 AEs after therapy, as well as low level of albumin‐bilirubin (ALBI) grade and low level of des‐gamma carboxy prothrombin (DCP) before therapy, were extracted as factors that contributed to OS. Log‐rank tests with the Kaplan–Meier method showed significant differences in OS among these factors. The OS of patients who discontinued owing to AEs was significantly shorter than that of other patients. Conclusion Not only factors before therapy but also treatment response and the appearance of AEs are involved in OS for atezolizumab/bevacizumab combination therapy. Although the development of AEs also contributed to OS, appropriate management of AEs is important to avoid discontinuing treatment with this combination.

Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan–Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI.

Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. This review focused on anti-HBc antibodies and HBcrAg and aimed to summarize the clinical significance of currently used assay systems and the issues involved. While anti-HBc is very significant for clinical diagnosis, the clinical significance of quantitative assay of anti-HBc antibody has been reevaluated with improvements in diagnostic performance, including its association with clinical stage and prediction of carcinogenesis and reactivation. In addition, concerning the new HBcrAg, a high-sensitivity assay method has recently been established, and its diagnostic significance, including the prediction of reactivation, is being reevaluated. On the other hand, the quantitative level of anti-HBc antibody expressed in different units among assay systems complicates the interpretation of the results. However, it is difficult to standardize assay systems as they vary in advantages, and caution is needed in interpreting the assay results. In conclusion, with the development of highly sensitive HBcrAg and anti-HBc antibody, a rapid and sensitive detection assay system has been developed and used in clinical practice. In the future, it is hoped that a global standard will be created based on the many clinical findings.

Abstract Background and Aim Regarding the gut–liver axis, fecal dysbiosis is implicated in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). The significance of mucosa‐associated microbiota (MAM, which is present in the mucin layer covering the intestinal mucosa) has not been well explored. We aimed to clarify the characteristics of MAM in patients with NAFLD. Methods MAM were obtained from seven patients with early‐stage NAFLD and seven controls by colonoscopy in five locations (terminal ileum, cecum, ascending and sigmoid colon, and rectum) using mucosal brushes. The microbial 16S rDNA profiles of the MAM and fecal microbiota of patients in the NAFLD and control groups were analyzed. Results α‐diversities of fecal microbiota were decreased in patients with NAFLD (observed species, Shannon index, and Chao1: 174.57 vs 134.86, 5.51 vs 4.65, and 206.34 vs 167.91; P = 0.048, 0.067, and 0.087, respectively), and microbial composition analyses by principal coordinate analysis differed between the fecal microbiota of patients with NAFLD and those of controls (permutational analysis of variance [PERMANOVA] of weighted and unweighted: Pseud‐F: 1.4179/P‐value: 0.05 and Pseud‐F: 2.1497/P‐value: 0.049, respectively). However, α‐diversities or microbial composition of MAM in most parts of the intestine did not differ significantly between the NAFLD and control groups. Unclassified Rikenellaceae, Oscillospira, Odoribacter, unclassified clostridiales, and Holdemania were decreased in the feces of patients with NAFLD (determined by linear discriminant analysis effect size), but five (except Holdemania) of the six genera were not decreased in the MAM of these patients. Conclusion In early‐stage NAFLD, MAM was uniform and relatively stable throughout the intestine, even when fecal dysbiosis appeared.

Abstract Background and Aim Molecular‐targeted therapies such as sorafenib and lenvatinib have long been used as first‐line treatment for advanced hepatocellular carcinoma (aHCC). However, adverse events or limited therapeutic effects may necessitate the change to another therapeutic option, known as post‐progression therapy. To investigate the significance of post‐progression therapy, we analyzed the outcomes of aHCC patients following first‐line molecular‐targeted therapy in a real‐world study. Methods This retrospective, multicenter study involved patients with aHCC who received sorafenib or lenvatinib as first‐line therapy between January 2011 and September 2021. Results In total, 513 patients were analyzed: 309 treated with sorafenib and 204 with lenvatinib. The overall response and disease control rates were 15 and 50%, respectively, in the sorafenib group and 30 and 75%, respectively, in the lenvatinib group (P

Objectives: Rapid plasma reagin (RPR) and Treponema pallidum (TP) antibody test kits are often used to diagnose syphilis, although the relationship between their measured values is unclear. We aimed to reveal the relevance of these kits’ results. Design and methods: In all, 143 sera from 110 patients were tested using 12 TP kits and 5 RPR kits and the results compared. Results: The specificity and sensitivity of RPR kits were 81–96% and 95–100%, respectively. The correlation coefficients (0.849–0.934) considerably differed between the manual RPR card test and latex agglutination (LA) assay kits. The following sensitivities were obtained: 82–91% for TP fluorescent treponemal antibody absorption assay (FTA-ABS), TP hemagglutination assay (HA), and TP particle agglutination assay (PA); 94–95% for TP LAs; and 92–100% for chemiluminescent immunoassay (CLIA), chemiluminescent enzyme immunoassay (CLEIA), and immunochromatography assay (IC). Correlation coefficients between TP kits were 0.753–0.974, and the measured values varied. Changes in RPR and quantifiable TP kits were the same for patients with reinfected syphilis and with syphilis under treatment. Conclusions: RPR tests had lower specificity than TP antibody tests. RPR card test and RPR LAs had similar specificity and sensitivity, but their measured values were different. RPR should be measured using automatic RPR LA without setting the upper limit of the reported value. RPR LA should also be standardized. The sensitivity of TP antibody was better in CLIA, CLEIA, and IC than in FTA-ABS, HA, PA, and LA. Therefore, TP antibody kits should be standardized and quantified.

The natural ingredient-based therapy extracted from various plants is assumed more tolerable to cancer patients' bodies than synthetic drugs. To tell successful novel cancer therapy, an indicator is needed to confirm the result. VEGF is a pro-angiogenic factor that leads the cancer cells' invasion to another organ and is associated with high mortality in patients. Hence, the VEGF level is widely used as one of the successful cancer therapy indicators. Purposed of research elucidated the effect of Mandarin orange peel ethanol extract (EEKJM) to improve the reduction of VEGF levels in colon cancer in vitro. This study was an experimental posttest and control group design to analyze different level of VEGF on cancer cells at end of the study. Research began with the preparation of EEKJM followed by a cytotoxic extract test using the MTT assay method. Furthermore, the measurement of VEGF levels by the VEGF ELISA kit protocol. One Way ANOVA was performed to analyze data. Results showed the cytotoxic test of the EEKJM and doxorubicin against WiDr cells was 240 g/ml and 1.59 µg/ml. VEGF levels showed decreasing after being induced with EEKJM and doxorubicin with doses ½ IC50 and ¼ IC50. Conclusion: EEKJM was able to reduce VEGF levels and viability of WiDr colon cancer cells. The advantages are as much as initial evidence of the ability of the orange to treat cancer even though further animal studies or evidence of a pathway of decrease of the VEGF or other signals are required. [ABSTRACT FROM AUTHOR]

Objective: To examine the potential risk of hepatitis B virus (HBV) spread in Indonesia by migrant workers, based on the molecular characteristics of HBV strains. Methods: Sera collected from migrant workers traveling to their destination countries (pre-migrant workers) and those returning to Indonesia (post-migrant workers) were screened for HBsAg by ELISA, followed by HBV DNA detection by PCR and (sub) genotype/subtype determination according to surface region and whole genome sequencing. Results: Of 87 pre-migrant workers, 15 (17.24%) were HBsAg-positive, whereas 15 (12.10%) of 124 post-migrant workers were HBsAg seropositive. HBV genotype analysis based on the S region showed that HBV-B3/adw2 was predominant (96.15%, 25/26) whereas 3.85% (1/26) of isolates were HBV-C3/adrq+. Whole genome sequencing of selected strains and phylogenetic tree analysis identified subgenotype B7 in three samples previously categorized as subgenotype B3 based on S region analysis, supporting a recent argument that subgenotypes B5/B7/B8/B9 could be considered as a quasi-subgenotype of B3. Conclusions: A high prevalence of HBsAg carriers was detected among migrant workers from Lombok Island, with no significant difference in prevalence between before and after returning to Indonesia. All strains were classified into genotypes common in Indonesia, and the results suggested that migrant workers are not a risk factor for HBV transmission into Indonesia.

Abstract Background A large-scale Japanese study showed that low skeletal muscle index (SMI) and intramuscular fat (IMF) deposition are associated with hepatocellular carcinoma (HCC) survival. Here, we evaluated the effects of SMI and IMF on the survival of Indonesian HCC patients, whose characteristics differ from those of Japanese patients. Methods SMI and mean muscle attenuation (MA) were evaluated using computed tomography images of the third lumbar vertebra (L3) in a prospective cohort of 100 Indonesian HCC patients. Clinical, laboratory and body composition data were analysed using the Kaplan–Meier method and Cox regression model to investigate which factors are associated with prognosis. Results Of 100 patients, 31 were diagnosed with sarcopenia (L3 SMI value ≤36.2 cm2/m2 for men and ≤ 29.6 cm2/m2 for women), and 65 had IMF deposition (MA value ≤44.4 HU for men and ≤ 39.3 HU for women). These groups had shorter median survival than the reference groups (both P

Abstract Background Hepatocellular carcinoma (HCC) can develop in patients who are negative for the hepatitis B surface antigen (HBsAg) in serum but positive for hepatitis B virus (HBV) DNA in the liver, referred to as occult HBV infection (OBI). Previous reports showed that HBV variants in OBI-related HCC are different from those in HBsAg-positive HCC. In the present study, HBV quasispecies based on the pre-S/S gene in OBI-related HCC patients were examined by high throughput sequencing and compared with those in HBsAg-positive HCC. Methods Nineteen tissue samples (9 OBI-related and 10 HBsAg-positive non-cancerous tissues) were collected at the time of surgery at Kobe University Hospital. The quasispecies with more than 1% variation in the pre-S/S region were isolated and analysed by ultra-deep sequencing. Results There were no significant differences in the major HBV populations, which exhibit more than 20% variation within the entire pre-S/S region, between OBI-related HCC and HBsAg-positive HCC. However, the prevalences of major populations with pre-S2 region mutations and of minor populations with polymerized human serum albumin-binding domain mutations were significantly higher in OBI-related HCC than in HBsAg-positive HCC. Moreover, the major variant populations associated with the B-cell epitope, located within the pre-S1 region, and the a determinant domain, located in the S region, were detected frequently in HBsAg-positive HCC. The minor populations of variants harbouring the W4R, L30S, Q118R/Stop, N123D and S124F/P mutations in the pre-S region and the L21F/S and L42F/S mutations in the S region were detected more frequently in OBI-related HCC than in HBsAg-positive HCC. Conclusions Ultra-deep sequencing revealed that the B-cell epitope domain in the pre-S1 region and alpha determinant domain in the S region were variable in HBsAg-positive HCC, although the quasispecies associated with the pre-S2 region were highly prevalent in OBI-related HCC. Trial registration Ref: R000034382/UMIN000030113; Retrospectively registered 25 November 2017.

Abstract Background Occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the serum and/or liver in HBsAg-negative individuals. OBI is associated with the risk of viral transmission, especially in developing countries, and with progressive liver disease and reactivation in immunosuppressive patients. The objective of this study was to evaluate the relation of OBI to HLA-DP single nucleotide polymorphisms (SNPs) encoding antigen-binding sites for the immune response to HBV infection. As HLA-DP variants affect the mRNA expression of HLA-DPA1 and HLA-DPB1 in the liver, we hypothesised that high levels of HLA-DPA1 and HLA-DPB1 expression favour OBI development. Methods The study enrolled 456 Indonesian healthy blood donors (HBsAg negative). OBI was defined as the presence of HBV-DNA in at least two of four open reading frames (ORFs) of the HBV genome detected by nested PCR. SNPs in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs2281388) were genotyped using real-time Taqman® genotyping assays. Results Of 122 samples positive for anti-HBs and/or anti-HBc, 17 were determined as OBI. The minor allele in rs3077 was significantly correlated with OBI [odds ratio (OR) = 3.87, 95% confidence interval (CI) = 1.58–9.49, p = 0.0015]. The prevalence of the minor allele (T) was significantly higher in subjects with OBI than in those without (59% and 33%, respectively). The combination of haplotype markers (TGA for rs3077–rs3135021–rs9277535) was associated with increased risk of OBI (OR = 4.90, 95%CI = 1.12–21.52 p = 0.038). The prevalence of OBI was highest in the isolated anti-HBc group among the three seropositive categories: anti-HBs

The VEGF gene polymorphism rs699947 related to clinical pathology, mortality, and recurrence of HCC. Few studies mentioned an association between VEGF gene polymorphisms with illness progression in chronic liver disease. We aimed to explore differences of VEGF gene polymorphism rs699947 in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma patients in Indonesian population.A cross-sectional study with consecutive sampling and without matching was performed during a 3 years period (2011-2014) at Dr. Sardjito General Hospital Yogyakarta, Indonesia. Blood DNA was sequenced from 123 subjects with chronic liver diseases [39 chronic hepatitis (CH), 39 liver cirrhosis (LC), and 45 hepatocellular carcinoma (HCC)]. 59 healthy subjects also participated. Using isolated VEGF genes for specific primers for rs699947, blood samples were examined by targeting DNA sequences with Applied Bio systems. All data were analyzed using STATA version 11.0 with significance level at P0.05). HBV was the dominant etiology in HCC, LC, and CH besides HCV and non HBV-HCV (PC vs. C>C, and genotypes distribution. Proportion of SNP -2578 A>C vs. C>C CH 1.8:1; HCC 1.4:1; healthy 1.7:1; but its proportion in LC was inversed (1:1.2). Genotype A was low in all subjects (5%-11%). Significant difference of allele distribution was found in healthy vs. LC, and HCC; CH vs. LC. Based on HWE analyses, distribution of allele C was dominant. There were not significant differences in deletion, insertion-deletion at -2547 until -2526, and haplotype (Ht) CCGACCCC (P>0.05). The OR analyses of allele and SNP showed that allele A can be a predictor of disease progression in LC to HCC (OR 2.26) and healthy to LC (OR 1.65); and SNP A>C also can be a predictor in healthy to HCC (OR 1.41) and CH (OR 1.14).The occurrence of allele A and SNP A>C VEGF gene (-2578) might predict illness progression from healthy to CH, LC or HCC and LC to HCC.

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC.

Background: The serum creatinine (SCr) concentration in neonates is generally high for its body size, compared to those of infants. The aim of the present study was to investigate the effect of maternal SCr on neonatal SCr through measurements of prenatal maternal SCr and neonatal SCr from birth to postnatal Day 5. In addition, postnatal changes in SCr were compared between term and preterm infants, given that few studies have addressed this topic. Methods: The retrospective study subjects were 151 neonates whose Scr was measured consecutively from birth to postnatal Day 5 and 124 mothers whose SCr was measured prenatally. Results: There were significant correlations between maternal SCr and neonatal SCr at birth (r = 0.858, p < 0.001) and on postnatal Day 1 (r = 0.235, p < 0. 001). The SCr of term infants (median 0.69 mg/dL, range 0.54 - 0.96 mg/ dL) were higher than those of preterm infants (median 0.63 mg/dL, range 0.43 - 1.23 mg/dL, p < 0.001) at birth; however, these values were reversed on postnatal Day 1 (Term: median 0.75 mg/dL, range 0.51 - 1.13 mg/dL, Preterm: median 0.88 mg/dL, range 0.56 - 1.25 mg/dL, p < 0.001). There were differences in the timing of reaching to peak SCr between preterm and term neonates. In addition, birth weight might affect SCr concentrations after birth. Conclusions: The results of this study suggest that neonatal SCr is influenced by maternal SCr, although the effect disappears by postnatal Day 2. Moreover, glomerular filtration rate differs between term and preterm infants. [ABSTRACT FROM AUTHOR]

Mutations of precore (A1896) and core promoter (T1762/A1764) of hepatitis B virus can reduce HBeAg production. These mutations are frequently found in the late HBeAg seroconversion. However, it has been a controversy about the role played by precore and core promoter mutations in determining outcome of chronic hepatitis B. In the present study, the variability of precore and core promoter of hepatitis B virus were analyzed using PCR amplification and sequencing, according to the outcome (viral load and HBeAg/anti-HBe) in chronic hepatitis B patients in Surabaya. The study groups included 5 patients with uncomplicated chronic hepatitis B and 10 patients with chronic hepatitis B and liver cirrhosis in Dr. Soetomo Hospital, Surabaya. The control group included 6 blood donors obtained from Indonesia Red Cross, Surabaya. All groups were HBsAg positive. Precore mutation A1896 was predominant in all groups (60%-67% of each), together with precore variant T1858. As reported, precore variant T1858 is a prerequisite for precore A1896 and characteristic for viral genotype. Nevertheless, core promoter mutations T1762/A1764 were predominant only in LC patients (60%). All of these mutations were found mostly after HBeAg seroconversion (anti-HBe+). Of most samples with anti-HBe+, precore mutation was related with low viral load (105 copies/mL). Precore mutation A1896 was predominant in all groups, but core promoter mutations T1762/A1764 were only predominant in LC patients. The precore mutation alone is possible not critical to indicate a poor outcome, the core promoter mutations must be considered also.

The prevalence of hepatitis C virus (HCV) infection has been as high as approximately 80% in patients with maintenance hemodialysis in public hospitals in Indonesia. However, the prevalence in private hospitals has not been examined yet. The aim of this study was to investigate the prevalence of anti-HCV antibody and the subtype distribution in patients with hemodialysis in a private hospital in Surabaya, Indonesia. Sera were obtained from 41 hemodialysis patients in a private hospital in Surabaya. The positive prevalence of anti-HCV antibody was carried out by the enzyme-linked immunosorbent assay (ELISA). Anti-HCV-positive sera were subjected to reverse transcription-PCR (RT-PCR) to detect HCV RNA and then direct sequencing. The HCV subtype was examined by phylogenetic analysis. Twenty five patients (61%) out of 41 were positive for anti-HCV antibody, and HCV-RNA was detected in 19 patients. The positive prevalence of anti-HCV antibody was 7.7% (one out of 13 patients) among patients who had undergone hemodialysis for less than one year, whereas it was 85.7% (24 out of 28 patients) among patients who had undergone hemodialysis for over one year. Phylogenetic analysis revealed HCV-1a (52.6%) was the most common subtype, followed by 1b (15.8%), 1c (15.8%), 2a (5.3%), and 3k (5.3%). In conclusion, the prevalence of HCV infection among hemodialysis patients in a private hospital was as high as that in general hospitals. The predominant subtype was HCV-1a, which is in accordance with the previous studies in general hospitals in Surabaya, Indonesia.

Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC) that can occasionally lead to the shortening of life expectancy. We aimed to make a new and more accurate prognostic model taking into account the course of disease after TACE. METHODOLOGY/PRINCIPAL FINDINGS: We performed a prospective cohort study involving 100 HCC patients who underwent TACE at Kobe University Hospital. Indirect calorimetry and blood biochemical examinations were performed before and 7 days after TACE. Time-dependent and time-fixed factors associated with 1-year mortality after TACE were assessed by multivariate analyses. A predictive model of 1-year mortality was established by the combination of odds ratios of these factors. Multivariate analyses showed that the ratio of non-protein respiratory quotient (npRQ) (7 days after/before TACE) and Cancer of Liver Italian Program (CLIP) score were independent factors of 1-year mortality after TACE (p = 0.014 and 0.013, respectively). Patient-specific 1-year mortality risk scores can be calculated by summarizing the individual risk scores and looking up the patient-specific risk on the graph. CONCLUSIONS: The short-term reduction of npRQ was a time-dependent prognostic factor associated with overall survival in HCC patients undergoing TACE. CLIP score was a time-fixed prognostic factor associated with overall survival. Using the prediction model, which consists of the combination of time-dependent (npRQ ratio) and time-fixed (CLIP score) prognostic factors, 1-year mortality risk after TACE would be better estimated by taking into account changes during the course of disease.

Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]≥4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]≥4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N≥2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection.The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]≥4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N≥2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy.

Background: Sofosbuvir plus ribavirin (RBV) therapy showed higher sustained virological response at 12 weeks after treatment (SVR12) than pegylated interferon (peg-IFN) plus RBV; however, liver function, fibrosis, and hepatocellular carcinoma markers have not been assessed so far. Summary: Patients ( n = 21) receiving Sofosbuvir plus RBV and those ( n = 24) receiving peg-IFN plus RBV were enrolled in this study. Changes in alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels, platelet (PLT) counts, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) in both groups were assessed in patients achieving SVR12. Also, fibrosis regression was assessed using pathophysiological biomarkers, such as hyaluronic acid, bone morphogenetic protein 7 (BMP-7), and connective tissue growth factor (CTGF) in the Sofosbuvir plus RBV group. In both groups, while the reduction in ALT levels was significant that of AFP was not. Compared with the baseline, although serum PLT count at the end of treatment (EOT) was significantly higher in the Sofosbuvir plus RBV group, it was significantly lower in the peg- IFN plus RBV group. Although a significant decline in fibrosis markers such as FIB-4 and APRI was observed between the baseline and at EOT in the Sofosbuvir plus RBV group, no significant change of these markers was observed in the peg-IFN plus RBV group. Moreover, BMP-7 and CTGF were significantly lower at EOT than the baseline in the Sofosbuvir plus RBV group. Key Message: The treatment with Sofosbuvir plus RBV results in not only a higher SVR, but also improves the liver function and the degree of fibrosis. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. Aim: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. Materials and Methods: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an inhouse, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-β, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. Results: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs ( p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype ( p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels ( p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs ( p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power ( p = 0.288). Serum IFN-α and IFN-β were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). Conclusion: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC. [ABSTRACT FROM AUTHOR]

The purpose of antiviral therapy in chronic hepatitis B (CHB) is generally to achieve a decrease and ultimately disappearance of HBs antigen (HBsAg). Interferon (IFN) therapy of CHB appears to be less effective in Asian countries than in European countries, and the advantage of IFN and nucleotide(s) analog (NA) combination therapy has yet to be fully investigated. The present study focused on the factors associated with a decrease in HBs antigen following IFN monotherapy or IFN + NA combination therapy. A total of 35 patients with CHB who received IFN-based therapy (mean ± standard deviation age 36.7±8.5 years; 27 males and 8 females) were enrolled in this study. Of the 35 patients, 21 patients received pegylated IFN monotherapy and 14 patients received IFN and adefovir (ADV) combination therapy. We examined the factors associated with reductions in the HBsAg titer of >1.0 log IU/ml from the initial HBsAg titer to the end of treatment and to 24 weeks after treatment. Although 13 patients (37%) had a reduction in HBsAg of >1.0 IU/ml at the end of treatment, it was only maintained to 24 weeks after treatment in 7 patients (20%). The HBV core-related antigen (HBcrAg) titer before treatment was significantly higher in patients with a decrease in HBsAg at the end of treatment than in patients without a decrease in HBsAg (6.56±0.78 vs. 5.30±1.66 log IU/ml, P<0.05). Moreover, an increase in alanine aminotransferase (ALT) of >2 times from baseline occurred significantly more frequently in patients with a decrease in HBsAg (62 vs. 14%, P<0.05). The proportion of patients with a decrease in HBsAg was significantly greater in patients who received IFN monotherapy than in patients who received IFN and ADV combination therapy (43 vs. 29%, P<0.05). The present results revealed that the HBcr antigen titer before therapy and an on-treatment elevation of ALT (indicative of host instruction flare) are important factors associated with a decrease in HBsAg titers after IFN-based therapy. The efficacy of IFN and ADV combination therapy was not apparent in terms of a reduction in the HBsAg titer. [ABSTRACT FROM AUTHOR]

Patients undergoing hemodialysis are at increased risk of infection with blood-borne viruses, including GB virus C (GBV-C) and torque teno virus (TTV). However, the prevalence and genotypic distribution of these viruses in the assessed patients undergoing hemodialysis remains unclear. The present study investigated these issues and the possibility of nosocomial transmission among patients undergoing hemodialysis in a unit in Yogyakarta, Indonesia. GBV-C RNA was detected in 92/161 patients (57.1%) by nested reverse-transcription polymerase chain reaction. Phylogenetic analysis of the 5'-untranslated region (UTR) classified the GBV-C isolates into genotypes 6 (85%), 2 (8%), 4 (6%), and 3 (1%). TTV DNA was detected in all patients by the amplification of the 5'-UTR and open reading frame-1 (ORF1) by nested and semi-nested polymerase chain reaction. Phylogenetic analysis based on the ORF1 revealed that genotype 1 was dominant (84%), followed by genotypes 2 (10%) and 3 (6%). The greater prevalence of GBV-C genotype 6 in patients undergoing hemodialysis compared with the general population and the identical sequences observed in multiple isolates provided strong evidence of patient-to-patient transmission. The prevalence of TTV in hemodialysis patients was similar to that observed in the general population, and only one pair of TTV isolates was identical. These results indicated that nosocomial infection was not the main cause of the high prevalence of TTV in patients undergoing hemodialysis. In conclusion, GBV-C and TTV infections are common in patients undergoing hemodialysis in Yogyakarta, Indonesia, and transmission is likely to be nosocomial in the case of GBV-C infection. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIM: Alcoholic liver disease (ALD) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Des-gamma-carboxy prothrombin (DCP) is elevated in many patients with HCC, but also in severe alcoholics without HCC. We aimed to clarify whether the DCP/NX-DCP ratio (NX-DCP-R) could have a high specificity in ALD patients without HCC. METHODS:We performed a prospective cohort study on a total of 703 consecutive outpatients of liver diseases including severe alcoholics and healthy volunteers, who underwent blood biochemical examinations at Kobe University Hospital. Serum DCP was measured by electrochemiluminescence immunoassay (ECLIA) using a monoclonal antibody, MU-3. A novel parameter, serum NX-DCP, which represents predominantly DCP caused by reduced vitamin K availability, was also measured by ECLIA using monoclonal antibodies P-16 and P-11. The diagnostic accuracy of DCP and NX-DCP-R in patients with and without excessive alcohol intake was statistically examined. RESULTS: DCP was significantly higher in alcoholics than in non-alcoholics (p = 0.005), whereas the NX-DCP-R did not differ between alcoholics and non-alcoholics (p = 0.375). DCP was significantly increased in the serum of each patient with alcoholic hepatitis and alcoholic cirrhosis (p < 0.05), whereas the NX-DCP-R was not increased (p > 0.05). CONCLUSIONS: NX-DCP-R, but not DCP, was not increased in alcoholics without HCC. As for negative screening for HCC, the specificity of the NX-DCP-R in alcoholics without HCC was better than that of DCP in alcoholics without HCC, and so could be a useful negative screening tool for HCC in millions of alcoholics worldwide. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) from gibbons was characterized, and the possibility of horizontal transmission between gibbons and humans was examined in a gibbon rehabilitation center in Central Kalimantan, Indonesia. Ten gibbons that were positive for the hepatitis B surface antigen (HBsAg) on arrival and 13 caretakers for those gibbons were included in this study. The duration of stay at the rehabilitation center ranged from 1 to 10 years. Serological and molecular analyses were performed. Six gibbons were positive for HBsAg, whereas HBV DNA was detected in all ten of the gibbons sampled. On the other hand, HBsAg was detected in only 1 of the 13 caretakers. HBV samples from seven gibbons and from the one infected human were chosen for complete genome sequencing. A phylogenetic analysis revealed that the cluster of gibbon strains in this study was distinct from strains previously reported from other countries. In the pre- S1 region, we found a unique amino acid residue substitution (P89K), three insertions between T87 and L88 in the genomes of three gibbons, and a 33-nucleotide deletion at the start of pre-S1 that is common in non-human primates. The caretaker sample was identified as HBV subgenotype B3, the most common type in Indonesia. For the complete HBV sequences, the similarity between gibbons in this study and other non-human primate and human HBV isolates was 90–91.9 % and 85.5–89.6 %, respectively. In conclusion, the gibbon HBV genotype was influenced by geographic location and species. To the best of our knowledge, this is the first report characterizing the HBV genes and genomes of indigenous gibbons in Indonesia. [ABSTRACT FROM AUTHOR]

Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a significant global health problem. The two viruses are transmitted with high efficacy via blood-to-blood contact, mainly intravenous drug use (IVDU), whereas HCV is less easily transmitted sexually. Antibody testing is the main screening method for HCV infection, although it may not be the optimal option for HIV infection. The aim of this study was to investigate HCV infection in HIV-positive patients, with and without a detectable anti-HCV antibody response. A total of 187 plasma samples were obtained from HIV-positive patients in Surabaya, Indonesia and examined for anti-HCV [HCV enzyme immunoassay (EIA) 3.0], HCV genotype/subtype [reverse transcription-polymerase chain reaction (RT-PCR) using primers targeting a part of NS5B/5'UTR followed by sequencing] and HCV viral load (quantitative RT-PCR). A total of 119 patients (63.6%) were found to be anti-HCV-positive and, among these, HCV RNA was detected in 73 (61.3%), with HCV-1a as the predominant subtype (31.5%). Of the 68 anti-HCV-negative samples, HCV RNA was detected in 26/68 (38.2%) mostly as the HCV-3a subtype (50%). High HCV viral loads were more common among the HCV-seropositive patients. The HCV-seropositive samples with detected HCV RNA were mostly obtained from HIV-positive patients with parenteral transmission (IVDU) (76.7%); however, the HCV-seronegative samples with detected HCV RNA were mostly from patients who had acquired HCV through heterosexual transmission (61.5%). In conclusion, HIV-positive patients were at high risk of becoming co-infected with HCV and several remained HCV-seronegative. Furthermore, there may exist differences in HCV seropositivity and subtypes between HIV-positive patients who acquired HCV sexually and those who acquired HCV parenterally. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) subgenotypes Cs (C1) and Ce (C2) are common in East Asia. To investigate the genomic difference of HBV genotype C between two separated regions, 50 subgenotype Cs‐infected Vietnamese and 70 subgenotype Ce‐infected Japanese patients were enrolled for analysis. The patients were categorized to either a hepatocellular carcinoma group (HCC) or a non‐HCC group including liver cirrhosis, chronic hepatitis, and asymptomatic carriers. HBV serology, HBV‐DNA level, and variations in core promoter/pre‐core region were examined. Phylogenetic analysis based on the full genome sequences and nucleotide sequences partly in the S gene and in the P gene revealed that all Japanese strains (70/70) were subgenotype Ce, and nearly all of the Vietnamese strains (50/51) were subgenotype Cs, excluding one subgenotype C5. C1858 and G1775 were common in the Vietnamese (64% and 40%) but not in the Japanese (0%). The prevalence of C/A1753 in Vietnamese was higher than that in the Japanese (32% vs. 17.1%), however the frequency of A1896 in the Japanese was significantly higher (32.9% vs. 12%, P < 0.05). Most of the Vietnamese patients with HCC had a high level of HBV‐DNA, the Japanese HCC had a relatively low level. In the Vietnamese, C/A1753 and C1858 were associated closely with T1762A1764, higher HBV‐DNA levels and higher HCC incidence. The multivariate analysis revealed that male, T1653 and C/A1753 were independent risk factors for HCC. The subgenotypes and unique mutations of HBV genotype C in the Vietnamese and Japanese differed, and C/A1753 and C1858 variants might play a role in the pathogenesis of liver disease in Vietnamese patients. J. Med. Virol. 79:1293–1304, 2007. © Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

The Solomon Islands is a multi‐ethnic nation with a high rate of hepatitis B virus (HBV) infection. The prevalence relative to ethnicity was examined in relation to HBV infection, genotypes, and mutations. Asymptomatic populations (n = 564, 308 Melanesian and 118 Micronesian) from the Western Province were enrolled. Positive samples for Hepatitis B surface antigen (HBsAg) were examined for serological status, genotyping, viral load, and mutations of the basic core promoter (BCP) and pre‐core (Pre‐C) regions. The positive rate for HBsAg was 21.5%. The major Melanesian genotype was C (HBV/C), whereas the major Micronesian genotype was D (HBV/D). The prevalence of Hepatitis B e antigen (HBeAg) in serum was lower in carriers of HBV/D than of HBV/C. While the prevalence of the BCP mutation (T1762A1764) tended to be higher in HBV/C, that of the Pre‐C mutation (T1846) was significantly higher in HBV/D (P < 0.0001). Genetic distance and phylogenetic analyses based on complete genome sequences were also carried out for two strains of HBV/C and two strains of HBV/D, and the findings were compared with those in the DDBJ/EMBL/GenBank database. The full‐length sequence revealed that strains from the Solomon Islands were classified into subgenotype C3 (HBV/C3) and D4 (HBV/D4), and that the HBV/D strains were related closely to those from Papua New Guinea. HBV infection in the Solomon Islands is hyperendemic, and the genotype is ethnicity‐specific. HBeAg appears to clear from the serum in young adulthood in HBV/D infection, which may be influenced by genotype‐dependent features in relation to viral mutations. J. Med. Virol. 79:229–235, 2007. © 2007 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

Interferon (IFN)-alpha treatment is a common therapy for chronic viral hepatitis and contributes to preventing hepatocarcinogenesis. However, it is not clear whether IFN-alpha directly inhibits the clonal expansion of pre-neoplastic hepatocytes. To clarify the mechanism by which IFN-alpha prevents hepatocarcinogenesis, we examined the effect of IFN-alpha in a chemically induced hepatocarcinogenesis model initiated by diethylnitrosamine (DEN) and promoted by 2-acetylaminofluorene (2-AAF) and partial hepatectomy, in which hepatocellular carcinoma (HCC) arises through pre-neoplastic foci without inflammation or fibrosis. The protocols of IFN-alpha administration were started simultaneously with chemical initiation and lasted for either 4 or 40 weeks. The pre-neoplastic foci and neoplastic HCC were evaluated at 4 or 40 weeks after chemical initiation, respectively. The effects of IFN-alpha were assessed by the expression of tumor-related genes and cell cycle-related genes in the pre-neoplastic foci, using immunohistochemistry and reverse transcriptionpolymerase chain reaction (RTPCR). As a result of IFN-alpha treatment, the numbers and average volume of pre-neoplastic foci were reduced. The proliferating cell nuclear antigen index and the expression of G1 cyclins were also reduced in the pre-neoplastic foci in the IFN-treated group. The expression of p21, which is an inhibitor of cyclin-kinase complexes was higher in the foci of the IFN-treated group, while p53 expression was not altered in this group, compared with the control group. IFN-alpha also suppressed the tumor development at 40 weeks after initiation. And in the long-term IFN-alpha-treated group, both the tumor numbers and average tumor size were markedly more reduced than those in the short-term-treated group. Therefore, it was demonstrated that longer treatment with IFN-alpha was more effective, compared with shorter treatment. In conclusion, it was shown that IFN-alpha directly prevented and delayed hepatocarcinogenesis through the suppression of pre-neoplastic cell proliferation and that it may partially depend on p21 induction through a p53-independent pathway. [ABSTRACT FROM AUTHOR]

Aim: To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice., Methods: The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed., Results: The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients' GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01)., Conclusion: Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest.

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV-infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia.

Hepatitis B virus (HBV) infection is major global issue, because chronic HBV infection is strongly associated with liver cancer. HBV spread worldwide with various mutations and variations. This variability, called quasispecies, is derived from no proof-reading capacity of viral reverse transcriptase. So far, thousands of studies reported that the variety of genome is closely related to the geographic distribution and clinical characteristics. Recent technological advances including capillary sequencer and next generation sequencer have made in easier to analyze mutations. The variety of HBV genome is related to not only antigenicity of HBs-antigen but also resistance to antiviral therapies. Understanding of these variations is important for the development of diagnostic tools and the appropriate therapy for chronic hepatitis B. In this review, recent publications in relation to HBV mutations and variations are updated and summarized.

Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-α has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long-term effect of IFN-α on CHB has not yet been elucidated. The ability of IFN-α treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-α treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-α relative to nucleoside/nucleos(t)ide analogs.