Co-targeting RNA Polymerases IV and V Promotes Efficient De Novo DNA Methylation in Arabidopsis.

The RNA-directed DNA methylation (RdDM) pathway in plants controls gene expression via cytosine DNA methylation. The ability to manipulate RdDM would shed light on the mechanisms and applications of DNA methylation to control gene expression. Here, we identified diverse RdDM proteins that are capable of targeting methylation and silencing in Arabidopsis when tethered to an artificial zinc finger (ZF-RdDM). We studied their order of action within the RdDM pathway by testing their ability to target methylation in different mutants. We also evaluated ectopic siRNA biogenesis, RNA polymerase V (Pol V) recruitment, targeted DNA methylation, and gene-expression changes at thousands of ZF-RdDM targets. We found that co-targeting both arms of the RdDM pathway, siRNA biogenesis and Pol V recruitment, dramatically enhanced targeted methylation. This work defines how RdDM components establish DNA methylation and enables new strategies for epigenetic gene regulation via targeted DNA methylation.

A One Precursor One siRNA Model for Pol IV-Dependent siRNA Biogenesis.

RNA-directed DNA methylation in Arabidopsis thaliana is driven by the plant-specific RNA Polymerase IV (Pol IV). It has been assumed that a Pol IV transcript can give rise to multiple 24-nt small interfering RNAs (siRNAs) that target DNA methylation. Here, we demonstrate that Pol IV-dependent RNAs (P4RNAs) from wild-type Arabidopsis are surprisingly short in length (30 to 40 nt) and mirror 24-nt siRNAs in distribution, abundance, strand bias, and 5'-adenine preference. P4RNAs exhibit transcription start sites similar to Pol II products and are featured with 5'-monophosphates and 3'-misincorporated nucleotides. The 3'-misincorporation preferentially occurs at methylated cytosines on the template DNA strand, suggesting a co-transcriptional feedback to siRNA biogenesis by DNA methylation to reinforce silencing locally. These results highlight an unusual mechanism of Pol IV transcription and suggest a "one precursor, one siRNA" model for the biogenesis of 24-nt siRNAs in Arabidopsis.

In operando visualization of redox flow battery in membrane-free microfluidic platform.

Redox flow batteries (RFBs) are attractive large-scale energy storage techniques, achieving remarkable progress in performance enhancement for the last decades. Nevertheless, an in-depth understanding of the reaction mechanism still remains challenging due to its unique operation mechanism, where electrochemistry and hydrodynamics simultaneously govern battery performance. Thus, to elucidate the precise reactions occurring in RFB systems, an appropriate analysis technique that enables the real-time observation of electrokinetic phenomena is indispensable. Herein, we report in operando visualization and analytical study of RFBs by employing a membrane-free microfluidic platform, that is, a membrane-free microfluidic RFB. Using this platform, the electrokinetic investigations were carried out for the 5,10-bis(2-methoxyethyl)-5,10-dihydrophenazine (BMEPZ) catholyte, which has been recently proposed as a high-performance multiredox organic molecule. Taking advantage of the inherent colorimetric property of BMEPZ, we unravel the intrinsic electrochemical properties in terms of charge and mass transfer kinetics during the multiredox reaction through in operando visualization, which enables theoretical study of physicochemical hydrodynamics in electrochemical systems. Based on insights on the electrokinetic limitations in RFBs, we verify the validity of electrode geometry design that can suppress the range of the depletion region, leading to enhanced cell performance.

Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis.

BACKGROUND: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. PATIENTS AND METHODS: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. RESULTS: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). CONCLUSIONS: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.

Molecular Packing Topology and Interactions to Decipher Mechanical Compliances in Dicyano-distyrylbenzene Derivatives.

Flexible optoelectronics is the need of the hour as the market moves toward wearable and conformable devices. Crystalline π-conjugated materials offer high performance as active materials compared to their amorphous counterpart, but they are typically brittle. This poses a significant challenge that needs to be overcome to unfold their potential in optoelectronic devices. Unveiling the molecular packing topology and identifying interaction descriptors that can seamlessly accommodate strain offers essential guiding principles for developing conjugated materials as active components in flexible optoelectronics. The molecular packing and interaction topology of eight crystal systems of dicyano-distyrylbenzene derivatives are investigated. Face-to-face π-stacks in an inclined orientation relative to the bending surface can accommodate expansion and compression with minimal molecular motion from their equilibrium positions. This configuration exhibits good compliance towards mechanical strain, while a similar structure with a criss-cross arrangement capable of distributing applied strain equally in opposite directions enhances the flexibility. Molecular arrangements that cannot reversibly undergo expansion and compression exhibit brittleness. In the isometric CT crystals, the disproportionate strength of the interactions along the bending plane and orthogonal directions makes these materials sustain a moderate bending strain. These results provide an updated explanation for the elastic bending in semiconducting π-conjugated crystals.

The prognostic value of a combined immune score in tumor and immune cells assessed by immunohistochemistry in triple-negative breast cancer.

BACKGROUND: This study aimed to develop a novel combined immune score (CIS)-based model assessing prognosis in triple-negative breast cancer (TNBC). METHODS: The expression of eight immune markers (PD-1, PD-L1, PD-L2, IDO, TIM3, OX40, OX40L, and H7-H2) was assessed with immunohistochemistry on the tumor cells (TCs) and immune cells (ICs) of 227 TNBC cases, respectively, and subsequently associated with selected clinicopathological parameters and survival. Data retrieved from The Cancer Genome Atlas (TCGA) were further examined to validate our findings. RESULTS: All immune markers were often expressed in TCs and ICs, except for PD-1 which was not expressed in TCs. In ICs, the expression of all immune markers was positively correlated between one another, except between PD-L1 and OX40, also TIM3 and OX40. In ICs, PD-1, PD-L1, and OX40L positive expression was associated with a longer progression-free survival (PFS; p = 0.040, p = 0.020, and p = 0.020, respectively). In TCs, OX40 positive expression was associated with a shorter PFS (p = 0.025). Subsequently, the TNBC patients were classified into high and low combined immune score groups (CIS-H and CIS-L), based on the expression levels of a selection of biomarkers in TCs (TCIS-H or TCIS-L) and ICs (ICIS-H or ICIS-L). The TCIS-H group was significantly associated with a longer PFS (p < 0.001). Furthermore, the ICIS-H group was additionally associated with a longer PFS (p < 0.001) and overall survival (OS; p = 0.001), at significant levels. In the multivariate analysis, both TCIS-H and ICIS-H groups were identified as independent predictors of favorable PFS (p = 0.012 and p = 0.001, respectively). ICIS-H was also shown to be an independent predictor of favorable OS (p = 0.003). The analysis of the mRNA expression data from TCGA also validated our findings regarding TNBC. CONCLUSION: Our novel TCIS and ICIS exhibited a significant prognostic value in TNBC. Additional research would be needed to strengthen our findings and identify the most efficient prognostic and predictive biomarkers for TNBC patients.

ALT Is Not Associated With Achieving Subcirrhotic Liver Stiffness and HCC During Entecavir Therapy in HBV-Related Cirrhosis.

BACKGROUND & AIMS: We investigated whether baseline and on-treatment alanine aminotransferase (ALT) levels during entecavir (ETV) therapy are associated with achieving subcirrhotic liver stiffness (LS) and hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS: We analyzed data from 347 treatment-naïve patients with HBV-related cirrhosis, who started ETV between 2006 and 2011 and were followed up for >5 years without developing HCC. The study outcomes were achieving subcirrhotic LS at 5 years of ETV, and risk of HCC development beyond 5 years of ETV. Subcirrhotic LS was defined as <12 kPa by transient elastography. RESULTS: After 5 years of ETV, 227 (65.4%) patients achieved subcirrhotic LS. During a median follow-up of 9.2 years, 49 (14.1%) patients developed HCC beyond 5 years of ETV. ALT levels at baseline, at 1 year of ETV therapy, and 5 years of ETV therapy were not associated with the probability of achieving subcirrhotic LS at 5 years of ETV therapy or risk of HCC development beyond 5 years of ETV therapy (all P > .05). Patients achieving subcirrhotic LS at 5 years of ETV therapy had significantly lower risk of HCC development than those who did not (adjusted hazard ratio, 0.33; 95% confidence interval, 0.17-0.64; P = .001). CONCLUSIONS: Baseline and on-treatment ALT levels were not associated with achieving subcirrhotic LS at 5 years of ETV therapy or with risk of HCC development beyond 5 years of ETV therapy in patients with HBV-related cirrhosis. Achieving subcirrhotic LS at 5 years of ETV therapy was independently associated with lower risk of HCC development beyond 5 years of ETV therapy.

Response-Guided Therapy With Cefotaxime, Ceftriaxone, or Ciprofloxacin for Spontaneous Bacterial Peritonitis: A Randomized Trial: A Validation Study of 2021 AASLD Practice Guidance for SBP.

INTRODUCTION: For the treatment of spontaneous bacterial peritonitis (SBP), cefotaxime, ceftriaxone, and ciprofloxacin were used as first-line agents. However, considering the increasing rate of antibiotic resistance, it is unclear which of these drugs can be initially recommended. This study aimed to compare the current efficacy of the 3 antibiotics, namely cefotaxime, ceftriaxone, and ciprofloxacin, for the treatment of SBP in patients with cirrhosis with ascites, when guided by therapeutic responses. METHODS: This study was a multicenter, prospective, randomized controlled trial. The inclusion criteria were 16- to 75-year-old patients with liver cirrhosis with ascites, having polymorphonuclear cell count of >250/mm 3 . We performed a follow-up paracentesis at 48 hours to decide continuing or changing the assigned antibiotics and then assessed the resolution rates at 120 and 168 hours of treatment. RESULTS: A total of 261 patients with cirrhosis who developed SBP were enrolled. Most of the patients were diagnosed as those with SBP within 48 hours of admission. The resolution rates at 120 hours, which is the primary endpoint, were 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively ( P = 0.388), by intension-to-treat analysis. The 1-month mortality was similar among the groups ( P = 0.770). The model for end-stage liver disease score and the SBP resolution were significant factors for survival. CONCLUSION: The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. In addition, these antibiotics administered based on response-guided therapy were still efficacious as initial treatment for SBP, especially in those with community-acquired infections.

Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS: This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS: The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION: Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.

Complex-Shape Solid-State Photonic Droplets Prepared via Phase Separation and Microfluidics.

Complex-shape solid-state cholesteric liquid crystal (CLCsolid) droplets were prepared via solvent removal, phase separation, and photopolymerization of uniformly sized reactive CLC (rCLC)/fluorocarbon oil (FCO)/dichloromethane (solvent) droplets produced via a microfluidic method. The interfacial energies between rCLC and FCO, rCLC and water, and FCO and water of a rCLC/FCO droplet in an aqueous solution were precisely controlled through the specified surfactants. The shape of the rCLC/FCO droplet was strongly dependent on the balances among these interfacial energies, enabling the preparation of complex-shape droplets through the controlled concentration of the used surfactants. The complex-shape rCLC/FCO droplets showed photonic patterns consisting of a central reflection from a convex surface, cross-communication from a convex surface between adjacent particles, a photonic reflection band from the outer upward-facing concave surface, and total internal reflection from the inner upward-facing surface. Complex-shape CLCsolid particles obtained after photopolymerization and extraction of a nonreactive chiral dopant and FCO showed photonic patterns similar to those before photopolymerization without much deterioration of the photonic structure. These complex patterns make CLCsolid and rCLC/FCO droplets promising anticounterfeiting materials.

A machine learning model for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B.

BACKGROUND: Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML-based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). METHODS: Treatment-naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. RESULTS: The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8-72.3) months of follow-up, 69 (7.2%) patients developed HCC. Our ML-based HCC risk prediction model had an area under the receiver-operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p < .05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut-off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p < .001). CONCLUSIONS: Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT.

Determination of ovalbumin sensing response of protein-imprinted bilayered hydrogel strips via measurement of mechanically driven bending angles based on swelling-induced deformation.

Novel detection method has been developed to explore changes in mechanical bending angles on a bilayer of polyethylene terephthalate (PET) and molecularly imprinted polymer (MIP). For an ovalbumin (OVA)-imprinted hydrogel layer, functional monomers were employed to achieve sufficient binding effect in the polymer matrix. The OVA amount added in the MIP precursor solution and the dimensions of OVA-imprinted hydrogel (MIH) strips were controlled to maximize the change in bending angles as an OVA sensing response within a valid detection range. The sensing behaviors were determined by monitoring the difference in the bending angles via protein adsorption based on the swelling-induced deformation of the OVA-extracted hydrogel (E-MIH) strip. The equilibrium adsorption capacity of the E-MIH strip was calculated via the Bradford protein assay. The detection limit, quantification limit, and imprinting factor were calculated. To compare the selectivity coefficients, the adsorption behaviors of three proteins were investigated. Finally, the reusability of the E-MIH strip was explored via repeated adsorption and extraction. Based on the results, the E-MIH strips demonstrated a promising protein sensing platform monitoring mechanical bending angles affected by swelling deformation.

An artificial intelligence model to predict hepatocellular carcinoma risk in Korean and Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk. METHODS: Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development. RESULTS: In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up. CONCLUSIONS: This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir. LAY SUMMARY: Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.

Predictive Performance of CAGE-B and SAGE-B Models in Asian Treatment-Naive Patients Who Started Entecavir for Chronic Hepatitis B.

BACKGROUND & AIMS: Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB. METHODS: We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs). RESULTS: Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P < .05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ2) (76.2 vs 71.4) and linear trend (χ2) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3). CONCLUSIONS: Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB.

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis With Serum Hepatitis B Virus DNA <2,000 IU/mL.

INTRODUCTION: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history. METHODS: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC). RESULTS: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively. DISCUSSION: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.

Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: A multicenter study.

Renal safety is a critical issue in chronic hepatitis B (CHB) patients receiving long-term entecavir (ETV) or tenofovir disofuroxil fumarate (TDF) therapy. We investigated their effects on estimated glomerular filtration rate (eGFR). Treatment-naive CHB patients receiving ETV or TDF for ≥1 year were recruited. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration equation. We calculated average annual percent change (AAPC) in eGFR using Joinpoint regression. At the beginning of the observation, the ETV group had more unfavorable conditions than the TDF group: lower eGFR and higher FIB-4 and APRI than the TDF group (all p < .001). After 6 years of antiviral therapy, the mean eGFR in the ETV group (n = 1793) was maintained (96.0 at first year to 95.6 ml/min/1.73 m2 at sixth year; AAPC -0.09%; p = .322), whereas that in the TDF group (n = 1240) significantly decreased annually (101.9 at first year to 96.9 ml/min/1.73 m2 at sixth year; AAPC -0.88%; p < .001). Notably, in the TDF group, even patients without diabetes (AAPC -0.80%; p = 0.001) or hypertension (AAPC -0.87%; p = .001) experienced significant decrease in eGFR. Expectably, accompanying diabetes (AAPC -1.59%; p = .011) or hypertension (AAPC -1.00%; p = .002) tended to accelerate eGFR decrease. TDF treatment (odds ratio 1.66, p < .001), along with eGFR<60 ml/min/1.73 m2 , serum albumin<3.5 mg/dl, and hypertension, were independently associated with ongoing renal dysfunction, defined as a negative slope of the mean eGFR change. In conclusion, compared with ETV, long-term TDF treatment induced slow, but progressive renal dysfunction. Although the annual eGFR change by TDF was small, careful monitoring is necessary, especially in patients requiring life-long therapy.

Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma.

Lenvatinib is an oral multikinase inhibitor approved for use as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, like other agents in this drug class, lenvatinib is associated with clinically important adverse events (AEs) that could adversely affect patient outcomes. Hypertension, diarrhea, decreased appetite/weight, hand-foot skin reaction, and proteinuria are among the most common AEs associated with lenvatinib therapy. This article provides strategies for the effective management of lenvatinib-associated AEs based on the expert opinion of authors and currently available literature. Due to the high risk of AEs in patients receiving lenvatinib, prophylactic measures and regular monitoring for AEs are recommended. Lenvatinib dose interruption, adjustment, or discontinuation of treatment may be required for patients who develop AEs. For grade 1 or 2 AEs, dose interruption is generally not required. For persistent or intolerable grade 2 or 3 AEs, lenvatinib treatment should be interrupted until symptoms improve/resolve to grade 0-1 or baseline levels. Thereafter, treatment should be resumed at the same or a lower dose. Disease progression may occur in patients who do not initially respond to treatment or receive a suboptimal lenvatinib dose following dose reduction, resulting in lack of efficacy. Therefore, to derive maximum treatment benefit and ensure long-term disease control, lenvatinib should be maintained at the highest possible dose when managing AEs. To conclude, lenvatinib-associated AEs can be managed with prophylactic measures, regular monitoring and symptomatic management, which can ensure continued treatment and maximum survival benefit in patients with advanced HCC receiving first-line lenvatinib therapy.

Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B.

BACKGROUND AND AIM: Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden. METHODS: Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden. RESULTS: In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 â†’ 0.48, P < 0.001; FIB-4, mean 3.60 â†’ 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 â†’ 0.43, P < 0.001; FIB-4, mean 2.80 â†’ 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years. CONCLUSION: Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.

Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B.

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.