A Comparison of Clinical Manifestations and Outcomes between Acute Sporadic Hepatitis A and Hepatitis E Infections in Thailand.

Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections often present as acute hepatitis with prodromal symptoms. These infections, transmitted via the oral-enteral route, constitute significant public health challenges, particularly in developing countries with subpar sanitary systems. The aim of the study was to describe the clinical manifestations, laboratory findings, and outcomes of hepatitis A and hepatitis E infections in Thailand. We conducted a retrospective chart review and analysis of 152 patients diagnosed with acute hepatitis A or hepatitis E from January 2007 to August 2018 at Siriraj Hospital. The hepatitis E cohort was older with a greater prevalence of comorbidities (hypertension, diabetes mellitus, chronic kidney disease, chronic hepatitis B, and post-kidney transplantation status) than the hepatitis A cohort. While the majority of hepatitis A patients presented with fever (98%) and jaundice (96%), these symptoms were less pronounced in hepatitis E patients. Furthermore, hepatitis A patients exhibited significantly higher aminotransferase and total bilirubin levels. However, clinical outcomes, such as hospitalization rates, progression to acute liver failure, and mortality, were comparable across both groups. In conclusion, although the clinical manifestations of hepatitis A and hepatitis E were similar, fever and jaundice were more prevalent and aminotransferase and bilirubin levels were higher in the HAV-infected group.

A Novel and Simplified Score for Determining Treatment Eligibility for Patients with Chronic Hepatitis B.

Background: International guidelines for hepatitis B infection (HBV) recommend initiating antiviral treatment based on viral replication with inflammation or fibrosis. HBV viral loads and liver fibrosis measurements are not widely available in resource-limited countries. Aim: To develop a novel scoring system for the initiation of antiviral treatment in HBV-infected patients. Methods: We examined 602 and 420 treatment-naïve, HBV mono-infected patients for derivation and validation cohorts. We performed regression analysis to identify parameters associated with the initiation of antiviral treatment based on the European Association for the Study of the Liver (EASL) guidelines. The novel score was developed based on these parameters. Results: The novel score (HePAA) was based on HBeAg (hepatitis B e-antigen), the platelet count, alanine transaminase, and albumin. The HePAA score showed excellent performance, with AUROC values of 0.926 (95% CI, 0.901-0.950) for the derivation cohort and 0.872 (95% CI, 0.833-0.910) for the validation cohort. The optimal cutoff was ≥3 points (sensitivity, 84.9%; specificity, 92.6%). The HePAA score performed better than the World Health Organization (WHO) criteria and the Risk Estimation for HCC in Chronic Hepatitis B (REACH-B) score, and it performed similarly to the Treatment Eligibility in Africa for HBV (TREAT-B) score. Conclusions: The HePAA scoring system is simple and accurate for chronic hepatitis B treatment eligibility in resource-limited countries.

Characteristics of Drug-induced Liver Injury in Chronic Liver Disease: Results from the Thai Association for the Study of the Liver (THASL) DILI Registry.

Background and Aims: The impact of drug-induced liver injury (DILI) on patients with chronic liver disease (CLD) is unclear. There are few reports comparing DILI in CLD and non-CLD patients. In this study, we aimed to determine the incidence and outcomes of DILI in patients with and without CLD. Methods: We collected data on eligible individuals with suspected DILI between 2018 and 2020 who were evaluated systematically for other etiologies, causes, and the severity of DILI. We compared the causative agents, clinical features, and outcomes of DILI among subjects with and without CLD who were enrolled in the Thai Association for the Study of the Liver DILI registry. Subjects with definite, or highly likely DILI were included in the analysis. Results: A total of 200 subjects diagnosed with DILI were found in the registry. Of those, 41 had CLD and 159 had no evidence of CLD in their background. Complementary and alternative medicine (CAM) products were identified as the most common class of DILI agents. Approximately 59% of DILI in the CLD and 40% in non-CLD group were associated with CAM use. Individuals with pre-existing CLD had similar severity including mortality. Twelve patients (6%) developed adverse outcomes related to DILI including seven (3.5%) deaths and five (2.5%) with liver failure. Mortality was 4.88% in CLD and 3.14% in non-CLD subjects over median periods of 58 (8-106) days and 22 (1-65) days, respectively. Conclusions: In this liver disease registry, the causes, clinical presentation, and outcomes of DILI in subjects with CLD and without CLD patients were not different. Further study is required to confirm our findings.

Prognostic Relevance of Metabolic Dysfunction-associated Steatohepatitis for Patients with Chronic Hepatitis B.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is prevalent in patients with chronic hepatitis B (CHB). The effect of the histologic MAFLD phenotype on long-term CHB outcomes is unknown. We performed a longitudinal study to determine the prognostic relevance of biopsy-proven hepatic steatosis and steatohepatitis for CHB patients. Methods: Clinical and laboratory data were obtained from CHB patients who underwent liver biopsy during 2002-2008 and were treated with antiviral drugs. A hepatopathologist reviewed the biopsy specimens. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (aHR) of outcomes, including all-cause mortality, liver transplantation, and liver-related events. Results: In accordance with Brunt's classification, 408 patients had steatohepatitis (n=34), "steatosis but not steatohepatitis" (n=118), or "non-steatosis" (n=256). All steatohepatitis patients had features of metabolic dysfunction. Over a mean follow-up of 13.8±3.1 years, 18 patients died or underwent liver transplantation. In multivariate-adjusted analysis, steatohepatitis (aHR, 6.37; 95% confidence interval [CI]: 1.59-25.5) compared with non-steatosis and advanced fibrosis (aHR, 11.3; 95% CI: 1.32-96.3) compared with no fibrosis were associated with overall mortality/liver transplantation. Thirty-five patients developed 43 liver-related events, among which 32 were hepatocellular carcinoma. These events were associated with steatohepatitis (aHR, 5.55; 95% CI: 2.01-15.3) compared with non-steatosis and advanced fibrosis (aHR, 6.23; 95% CI: 1.75-22.2) compared with no fibrosis. The steatosis but not steatohepatitis group had a non-significantly higher risk of overall mortality and liver-related events. Conclusions: Metabolic dysfunction-associated steatohepatitis increased the risk of long-term mortality/transplantation and liver-related events in CHB patients.

Effect of a 12-week home-based exercise training program on aerobic capacity, muscle mass, liver and spleen stiffness, and quality of life in cirrhotic patients: a randomized controlled clinical trial.

BACKGROUND: Physical inactivity and sarcopenia are two important predictors associated with increased morbidity and mortality in patients with cirrhosis. At present, the benefit of a home-based exercise training program is not well established in cirrhotic patients. The main objective of this study was to evaluate the effect of a 12-week home-based exercise training program on aerobic capacity in cirrhotic patients. METHODS: This is a randomized controlled study. Patients with compensated cirrhosis were randomized by a block of 4 with concealed allocation to the home-based exercise training (n = 20) or control (n = 20). Both groups received protein supplementation (9 g/day) for 12 weeks. The home-based exercise training program included several aerobic/isotonic moderate-intensity continuous training exercises for 40 min per session, at least four times a week, with a total duration of 12 weeks. The heart rate was continuously monitored using a Garmin® watch. In the control group, patients received exercise instruction without active encouragement and continuous monitoring. The primary outcome was a change in the 6-min walk test from baseline. Secondary outcomes were the difference in thigh muscle thickness, liver stiffness, spleen stiffness, and quality of life. RESULTS: A total of 40 patients were enrolled prospectively. The mean age was 56.3 ± 7.8 years, with a male predominance of 65%. The mean body mass index was 25.23 ± 3.0 kg/m2, and all were Child-Pugh A. Chronic hepatitis B or C was the primary cause of cirrhosis. The baseline values were a 6-min walk test of 475 ± 70 m, liver stiffness of 15.3 ± 9.3 kPa, spleen stiffness of 29.8 ± 21.7 kPa, and thigh muscle thickness (average compression index) of 0.64 ± 0.2 cm/m2. All baseline characteristics between the two groups were not different except the mean muscle mass which was significantly higher in the home-based exercise training group (p = 0.03, 95% CI 0.01 to 0.17). At the end of the study, no significant difference in the 6-min walk test was observed (p = 0.36, 95% CI -15.5 to 41.7). Liver stiffness measurement significantly improved in both groups, but no significant difference between groups was demonstrated (p = 0.77, 95% CI -1.3 to 1.8). Thigh muscle thickness was not different between groups. The fatigue domain of the quality of life index was significantly improved in the home-based exercise training group compared with the control group (p = 0.05, 95% CI 0.00 to 0.67). No adverse events occurred in a home-based exercise training program. CONCLUSIONS: A 12-week moderate-intensity home-based exercise training program in compensated cirrhotic patients significantly improved the fatigue domain of the quality of life index without an increase in adverse events. However, no benefit in terms of aerobic capacity, thigh muscle mass, liver stiffness, and spleen stiffness was demonstrated. TRIAL REGISTRATION: Thai Clinical Trials Registry number TCTR20190926002, 26/09/2019 (Retrospectively registered).

Comparison of viral control between two tenofovir dose reduction regimens (300 mg every 48 hours versus 300 mg every 72 hours) in chronic hepatitis B patients with moderate renal impairment from tenofovir-induced renal dysfunction.

Long-term use of tenofovir disoproxil fumarate (TDF) can induce renal dysfunction that requires TDF dose reduction. Previous studies showed that systemic drug use exerts a threefold higher risk of moderate renal impairment. This study aimed to compare viral control between two tenofovir dose reduction regimens in chronic hepatitis B (CHB) patients with moderate renal impairment from TDF-induced renal dysfunction. This noninferiority, randomized controlled study was conducted at the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Virologically suppressed CHB patients treated with TDF who had moderate renal impairment were randomly allocated to receive TDF 300 mg either every 48 or 72 hours. Forty-six patients (67.4% male) with a mean age of 62.8 ± 7.8 years were enrolled. Among all patients, 34.8% were HBeAg-positive, and 23.9% had cirrhosis. All included patients completed 12 months of follow-up. No patients had virological breakthrough. After dose reduction, estimated glomerular filtration rate (eGFR) was improved in both groups, but a higher proportion of patients had an eGFR > 60 mL/min/1.73 m2 in the TDF every 72 hours group. Other renal parameters, including serum phosphate, tubular maximal reabsorption for phosphate per GFR, urine protein-to-creatinine ratio, urine sugar and urine neutrophil gelatinase-associated lipocalin, were not significantly different between groups. Among TDF-treated CHB patients with TDF-induced moderate renal impairment, more aggressive dose reduction in TDF from every 48 hours to every 72 hours did not affect virological breakthrough. A higher proportion of patients in the TDF every 72 hours group had improvement in renal function.

Phylogenetic analysis of two new complete genomes of the hepatitis E virus (HEV) genotype 3 from Thailand.

Hepatitis E virus (HEV) is a causative agent of acute viral hepatitis globally. Evolutionary phylogeny classifies the HEV into eight genotypes that correlate with the viral transmission. Only four genotypes have been proven to be responsible for transmission in humans. However, there has been no report on the genomics and genotyping of HEV in Thailand during the past ten years. Here, we identified the genotype distributions of the Thai isolates of HEV and we sequenced two HEV genomes. We screened for 18 Thai isolates of HEV from Siriraj Hospital in Bangkok, from 2014-2016. The HEV genomes were sequenced from the serum and feces of a patient. The results showed that all Thai isolates of HEV were identified as genotype 3 (HEV-3). The ORF2 and genome phylogenies suggested two subgenotypes, called 3.1 and 3.2. The Thai isolates of HEV were frequently found in the subgenotype 3.1. The genome sequences of the two Thai isolates of HEV from the serum and fecal samples of the same patient showed 91% nucleotide similarity with the HEV genotype 3. Comparisons between the HEV genome and the ORF2 phylogenies illustrated that the ORF2 tree can be used to identify HEV genotypes, but it has less phylogenetic power for the HEV evolution. The two new genome sequences of HEV-3 from Thailand could contribute valuable information to the HEV genome study. (226 words).

Reverse transcriptase droplet digital PCR vs reverse transcriptase quantitative real-time PCR for serum HBV RNA quantification.

Serum hepatitis B virus (HBV) RNA is a novel marker reflecting the activity of covalently closed circular DNA. However, the methodology for detecting HBV RNA has been a technical challenge. In this study, the performance of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for quantifying HBV RNA was compared with that of reverse transcription quantitative real-time PCR (RT-qPCR) in serum samples collected from treatment-naïve patients with different phases of chronic hepatitis B (CHB). A total of 417 serum samples, including 136 HBeAg-positive CHB and 281 HBeAg-negative CHB were examined. HBV RNA levels measured by RT-ddPCR and RT-qPCR showed a high degree of linearity and quantitative correlation. The limit of detections of RT-ddPCR and RT-qPCR assays were 102 and 103 copies/mL, respectively. Our results also demonstrated that RT-ddPCR was superior to RT-qPCR in terms of its consistency for quantifying HBV RNA across all concentrations. In the HBeAg-positive group, serum HBV RNA levels based on RT-ddPCR were moderately correlated with HBV DNA (r = 0.591, P < .001) and HBsAg (r = 0.502, P < .001). Among patients with HBeAg-negative CHB, serum HBV RNA levels were moderately correlated with HBV DNA (r = 0.603, P < .001) but had weak correlation with HBsAg (r = 0.203, P = .001). In summary, RT-ddPCR could enhance the sensitivity of serum HBV RNA detection, particularly among the HBeAg-negative group with low viral loads. Thus, RT-ddPCR could serve as an optimal method for HBV RNA quantification in clinical practice.

Evaluation of aspartate aminotransferase to platelet ratio index and fibrosis 4 scores for hepatic fibrosis assessment compared with transient elastography in chronic hepatitis C patients.

BACKGROUND AND AIM: Fibrotic stage (FS) assessment is essential in chronic hepatitis C treatment cascade. Liver stiffness measurement (LSM) using transient elastography (TE) is reliable and correlated with liver biopsy. However, TE may not be widely available. This study aimed to evaluate the diagnostic performances of aspartate aminotransferase to platelet ratio index (APRI) and fibrosis 4 (FIB-4) scores compared with TE. METHODS: We conducted a multicenter, cross-sectional study, including all chronic hepatitis C virus (HCV) monoinfection patients with successful and reliable LSM, at 10 centers in Thailand from 2012 to 2017. Characteristics and laboratory data within 3 months of TE were retrospectively reviewed. Using TE as a reference standard, the diagnostic performances of APRI and FIB-4 were evaluated. TE cut-off levels of 7.1 and 12.5 kPa represented significant fibrosis (SF) and cirrhosis, respectively. RESULTS: The distribution of FS by TE in 2000 eligible patients was as follows: no SF 28.3%, SF 31.4%, and cirrhosis 40.3%. APRI ≥ 1 provided 70.1% sensitivity and 80.6% specificity, with an area under the receiver operator characteristics curve (AUROC) of 0.834 for cirrhosis. The specificity increased to 96.3% when using a cut-off level of APRI ≥ 2. FIB-4 ≥ 1.45 provided a sensitivity, specificity, and AUROC of 52.4%, 91.0%, and 0.829 for cirrhosis, respectively. For SF, APRI performed better than FIB-4, with an AUROC of 0.84 versus 0.80 (P < 0.001). APRI score < 0.5 and FIB-4 score > 1.45 yielded sensitivities of 82.3% and 74.4% and specificities of 65.4% and 69.8%, respectively. CONCLUSIONS: APRI and FIB-4 scores had good diagnostic performances for FS assessment compared with TE, especially for cirrhosis. APRI may be used as the noninvasive assessment in resource-limited settings for HCV patients' management.

A Nationwide Survey of the Seroprevalence of Hepatitis E Virus Infections Among Blood Donors in Thailand.

Hepatitis E virus (HEV) is a common cause of acute hepatitis infections. Our previous 3-year study at two large Thai hospitals established an occurrence of 4-5% of HEV infections from swine HEV genotype 3 in suspected acute hepatitis patients, with the high incidence in older adults. This study was a serosurvey to determine the prevalence of HEV infections among Thai adults. We obtained sera from 630 healthy blood donors with a median age of 38 (18-64) years who attended Thai Red Cross transfusion units throughout Thailand. The donors were domiciled in 16 provinces in the northern (n = 159), central (n = 193), northeastern (n = 158), and southern (n = 120) regions. The seroprevalence of IgG antibody to HEV (anti-HEV) was determined by the EUROIMMUN test kit, using indirect enzyme-linked immunosorbent assay (ELISA) based on recombinant antigens derived from ORF2 of HEV genotypes 1 and 3. Demographic data, including information related to HEV infection risk (the number of pigs and the proportion of Muslims in each province), were also obtained. The overall anti-HEV prevalence among Thai adults was 29.7%. The frequencies of anti-HEV found in the northern (28.9%, 95% confidence interval [CI] = 22.4-36.4), northeastern (34.8%, 95% CI = 27.8-42.5), and central (35.8%, 95% CI = 29.3-42.7) regions were similar, whereas the frequency in the southern (14.2%, 95% CI = 9.0-21.5) region, known to have a large Muslim population, was low. An increasing frequency of the specific antibody was observed among the elderly. A low HEV infection rate was associated with an Islamic population where there are low number of pigs and low swine consumption. Furthermore, the higher anti-HEV incidences in the northeastern provinces might relate to the local cultural practice of consuming undercooked pork. Besides the need for an HEV vaccination in the future, there is a requirement for rapid early diagnosis; the undertaking of prevention-management campaigns might also reduce the number of infected patients.

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon-based therapy in patients with hepatitis B e antigen-negative chronic hepatitis B.

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long-term outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG-IFN)-based therapy. Serial serum samples from 91 patients with HBeAg-negative CHB previously treated with PEG-IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post-treatment follow-up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre-treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut-off 2.0 log10  copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut-off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log10 copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG-IFN-based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising "stopping rule" in patients infected with HBV genotypes B or C.

Validation of the prognostic models in acute-on-chronic liver failure precipitated by hepatic and extrahepatic insults.

BACKGROUND: Patients with acute-on-chronic liver failure (ACLF) precipitated by hepatic injury and extrahepatic insults had distinct clinical phenotypes, and prognosis. This study aimed to validate prognostic models for ACLF and to explore their discriminative abilities in ACLF population categorized by the etiologies of precipitating events. METHODS: This study collected data from 343 consecutive cirrhotic patients hospitalized with the diagnosis of ACLF according to the EASL-CLIF-Consortium definition. The discrimination abilities of prognostic models at the onset of ACLF were tested with the concordance index and area under the receiver operating characteristic curve. RESULTS: Among the entire cohort, 103 patients survived with medical management, nine patients were transplanted, and 231 patients died without liver transplantation. The predictive accuracy of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) for 28-day mortality was similar to the CLIF Consortium Organ Failure (CLIF-C OF) but significantly higher than the CLIF Consortium ACLF, the Child-Turcotte-Pugh, the model for end-stage liver disease (MELD), the MELD-sodium, the integrated MELD, and the Acute Physiology and Chronic Health Evaluation II. Of note, 44 patients had acute hepatic insult triggering ACLF (hepatic-ACLF), 244 were exclusively precipitated by bacterial infection or gastrointestinal bleeding (extrahepatic-ACLF), and 55 cases had no any identifiable potential precipitating events. Patients with hepatic-ACLF had significantly higher 28-day mortality than extrahepatic-ACLF patients. The CLIF-SOFA and CLIF-C OF displayed the highest accuracy significantly outperforming other scoring systems in predicting mortality among patients with hepatic-ACLF and those with extrahepatic-ACLF. CONCLUSION: The CLIF-SOFA and simpler CLIF-C OF are reliable measures of mortality risk in ACLF patients precipitated by either hepatic or extrahepatic insults. Both validated models could be used to stratify the risk of death and improve management of ACLF.

Next generation sequencing identifies baseline viral mutants associated with treatment response to pegylated interferon in HBeAg-positive chronic hepatitis B.

Current data of hepatitis B virus (HBV) variants associated with treatment outcome identified by next generation sequencing (NGS) are limited. This study was aimed at determining the role of baseline sequence variations in the enhancer II (EnhII), basal core promotor (BCP) and pre-core (PC) regions of HBV genotype C in patients treated with pegylated interferon (PEG-IFN). Patients with HBeAg-positive chronic hepatitis B (CHB) treated with 48-week PEG-IFN were enrolled. Combined response (CR) at week 96 was defined by HBeAg seroconversion plus HBV DNA < 2000 IU/mL and HBsAg < 1000 IU/mL. Pre-treatment viral mutations were characterized by Sanger sequencing and NGS (Miseq Illumina platform). Among 47 patients (32 male, mean age 32.4 years), CR was achieved in 12 (25.5%) individuals. Overall, NGS was superior to Sanger sequencing in detecting mutations (61.7% vs. 38.3%, P < 0.001). Based on NGS, the prevalence of T1753V (T1753C/A/G) and A1762T/G1764A variants were significantly lower in responders compared to non-responders (8.3% vs. 51.4%, P = 0.009 and 33.3% vs. 68.6%, P = 0.032, respectively). No significant difference between groups was found regarding C1653T and G1896A mutants. The absence of T1753V and A1762T/G1764A mutations were factors associated with CR (OR 11.65, 95%CI 1.36-100.16, P = 0.025, and OR 4.36, 95%CI 1.08-17.63, P = 0.039, respectively). The existence of pre-treatment T1753V, A1762T/G1764A mutations and their combination yielded negative predictive values of 94.7%, 85.7% and 93.8%, respectively. The presence of HBV mutants in the BCP region determined by NGS at baseline was associated with poor treatment outcome in patients with HBeAg-positive CHB receiving PEG-IFN.

Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.

Factors affecting mortality and resource use for hospitalized patients with cirrhosis: A population-based study.

Hospitalizations for advanced liver disease are costly and associated with significant mortality. This population-based study aimed to evaluate factors associated with in-hospital mortality and resource use for the management of hospitalized patients with cirrhosis.Mortality records and resource utilization for 52,027 patients hospitalized with cirrhosis and/or complications of portal hypertension (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, or hepatorenal syndrome) were extracted from a nationally representative sample of Thai inpatients covered by Universal Coverage Scheme during 2009 to 2013.The rate of dying in the hospital increased steadily by 12% from 9.6% in 2009 to 10.8% in 2013 (P < .001). Complications of portal hypertension were independently associated with increased in-hospital mortality except for ascites. The highest independent risk for hospital death was seen with hepatorenal syndrome (odds ratio [OR], 5.04; 95% confidence interval [CI], 4.38-5.79). Mortality rate remained high in patients with infection, particularly septicemia (OR, 4.26; 95% CI, 4.0-4.54) and pneumonia (OR, 2.44; 95% CI, 2.18-2.73). Receiving upper endoscopy (OR, 0.29; 95% CI, 0.27-0.32) and paracentesis (OR, 0.93; 95% CI, 0.87-1.00) were associated with improved patient survival. The inflation-adjusted national annual costs (P = .06) and total hospital days (P = .07) for cirrhosis showed a trend toward increasing during the 5-year period. Renal dysfunction, infection, and sequelae of portal hypertension except for ascites were independently associated with increased resource utilization.Renal dysfunction, infection, and portal hypertension-related complications are the main factors affecting in-hospital mortality and resource utilization for hospitalized patients with cirrhosis. The early intervention for modifiable factors is an important step toward improving hospital outcomes.

Diagnostic performance of transient elastography for detection of methotrexate-induced liver injury using Roenigk classification in Asian patients with psoriasis: a retrospective study.

Liver biopsy, the gold standard for monitoring methotrexate-induced liver fibrosis in psoriasis patients, has potential morbidity and mortality. Transient elastography (TE) has been widely used as an alternative non-invasive method. Currently, psoriasis-specific data of TE comparing to Roenigk histopathology is lacking. This retrospective study assessed the diagnostic performance of TE in the detection of methotrexate-induced liver injury and liver fibrosis in Asian psoriasis patients. Risk factors that associated with liver injury by TE and histopathology were also determined. Psoriasis patients who had received methotrexate and undergone both TE and liver biopsy (gold standard) examinations between 2005 and 2016 were enrolled. Ten of 41 patients developed methotrexate-induced liver injury (Roenigk grade ≥3a) and two of them had significant liver fibrosis (Metavir fibrosis stage ≥2). Area under the receiver operating characteristic curve (AUROC = 0.78) indicated that TE was capable of identifying patients with and without liver injury. Using a cut-off TE value of 7.1 kilopascal (kPa), this ultrasound-based elastography yielded 50% sensitivity and 83.9% specificity for detecting methotrexate-induced liver injury and had 50% sensitivity and 76.9% specificity for identifying significant liver fibrosis. A total cumulative dosage of methotrexate, age, gender, metabolic syndrome, and metabolic components were not significantly associated with TE values ≥7.1 kPa and Roenigk grade ≥3a. Thus, using clinical context, laboratory information, and a cut-off TE value of 7.1, TE is an attractable non-invasive tool for identify psoriasis patients who have a low probability of methotrexate-induced liver injury and significant liver fibrosis. Liver biopsy can be reserved for selected patients.

Alanine aminotransferase course, serum hepatitis B virus DNA, and liver stiffness measurement for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B.

AIM: To evaluate the utility of the combination of alanine aminotransferase (ALT) course, hepatitis B virus (HBV) DNA level, and liver stiffness measurement (LSM) for determining significant liver disease in hepatitis B e antigen (HBeAg)-negative patients. METHODS: Three hundred and ninety nine consecutive HBeAg-negative patients with HBV DNA >2000 IU/mL and documented serial measurements of ALT were enrolled to undergo LSM followed by liver biopsy. RESULTS: Using ALT <40 IU/L as a normal value, 142 patients had persistently normal ALT (PNALT), whereas 257 had persistently or intermittently elevated ALT (PIEALT) in the prior year. Among patients with HBV DNA of 2000-19 999, 20 000-199 999, and ≥200 000 IU/mL, significant pathological lesions defined as the presence of moderate to severe necroinflammation and/or significant fibrosis by METAVIR scoring was present in 40%, 45%, and 71% of the PIEALT group, and 15%, 31%, and 36% of the PNALT group, respectively. In PNALT patients with HBV DNA <20 000 IU/mL, liver biopsy could be avoided in 88% when LSM <7 kPa is used as an indicator of non-significant liver histology but 12% of those who indeed had significant pathological lesions would be missed. In PIEALT patients with HBV DNA ≥20 000 IU/mL, the need for liver biopsy could be reduced by 53% with a false positive rate of 14% when LSM ≥7 kPa is used as a predictor of significant pathological lesions. CONCLUSION: The combination of serial ALT, viral load, and LSM appears to be a promising non-invasive tool. A management algorithm for HBeAg-negative patients comprising these non-invasive measures is proposed with liver biopsy being pursued in selected cases.

Comparison between disease free survival of hepatocellular carcinoma after hepatic resection in chronic hepatitis B patients with or without cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients can develop in those with cirrhotic and non-cirrhotic liver Not only impairment of liver status, but also the extension of tumor and difference of pathogenesis may also affect characteristics of patient and tumor including survival and recurrence. OBJECTIVE: To evaluate the disease free survival, prognostic factors and features of HCC after hepatic resection in CHB patients with and without cirrhosis. MATERIAL AND METHOD: Two hundred fifteen HBV-related HCC patients underwent hepatic resection and were analyzed. Cirrhotic and non-cirrhotic groups were compared for differences inpatient and tumor characteristics, disease-free survival including prognostic factors. RESULTS: In comparison with cirrhotic patients, non-cirrhotic patients had more family history of HCC, more preserved liver function, were less HBeAg positive, and had lower HBV viral load. HCC characteristics in non-cirrhotic groups showed significantly larger (5.8 ± 3.7 vs. 4.9 ± 3.9 cm, p = 0.036) and operative data revealed that non-cirrhotic patients underwent more major surgery (50.7 vs. 18.3%, p < 0.001), and had shorter hospital stay (10.8 ± 8.9 vs. 8.1 ± 4.3 days, p = 0.006) than cirrhotic ones. Operative time, blood loss and requirement of PRC transfusion were similar in both groups. Pathological profiles of HCC and liver parenchyma were comparable in both cirrhotic and non-cirrhotic patients. The disease-free survival of non-cirrhotic patients was longer than cirrhotic patients (Median disease free survival were 21 and 11 months respectively, p = 0.022). The independent predictive factor of lower disease-free survival of non-cirrhotic CHB patients who underwent hepatic resection was lymph node involvement (Hazard ratio (HR), 4.598. 95% confidence interval (CI), 1.1-19.212; p = 0.037) while of cirrhotic patients, factors were age > 50 years old (HR, 2.998; 95% CI, 1.298-6.925; p = 0.01), multifocal tumor (HR, 5.835; 95% CI, 1.122-30.342; p = 0.036) andportal vein involvement (HR, 3.722; 95% CI, 1.121-12.353; p = 0.032). HBV treatment after HCC diagnosis was a significant predictor in the cirrhotic group by univariate analysis (p = 0.04). CONCLUSION: Imaging and histological findings of HCC in cirrhotic and non-cirrhotic CHB patients were not different, except for larger tumor size in non-cirrhotic patients. Lymph node involvement is the predictor of HCC recurrence in non- cirrhotic CHB patients. Age > 50 year old and multifocal tumor and portal vein involvement are the predictors of HCC recurrence in cirrhotic CHB patients. These groups may need surveillance that is more intensive after hepatic resection. Antiviral therapy may lower the risk of HCC recurrence among CHB cirrhotic patients.

Clinical characteristics of hepatitis B and C virus infections in HIV-infected patients.

BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) share a common route of transmission with human immunodeficiency virus (HIV). HIV co-infected with HBV or HCV was associated with a progression to severe liver disease, increased risk of hepatotoxicity from antiretroviral therapy and reduced survival. Data regarding HBV and HCV infection in HIV-positive individuals in Thailand is limited. OBJECTIVES: To investigate the prevalence and clinical characteristics of HBV and HCV infection in HIV-infected patients in Siriraj Hospital. MATERIAL AND METHOD: A retrospective study was conducted in adult HIV-positive followed up at the Infectious Disease Clinic, Siriraj Hospital. Prevalence of HBV and HCV infections and clinical characteristics were analyzed. RESULTS: 250 HIV-positive patients were enrolled, mean age was 38.8 years and 57.2% were male. HBV infection was found in 6.5% (15/231), and HCV infection was 7.7% (17/222). One patient had both HBV and HCV infections. In multivariate analysis, factors associated with either HBV or HCV co-infection included male gender (77.4% vs. 55%; p 0.008), history of salmonellosis (9.7% vs. 2.5%; p 0.042) or elevated serum alanine aminotransferase (ALT) level (34 U/L vs. 25 U/L; p 0.018). Factors associated with HBV infection, compared with those without hepatitis virus infection, included male gender (86.7% vs. 56%; p 0.038), history of salmonellosis (20% vs. 2.3%; p 0.005), elevated serum ALT level (42 U/L vs. 25 U/L; p 0.012) and low CD4 percent (1.05% vs. 5.02%; p 0.04). In this study, we did not find any factor associated with HCV infection in HIV patients. CONCLUSION: The prevalence of HBV and HCV infection in HIV-infected Thai patients is significant. Male gender, history of salmonellosis, elevated serum ALT levels, and low CD4 percent are associated with HBV co-infection.

Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice.

UNLABELLED: Virological breakthrough (VBT) is the first manifestation of antiviral drug resistance during nucleos(t)ide analogue (NUC) treatment of chronic hepatitis B (CHB), but not all VBTs are due to drug resistance. This study sought to determine the incidence of VBT and genotypic resistance (GR) in patients with CHB who were receiving NUCs in clinical practice. Records of patients with CHB who were receiving NUCs were reviewed. All patients with VBT were tested for drug resistance mutations. Of 148 patients included, 73% were men and mean age was 44.9 years. During a mean follow-up of 37.5 ± 20.1 months, 39 (26%) patients had at least 1 VBT. Of these 39 patients, 15 (38%) were not confirmed to have VBT on retesting, and 10 of these 15 had no evidence of GR. The cumulative probability of VBT, confirmed VBT, and GR at 5 years was 46.1%, 29.7%, and 33.9%, respectively. In multivariate analysis, failure to achieve undetectable hepatitis B virus (HBV) DNA was the only factor significantly associated with VBT. Among the 10 patients who had VBT but no confirmed VBT or GR and who were maintained on the same medications, serum HBV DNA decreased in all 10, and nine had undetectable HBV DNA at a mean of 6.8 months after the VBT. Four patients had persistently undetectable HBV DNA, six had transient increase in HBV DNA during follow-up, and none had GR. CONCLUSION: VBT was common in patients with CHB receiving NUCs in clinical practice, but nearly 40% of the VBTs were not related to antiviral drug resistance. Counseling of patients with CHB on medication adherence and confirmation of VBT and/or GR can avoid unnecessary changes in antiviral medications.