Model for end-stage liver disease-3.0 vs. model for end-stage liver disease-sodium: mortality prediction in Korea.

BACKGROUND/AIMS: The model for end-stage liver disease (MELD) serves as an indicator for short-term mortality among patients diagnosed with liver cirrhosis (LC) and is used to prioritize patients for liver transplantation. In 2021, the updated version of MELD, MELD-3.0, was introduced to improve the accuracy of the mortality prediction of MELD. Therefore, this study aimed to compare the efficacy of MELD 3.0 and MELD-Na in predicting mortality among Korean patients with LC. METHODS: A retrospective review was conducted using the medical records of patients diagnosed with LC who were admitted to Konkuk University Hospital From 2011 to 2021. The study calculated the predictive values of MELD-Na and MELD-3.0 for 3- and 6-months mortality using the area under the receiver operating curve (AUROC) and compared the results using the DeLong test. RESULTS: Of the 3,034 patients enrolled in the study, 339 (11.2%) died within 3 months and 421 (14.4%) died within 6 months. The AUROCs values for predicting 3 months mortality were 0.846 for MELD-Na and 0.851 for MELD-3.0. The corresponding AUROC values for predicting 6 months mortality were 0.843 for MELD-Na and 0.848 for MELD-3.0. MELD-3.0 exhibited better discrimination ability than MELD-Na for both 3 (p = 0.03) and 6 months mortality (p = 0.01). CONCLUSION: Our study found a significant difference between the performance of MELD-3.0 and MELD-Na in Korean patients with LC.

Locked nucleic acid real-time polymerase chain reaction method identifying two polymorphisms of hepatitis B virus genotype C2 infections, rt269L and rt269I.

BACKGROUND: The presence of two distinct hepatitis B virus (HBV) Pol RT polymorphisms, rt269L and rt269I, could contribute to the unique clinical or virological phenotype of HBV genotype C2. Therefore, a simple and sensitive method capable of identifying both types in chronic hepatitis B (CHB) patients infected with genotype C2 should be developed. AIM: To develop a novel simple and sensitive locked nucleic acid (LNA)-real time-polymerase chain reaction (RT-PCR) method capable of identifying two rt269 types in CHB genotype C2 patients. METHODS: We designed proper primer and probe sets for LNA-RT-PCR for the separation of rt269 types. Using synthesized DNAs of the wild type and variant forms, melting temperature analysis, detection sensitivity, and endpoint genotyping for LNA-RT-PCR were performed. The developed LNA-RT-PCR method was applied to a total of 94 CHB patients of genotype C2 for the identification of two rt269 polymorphisms, and these results were compared with those obtained by a direct sequencing protocol. RESULTS: The LNA-RT-PCR method could identify two rt269L and rt269I polymorphisms of three genotypes, two rt269L types ['L1' (WT) and 'L2'] and one rt269I type ('I') in single (63 samples, 72.4%) or mixed forms (24 samples, 27.6%) in 87 (92.6% sensitivity) of 94 samples from Korean CHB patients. When the results were compared with those obtained by the direct sequencing protocol, the LNA-RT-PCR method showed the same results in all but one of 87 positive detected samples (98.9% specificity). CONCLUSION: The newly developed LNA-RT-PCR method could identify two rt269 polymorphisms, rt269L and rt269I, in CHB patients with genotype C2 infections. This method could be effectively used for the understanding of disease progression in genotype C2 endemic areas.

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK-eIF2α-ATF4 axis in an HBx protein-dependent manner.

BACKGROUND: In our previous report, the rt269I type versus the rt269L type in genotype C2 infection led to poor clinical outcomes and enhanced mitochondrial stress in infected hepatocytes. Here, we sought to investigate differences between the rt269L and rt269I types in mitochondrial functionality in hepatitis B virus (HBV) genotype C2 infection, mainly focusing on endoplasmic reticulum (ER) stress-mediated autophagy induction as an upstream signal. METHODS: Mitochondrial functionality, ER stress signaling, autophagy induction, and apoptotic cell death between rt269L-type and rt269I-type groups were investigated via in vitro and in vivo experiments. Serum samples were collected from 187 chronic hepatitis patients who visited Konkuk or Seoul National University Hospital. RESULTS: Our data revealed that genotype C rt269L versus rt269I infection led to improved mitochondrial dynamics and enhanced autophagic flux, mainly due to the activation of the PERK-eIF2α-ATF4 axis. Furthermore, we demonstrated that the traits found in genotype C rt269L infection were mainly due to increased stability of the HBx protein after deubiquitination. In addition, clinical data using patient sera from two independent Korean cohorts showed that, compared with rt269I, rt269L in infection led to lower 8-OHdG levels, further supporting its improved mitochondrial quality control. CONCLUSION: Our data showed that, compared with the rt269I type, the rt269L type, which presented exclusively in HBV genotype C infection, leads to improved mitochondrial dynamics or bioenergetics, mainly due to autophagy induction via activation of the PERK-eIF2α-ATF4 axis in an HBx protein-dependent manner. This suggests that HBx stability and cellular quality control in the rt269L type predominating in genotype C endemic areas could at least partly contribute to some distinctive traits of genotype C infection, such as higher infectivity or longer duration of the hepatitis B e antigen (HBeAg) positive stage.

MELD-GRAIL-Na Is a Better Predictor of Mortality Than MELD in Korean Patients with Cirrhosis.

Background and Objectives: The Child-Pugh (CP) score and Model for End-Stage Liver Disease (MELD) are classical systems for predicting mortality in patients with liver cirrhosis (LC). The MELD-GFR assessment in liver disease-sodium (MELD-GRAIL-Na) was designed to better reflect renal function and, therefore, provide better mortality predictions. This study aimed to compare the prediction accuracy of MELD-GRAIL-Na compared to CP and MELD in predicting short-term (1- and 3-month) mortality in Korean patients. Materials and Methods: Medical records of patients with LC admitted to the Konkuk University Hospital from 2015 to 2020 were retrospectively reviewed. Predictive values of the CP, MELD, and MELD-GRAIL-Na for 1-month and 3-month mortality were calculated using the area under the receiver operating curve (AUROC) and were compared using DeLong's test. Results: In total, 1249 patients were enrolled; 102 died within 1 month, and 146 within 3 months. AUROCs of CP, MELD, and MELD-GRAIL-Na were 0.831, 0.847, and 0.857 for 1-month mortality and 0.837, 0.827, and 0.835 for 3-month mortality, respectively, indicating no statistical significance. For patients with CP classes B and C, AUROCs of CP, MELD, and MELD-GRAIL-Na were 0.782, 0.809, and 0.825 for 1-month mortality and 0.775, 0.769, and 0.786 for 3-month mortality, respectively. There was a significant difference between CP and MELD-GRAIL-Na in predicting 1-month mortality (p = 0.0428) and between MELD and MELD-GRAIL-Na in predicting 1-month (p = 0.0493) and 3-month mortality (p = 0.0225). Conclusions: Compared to CP and MELD, MELD-GRAIL-Na was found to be a better and more useful system for evaluating short-term (1- and 3-month) mortality in Korean patients with cirrhosis, especially those with advanced cirrhosis (CP class B and C).

Switching from Tenofovir-Based Combination Therapy to Tenofovir Monotherapy in Multidrug-Experienced Chronic Hepatitis B Patients: a 5-Year Experience at Two Centers.

Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.

Comparison of Non-Invasive Clinical Algorithms for Liver Fibrosis in Patients With Chronic Hepatitis B to Reduce the Need for Liver Biopsy: Application of Enhanced Liver Fibrosis and Mac-2 Binding Protein Glycosylation Isomer.

BACKGROUND: Non-invasive clinical algorithms for the detection of liver fibrosis (LF) can reduce the need for liver biopsy (LB). We explored the implementation of two serum biomarkers, enhanced liver fibrosis (ELF) and Mac-2 binding protein glycosylation isomer (M2BPGi), in clinical algorithms for LF in chronic hepatitis B (CHB) patients. METHODS: Two clinical algorithms were applied to 152 CHB patients: (1) transient elastography (TE) followed by biomarkers (TE/ELF and TE/M2GPGi); (2) biomarker test followed by TE (ELF/TE and M2BPGi/TE). Using the cut-off value or index for the detection of advanced LF (TE≥F3; 9.8 in ELF and 3.0 in M2BPGi), LB was expected to be performed in cases with discordant TE and biomarker results. RESULTS: In both algorithms, the expected number of LBs was lower when using M2BPGi than when using ELF (TE/ELF or ELF/TE, 13.2% [N=20]; TE/M2BPGi or M2BPGi/TE, 9.9% [N=15]), although there was no statistical difference (P=0.398). In the TE low-risk group (TE≤F2), the discordance rate was significantly lower in the TE/M2BPGi approach than in the TE/ELF approach (1.5% [2/136] vs. 11.0% [15/136], P=0.002). In the biomarker low-risk group, there was no significant difference between the ELF/TE and M2BPGi/TE approaches (3.9% [5/126] vs. 8.8% [13/147], P=0.118). CONCLUSIONS: Both ELF and M2BPGi can be implemented in non-invasive clinical algorithms for assessing LF in CHB patients. Given the lowest possibility of losing advanced LF cases in the low-risk group when using the TE/M2BPGi approach, this combination seems useful in clinical practice.

Changes in the Hepatitis B Surface Antigen Level According to the HBeAg Status and Drug Used in Long-term Nucleos(t)ide Analog-treated Chronic Hepatitis B Patients.

Backgrounds/Aims: The HBsAg levels have been used to monitor the chronic hepatitis B (CHB) treatment response to antiviral therapy. On the other hand, it is unclear if the HBsAg quantification levels at each treatment point differ according to the HBeAg status and drug in CHB patients. This study compared the changes in HBsAg in CHB patients according to the HBeAg status and treatment drugs. Methods: CHB patients with at least 1 year of follow-up treatment with one drug, either entecavir (ETV) or tenofovir (TDF), were enrolled in this study. The mean HBsAg levels were measured annually for up to 6 years. A linear mixed model was used to compare the HBsAg quantification levels during the follow-up period. An independent samples t-test was used to analyze the differences in the HBsAg quantification levels at each treatment time point. Results: Ninety-seven patients were enrolled in this study; 59 among them were HBeAg-positive. Two patients in the TDF group achieved HBsAg seroconversion. The HBsAg level decreased during the follow-up in the ETV and TDF groups. The HBsAg level was lower in the TDF group than the ETV group during the follow-up. On the other hand, subgroup analysis showed that this trend was the same only in the HBeAg-negative patients, not in the HBeAg-positive patients. In the HBeAg-negative patients, HBsAg level in the TDF group was significantly lower than that in the ETV group at 36, 48, and 72 months. The change in HBsAg level from the baseline increased at a decreasing rate during the follow-up in both groups. Furthermore, the change in the HBsAg level in the TDF group was significantly larger than that of the ETV group at 36 months in the HBeAg-negative patients. Conclusions: Although TDF might be more efficient than ETV in reducing the HBsAg level in HBeAg-negative patients in a few years, HBsAg seroconversion occurred very rarely. A further large-scale, long-term study will be needed to confirm the antiviral effects on the HBsAg level.

Comparative study for predictability of type 1 gastric variceal rebleeding after endoscopic variceal ligation: High-frequency intraluminal ultrasound study.

BACKGROUND: The efficacy of endoscopic ultrasonography for the follow-up of gastric varices treated with endoscopic variceal ligation (EVL) has not been established. AIM: To evaluate the diagnostic correlation of esophagogastroduodenoscopy (EGD) and high-frequency intraluminal ultrasound (HFIUS) for type 1 gastric varices (GOV1) after EVL and to identify the predictability for rebleeding of EGD and HFIUS. METHODS: In liver cirrhosis patients with GOV1, we performed endoscopic follow-up using EGD and HFIUS synchronously after EVL for hemorrhage from GOV1. Endoscopic grading and red color signs were analyzed using EGD, and the largest variceal cross-sectional areas were measured using HFIUS. In addition, 1-year follow-up was performed. Variceal rebleeding was defined as the presence of hematemesis, hematochezia, or melena without other evidence of bleeding on endoscopic follow-up. RESULTS: In 26 patients with GOV1, variceal cross-sectional areas on HFIUS of GOV1 was poorly correlated with EGD grading of GOV1 (r = 0.36). In 17 patients who completed the 1-year follow-up, variceal cross-sectional areas on HFIUS was a good predictor of subsequent rebleeding, whereas EGD grading was not a predictor of subsequent rebleeding. CONCLUSION: HFIUS measurement is more predictive of GOV1 rebleeding than EGD grading, so HFIUS measurement may be necessary for endoscopic follow-up after EVL in patients with GOV1.

The effect of nucleos(t)ide analogues on clinical outcomes of patients treated with transarterial chemoembolization and radiofrequency ablation for hepatitis B virus-related hepatocellular carcinoma.

Background/Aims: Because hepatitis B virus (HBV) replication has been known to play an important role in cancer recurrence after curative treatment of HBV-related hepatocellular carcinoma (HCC), we examined whether treatment based on nucleos(t)ide analogues (NAs) might decrease the recurrence rate and improve patient survival. Methods: The retrospective cohort study enrolled 73 patients with chronic hepatitis B who were treated with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) with curative intent for HCC. Among those, 30 and 43 patients were treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), respectively. Results: Of the 73 patients, 51 experienced HCC recurrence, and 14 patients were dead during a follow-up of 73±34 months. Multivariate analyses showed that tumor size (hazard ratio [HR], 1.590; 95% confidence-interval [CI], 1.106-2.285; P=0.012) and Child-Pugh class B (vs. class A/non cirrhosis; HR, 5.794; 95% CI, 2.311-14.523; P=0.001) was significantly associated with HCC recurrence, and Child-Pugh class B (HR, 7.357; 95% CI, 2.100-25.777; P=0.002) was an independent unfavorable prognostic factor for survival. During NAs therapy, TDF was superior to ETV for complete viral response at 1 year after the date of combination of TACE and RFA (P=0.016). However, the risks of HCC recurrence and survival were not significantly different between those treated with TDF versus ETV. Conclusions: TDF was superior to ETV for achieving complete viral response. However, the recurrence and mortality after TACE and RFA for HBV-related HCC were not significantly different between patients treated with TDF versus ETV.

Comparison of the efficacy and safety of direct-acting antiviral therapy with or without hepatitis C-related hepatocellular carcinoma.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) treatment has dramatically improved since direct-acting antiviral (DAA) therapy was introduced. However, the use of DAA therapy in CHC patients with hepatocellular carcinoma (HCC) remains controversial. We investigated the DAA treatment response in CHC patients with HCC. METHODS: We retrospectively analyzed CHC patients treated with DAA from 2016 to 2018. Patients were divided into two groups based on their HCC-history before DAA therapy. Baseline characteristics, sustained virologic response at 12 weeks (SVR 12), and HCC recurrence after DAA therapy were evaluated. We also used propensity score matching (PSM) in a 2:1 ratio to reduce confounding variables. RESULTS: A total of 192 patients were enrolled; 78.1% were treatment-naïve, and 34.9% had liver cirrhosis (LC). Among these patients, 168 did not have HCC, and 24 had HCC. The HCC group was older (57.0 years vs. 72.0 years, p < 0.001), had a higher incidence of LC (26.2% vs. 95.8%, p < 0.001), fibrosis-4 index (2.6 vs. 9.2, p < 0.001), liver stiffness measurement (7.0 kPa vs. 17.4 kPa, p = 0.012), and α-fetoprotein (4.4 ng/mL vs. 8.2 ng/mL, p ≤ 0.001). The SVR 12 rate was 97.0% in the non- HCC group and 91.7% in the HCC group (p = 0.213). HCC recurrence was observed in 14 patients (58.3%) in the HCC group. CONCLUSION: DAA treatment efficacy in CHC patients with or those without HCC were not significantly different, and HCC recurrence was relatively common.

Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study.

OBJECTIVE: Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study. DESIGNS: This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC). RESULTS: During follow-up (median=26.9 months, IQR=12.2-49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38). CONCLUSION: The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.

Risk Factors for Liver Function Deterioration after Transarterial Chemoembolization Refractoriness in Child-Pugh Class A Hepatocellular Carcinoma Patients.

Background/Aims: A switch to systemic therapy, such as sorafenib, should be considered for hepatocellular carcinoma (HCC) patients refractory to transarterial chemoembolization (TACE). On the other hand, treatment changes are difficult if the liver function worsens to Child-Pugh B or C. Therefore, predicting the risk factors for non-responsiveness to TACE and deteriorating liver function may be helpful. Methods: Newly diagnosed Child-Pugh A HCC patients who underwent TACE from January 2012 to June 2018 were included. After 1 year, this study evaluated whether there was a treatment response to TACE and whether the Child-Pugh class had worsened. Results: Among 121 patients, 65 were refractory and 56 responded to TACE. In multivariable logistic regression analysis, the tumor size, tumor number, and albumin at the time of the diagnosis of HCC were significant prognostic factors for the treatment response to TACE. Among 65 patients who presented TACE-refractoriness, 27 showed liver function deterioration from Child-Pugh class A to class B or C after TACE. In multivariable logistic regression analysis, bilirubin at the diagnosis of HCC was a significant prognostic factor for liver function deterioration. A predictive algorithm based on the regression equations revealed a sensitivity, specificity, positive predictive value, and negative predictive value of 74.1%, 74.5%, 45.5%, and 90.9%, respectively, for TACE-refractoriness and liver function deterioration. Conclusions: The prognostic model incorporating the tumor size, tumor number, albumin, and bilirubin at the diagnosis of HCC may help identify patients who show a poor response to TACE and aggravation of liver function after TACE, who may benefit from early switching into systemic therapy before liver function aggravation.

Prognostic impact of hepatitis B or C on intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy, arising from the peripheral intrahepatic bile duct epithelium. Hepatitis B virus (HBV) or hepatitis C virus (HCV) may be involved in the development of ICC. We explored the prognostic value of hepatitis virus infection, as well as other prognostic factors affecting survival in patients with ICC. METHODS: A retrospective chart review was performed for patients diagnosed with ICC between August 2005 and December 2018 at Konkuk University Medical Center. We identified a total of 131 patients with ICC. Overall survival rates of patients with and without hepatitis were determined. Univariate and multivariate analyses were used to estimate factors influencing survival outcomes. RESULTS: A total of 17.6% (23/131) of patients were positive for HBV or HCV. Hepatitis B positive ICC patients were significantly younger with higher albumin and higher α-fetoprotein than those without hepatitis viral infections. The median survival of hepatitis-positive and hepatitis-negative groups was 280 and 213 days, respectively. Survival rates were not significantly different between the two groups (p = 0.279). Multivariate analyses indicated that lower serum carbohydrate antigen 19-9 (CA 19-9) (p < 0.001), lower T stage (p = 0.042), the absence of lymph-node metastasis (p = 0.043), and receiving curative surgery (p = 0.033) were independent predictors of better outcomes. CONCLUSION: While hepatitis influenced a number of clinical features in ICC patients, it did not affect survival rate. Prognostic factors influencing survival outcomes with ICC were CA 19-9 level, T stage, the presence of lymph node metastasis, and curative surgery.

Impact of Interferon-Based Treatment on Quality of Life and Work-Related Productivity of Korean Patients with Chronic Hepatitis C.

Background/Aims: Chronic hepatitis C virus (HCV) infections put patients at risk of serious liver disease and adversely affects patient quality of life (QoL). MOSAIC (International Multicenter Prospective Observational Study to Evaluate the Epidemiology, Humanistic and Economic Outcomes of Treatment for Chronic Hepatitis C Virus) was a prospective, non-interventional, international, multicenter study that aimed to describe the epidemiology of the infection, the impact of the infection on health-related QoL (HRQoL) and daily activities, and healthcare resource use related to HCV and treatment. Here, we present the results on HRQoL and daily activity impairment in consecutively enrolled South Korean patients treated with interferon (IFN)-containing regimens prospectively followed for up to 48 weeks. Methods: General HRQoL, HCV-specific HRQoL, perceived health state, and work/general activity impairments were measured using the EuroQoL 5-dimension 5-level (EQ-5D-5L), HCV patient-reported outcomes (HCV-PRO), EQ-5D Visual Analog Scale, and Work Productivity and Activity Impairment questionnaires, respectively. Results: Thirty-three of the 100 enrolled patients initiated IFN-based treatment, with an intended duration of 24 weeks for 20 patients and 48 weeks for 12 patients; this information was missing for one patient. Fourteen patients (42.4%) prematurely withdrew. After treatment initiation, IFN-treated patients showed a trend towards deterioration of both general (baseline: 0.87±0.103, week 4: 0.77±0.153) and HCV-specific (baseline: 76.2±19.5, week 4: 68.2±22.3) HRQoL. The scores recovered somewhat towards the end of treatment (EOT) (0.84±0.146 for EQ-5D-5L and 70.8±21.9 for HCV-PRO). The perceived health state and work/general activity impairment displayed similar temporal patterns. Conclusions: Initiating IFN-based treatment prompted some deterioration in general and HCV-related HRQoL, accompanied by impaired daily activities and most work productivity measures; however, the HRQoL and productivity scores improved towards the EOT. HRQoL impairment upon treatment initiation likely contributed to treatment discontinuation.

Tenofovir is a more suitable treatment than entecavir for chronic hepatitis B patients carrying naturally occurring rtM204I mutations.

BACKGROUND: Hepatitis B virus (HBV) DNA polymerase mutations usually occur to long term use of nucleos(t)ide analogues (NAs), but they can occur spontaneously in treatment-naïve chronic hepatitis B (CHB) patients. The naturally occurring HBV DNA polymerase mutations might complicate antiviral therapy with NAs, leading to the generation of drug-resistant viral mutants and disease progression. The most common substitutions are known to be YMDD-motif mutations, but their prevalence and the influence on antiviral therapy is unclear. AIM: To investigate prevalence of the naturally occurring rtM204I mutations in treatment-naïve CHB genotype C2 patients and their influence on antiviral therapy. METHODS: A total of 410 treatment-naïve CHB patients infected with HBV genotype C2 strains were enrolled in this retrospective study. Among the 410 patients, 232 were treated with NAs for at least 12 mo. Significant fibrosis was defined as fibrosis-4 index > 3.25 or aspartate aminotransferase to platelet ratio index > 1.5. Complete viral response (CVR) during NAs was defined as undetectable serum HBV DNA (< 24 IU/mL). The rtM204I variants were analyzed by a newly developed locked nucleotide probe (LNA probe) based real-time PCR (LNA-RT-PCR) method. RESULTS: The LNA-RT-PCR could discriminate rtM204I mutant-type (17 patients, 4.2%) from rtM204 wild-type (386 patients, 95.8%) in 403 of 410 patients (98.3% sensitivity). Multivariate analysis showed that naturally occurring rtM204I variants were more frequently detected in patients with significant fibrosis [odd-ratio (OR) 3.397, 95% confidence-interval (CI) 1.119-10.319, P = 0.031]. Of 232 patients receiving NAs, multivariate analysis revealed that achievement of CVR was reversely associated with naturally occurring rtM204I variants prior to NAs treatment (OR 0.014, 95%CI 0.002-0.096, P < 0.001). Almost patients receiving tenofovir achieved CVR at 12 mo of tenofovir, irrespective of pre-existence of naturally occurring rtM204I mutations (CVR rates: patients with rtM204I, 100%; patients without rtM204I, 96.6%), whereas, pre-existence of naturally-occurring rtM204I-mutations prior to NAs significantly affects CVR rates in patients receiving entecavir (at 12 mo: Patients with rtM204I, 16.7%; patients without rtM204I, 95.6%, P < 0.001). CONCLUSION: The newly developed LNA-RT-PCR method could detect naturally occurring rtM204I mutations with high-sensitivity. Theses mutations were more frequent in patients with liver fibrosis. Tenofovir is a more suitable treatment than entecavir for CHB patients carrying the naturally occurring rtM204I mutations.

rt269I Type of Hepatitis B Virus (HBV) Leads to HBV e Antigen Negative Infections and Liver Disease Progression via Mitochondrial Stress Mediated Type I Interferon Production in Chronic Patients With Genotype C Infections.

Hepatitis B virus infection is a serious global health problem and causes life-threatening liver disease. In particular, genotype C shows high prevalence and severe liver disease compared with other genotypes. However, the underlying mechanisms regarding virological traits still remain unclear. This study investigated the clinical factors and capacity to modulate Type I interferon (IFN-I) between two HBV polymerase polymorphisms rt269L and rt269I in genotype C. This report compared clinical factors between rt269L and rt269I in 220 Korean chronic patients with genotype C infections. The prevalence of preC mutations between rt269L and rt269I was compared using this study's cohort and the GenBank database. For in vitro and in vivo experiments, transient transfection using HBV genome plasmid and HBV virion infection using HepG2-hNTCP-C4 and HepaRG systems and hydrodynamic injection of HBV genome into mice tails were conducted, respectively. This report's clinical data indicated that rt269I vs. rt269L was more significantly related to HBV e antigen (HBeAg) negative serostatus, lower levels of HBV DNA and HBsAg, and disease progression. Our epidemiological study showed HBeAg negative infections of rt269I infections were attributed to a higher frequency of preC mutations at 1896 (G to A). Our in vitro and in vivo studies also found that rt269I could lead to mitochondrial stress mediated STING dependent IFN-I production, resulting in decreasing HBV replication via the induction of heme-oxygenase-1. In addition, we also found that rt269I could lead to enhanced iNOS mediated NO production in an IFN-I dependent manner. These data demonstrated that rt269I can contribute to HBeAg negative infections and liver disease progression in chronic patients with genotype C infections via mitochondrial stress mediated IFN-I production.

Assessing significant fibrosis using imaging-based elastography in chronic hepatitis B patients: Pilot study.

BACKGROUND: Accurate detection of significant fibrosis (fibrosis stage 2 or higher on the METAVIR scale) is important especially for chronic hepatitis B (CHB) patients with high viral loads but with normal or mildly elevated alanine aminotransferase (ALT) levels because the presence of significant fibrosis is accepted as the indication for antiviral treatment. Liver biopsy is the reference standard for diagnosing significant fibrosis, but it is an invasive procedure. Consequently, noninvasive imaging-based measurements, such as magnetic resonance elastography (MRE) or two-dimensional shear-wave elastography (2D-SWE), have been proposed for the quantitative assessment of liver fibrosis. AIM: To explore MRE and 2D-SWE to identify fibrosis stage, and to compare their performance with that of serum-based indices. METHODS: The study enrolled 63 treatment-naïve CHB patients with high viral loads but with normal or mildly elevated ALT levels who underwent liver biopsy before a decision was made to initiate antiviral therapy. MRE and 2D-SWE were performed, and serum-based indices, such as FIB-4 and aspartate transaminase to platelet ratio index (APRI), were calculated. The diagnostic performances of MRE, 2D-SWE, FIB-4, and APRI for assessing significant fibrosis (≥ F2) and cirrhosis (F4) were evaluated with liver histology as the reference standard, using receiver operating characteristic analyses. RESULTS: The liver fibrosis stage was F0/F1 in 19, F2 in 14, F3 in 14, and F4 in 16 patients, respectively. MRE significantly discriminated F2 from F0/1 (P = 0.022), whereas 2D-SWE showed a broad overlap in distinguishing those stages. MRE showed a higher correlation coefficient value with fibrosis stage than 2D-SWE with fibrosis stage (0.869 vs 0.649, Spearman test; P < 0.001). Multivariate linear regression analyses showed that fibrosis stage was the only factor affecting the values of MRE (P < 0.001), whereas body mass index (P = 0.042) and fibrosis stage (P < 0.001) were independent factors affecting 2D-SWE values. MRE performance for diagnosing significant fibrosis was better [area under the curve (AUC) = 0.906, positive predictive value (PPV) 97.3%, negative predictive value (NPV) 69.2%] than that of FIB-4 (AUC = 0.697, P = 0.002) and APRI (AUC = 0.717, P = 0.010), whereas the performance of 2D-SWE (AUC = 0.843, PPV 86%, NPV 65%) was not significantly different from that of FIB-4 or APRI. CONCLUSION: Compared to SWE, MRE might be more precise non-invasive assessment for depicting significant fibrosis and for making-decision to initiate antiviral-therapy in treatment-naïve CHB patients with normal or mildly-elevated ALT levels.

Efficacy and Safety of Combined Radiofrequency Ablation with Transarterial Chemoembolization in Patients with Barcelona Clinic Liver Cancer Stage A Hepatocellular Carcinoma Ineligible for Curative Treatment.

Background/Aims: Surgical resection or ablation is recommended for the treatment of early hepatocellular carcinoma (HCC), whereas transarterial chemoembolization (TACE) is frequently used in early HCC ineligible for curative resection. We evaluated the clinical effects and safety of radiofrequency ablation (RFA) shortly after TACE in patients with Barcelona clinic liver cancer (BCLC) stage A HCC. Methods: Sixty-seven BCLC stage A HCC patients who failed to achieve complete response to TACE as either a first line treatment and who subsequently received RFA at the Konkuk University Medical Center from January 2005 to December 2017 were included. Evaluation indices included treatment response, overall survival rate, recurrence-free survival, prognostic factors, and procedure-related complications. Results: Median follow-up was 46.9 months. Fifty-four (80.6%) patients were of Child-Pugh class A, and 13 (19.4%) were of class B. Modified UICC stages were I in 10 (14.9%), II in 46 (68.7%), and III in 11 (16.4%) patients. In the 67 study subjects, cumulative recurrence-free survival rates were 86.8%, 55.9% and 29.7% at 1, 3, and 5 years, respectively, and overall survival rates were 100%, 93.4%, and 83.5% at 1, 3, and 5 years, respectively. Tumor size significantly predicted recurrence. No treatment-related death occurred. Conclusions: Combination of RFA was an efficient and safe treatment for BCLC stage A HCC patients that failed to achieve complete response to initial TACE. We suggest TACE plus RFA be considered as a curative option for early HCC patients ineligible for curative resection of RFA.