Impact of HCV eradication by directly acting antivirals on glycemic indices in chronic hepatitis C patients -a nationwide Taiwan HCV registry.

BACKGROUND/AIMS: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive. METHODS: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%). RESULTS: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001). CONCLUSIONS: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

INTRODUCTION: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). METHODS: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. RESULTS: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. CONCLUSION: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Effectiveness and safety of 8-week glecaprevir/pibrentasvir in HCV treatment-naïve patients with compensated cirrhosis: real-world experience from Taiwan nationwide HCV registry.

BACKGROUND: Large-scale real-world data of the 8-week glecaprevir/pibrentasvir (GLE/PIB) therapy for treatment-naïve patients of chronic hepatitis C virus (HCV) infection with compensated cirrhosis is scarce. METHODS: The TASL HCV Registry (TACR) is an ongoing nationwide registry program that aims to set up a database and biobank of patients with chronic HCV infection in Taiwan. In this study, data were analyzed as of 31 October 2021 for treatment-naïve HCV patients with compensated cirrhosis receiving 8-week GLE/PIB therapy. Effectiveness reported as sustained virologic response at off-therapy week 12 (SVR12) and safety profiles were assessed. Patient characteristics potentially related to SVR12 were also evaluated. RESULTS: Of the 301 patients enrolled, 275 had available SVR12 data. The SVR12 rate was 98.2% (270/275) in the modified intention-to-treat (mITT) population and 89.7% (270/301) in the ITT population. For those mITT patients with genotype 3, FibroScan > 20 kPa, platelet < 150,000/µl, and FibroScan > 20 kPa and platelet < 150,000/µl, the SVR12 rates were 100% (6/6), 100% (12/12), 98.0% (144/147), 100% (7/7), respectively. Overall, 24.9% (75/301) patients experienced adverse events (AEs). The most frequent AEs (> 5%) included fatigue (9.0%) and pruritus (7.0%). Seven (2.3%) patients experienced serious AEs and two (0.7%) resulted in permanent drug discontinuation. None of them were considered as GLE/PIB-related. CONCLUSIONS: In this large-scale real-world Taiwanese cohort, 8-week GLE/PIB therapy was efficacious and well tolerated for treatment-naïve compensated cirrhosis patients. SVR12 rates were similarly high as in the clinical trials, including those with characteristics of advanced liver disease.

Nationwide registry of glecaprevir plus pibrentasvir in the treatment of HCV in Taiwan.

The study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in Taiwan. The Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). The overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). The results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.

Molecular structures of nonvolatile components in the Haihong fruit wine and their free radical scavenging effect.

In order to investigate the correlation between free radical scavenging effect and the related molecular structures of active substances in the Haihong fruit (Malus Micromalus Makino) wine, sixteen kinds of components were isolated from the fruit wine. The structures of thirteen components were identified by UV, FTIR, LC-MS, 1D-NMR and 2D-NMR. The scavenging abilities of the fruit wine on DPPH (2,2-Diphenyl-1 -picrylhydrazyl radical), OH, O2- and the protective effects on red blood cell, SOD (Superoxide Dismutase), CAT(Catalase) and GPX(glutathione peroxidases) in aging mice tissues were studied. Results showed that the structures of o-diphenol and m-diphenol play an important role in scavenging free radicals. A larger conjugation system in functional molecule is conducive to getting a higher scavenging rate of free radicals. When the chemical shift of phenol hydrogen is lower, the anti-oxygenation ability is stronger. The fruit wine exhibits a strong scavenging ability on free radicals. It can inhibit the damage of red blood cells caused by OH radical.

MiR-139-5p inhibits the proliferation of gastric cancer cells by targeting Regulation of Nuclear Pre-mRNA Domain Containing 1B.

Regulation of Nuclear Pre-mRNA Domain Containing 1B (RPRD1B) has been of great interest in the field of oncology in recent years. The relationship between miRNAs and RPRD1B in gastric cancer (GC) has not been adequately reported. This study was designed to screen RPRD1B-targeted miRNAs and investigate its regulatory mechanism in GC cells. Quantitative RT-PCR and in situ hybridization were used to detect miRNA expression in GC tissues. Colony formation, EdU cell proliferation assay, and flow cytometry were used to analyze the cell cycle. Database-assisted gene expression analysis revealed that RPRD1B was targeted and regulated by miRNA-139-5p in GC. miRNA-139-5p expression was higher in GC tissue than in normal tissues and significantly correlated with tumor size, pathological stage, and disease-free survival of GC (p < 0.05). MiRNA-139-5p regulates GC cell proliferation and affects the transition from G1 to S phase. It binds explicitly to the 2013-2019 sites of the 3'UTR of RPRD1B and negatively regulates RPRD1B expression. We demonstrated that the ability of miR-139-5p to regulate GC cell proliferation depends on RPRD1B. This process is accompanied by changes in Cyclin D1 protein expression. We established a miR-139-5p/RPRD1B/tumor proliferation axis in GC, which may serve as novel biomarkers and drug targets for GC.

APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.

Anti-oxidation and anti-aging activity of polysaccharide from Malus micromalus Makino fruit wine.

Malus micromalus Makino fruit wine was used as a raw material and a water soluble polysaccharide (MWP-2) was successfully separated from it by fractionated extraction, alcohol precipitation, macroporous resin purification, cellulose column purification, running water dialysis, and vacuum freeze drying. The structure of MWP-2 was preliminarily analyzed by high performance gel-permeation chromatography (HPGPC), ion chromatograph (IC) and FT-IR. The anti-oxidation and the anti-aging activity of MWP were studied. Results showed that the relative molecular mass of MWP-2 was 1 × 105 Da and it was composed of galactose, glucose, mannose and fructose in the mole ratio of 1:33.2:8.4:7.2. Antioxidant experiments in vitro showed that MWP had different degrees of scavenging effects on the hydroxyl radicals, DPPH (1,1-two phenyl-2-bitter hydrazine radical) free radical, and superoxide radicals, presenting a certain dose effect relationship. However, the anti-aging experiments in vivo showed that MWP could significantly inhibit the apoptosis of cerebral cortex cells and the formation of lipid peroxide in the cerebral cortex of aging model mice, improve the activity of the antioxidant enzyme system, and exert a certain anti-aging effect.

APASL clinical practice recommendation: how to treat HCV-infected patients with renal impairment?

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.

Influences of molding processes and different dispersants on the dispersion of chopped carbon fibers in cement matrix.

Chopped carbon fiber-reinforced cement composite (CFRC) has become one of the potential smart materials in recent years. The key process of preparing this kind of composite at the early stage is how to disperse carbon fibers evenly into the cement matrix to achieve CFRC composite with good properties. In this study, a three-step mixing process and a six-step mixing process for the preparation of CFRC were suggested, respectively. The fracture morphology was observed by scanning electron microscopy. The influence of mass fractions of three common dispersants methyl cellulose (MC), carboxymethyl cellulose sodium (CMC) and hydroxyethyl cellulose (HEC) on the dispersion of short carbon fibers in water under certain temperature was investigated prior to the manufacture of CFRC. The correlation between mass fraction and viscosity was discussed, and the dispersion effect was assessed from the structure of dispersants and molding process. A hypothetical capsule theory was proposed to reasonably explain the dispersion effect of MC, CMC, and HEC. The experiments showed that pre-dispersion by ultrasonic vibration improved the dispersion of carbon fibers greatly. The dispersivity of carbon fibers was closely related to the category and mass fractions of dispersants. With the same mass fraction of dispersants at a certain temperature, the dispersion effect was in order of HEC > CMC > MC. Meanwhile, when the mass fraction of HEC was between 0.6 and 0.8 wt% by weight of cement and the mass fraction in the aqueous solution was between 1.65 and 1.80 wt%, carbon fibers dispersed most ideally and distributed further uniformly in the cement matrix.

The autophagy marker LC3 strongly predicts immediate mortality after surgical resection for hepatocellular carcinoma.

The remnant liver's ability to regenerate may affect post-hepatectomy immediate mortality. The promotion of autophagy post-hepatectomy could enhance liver regeneration and reduce mortality. This study aimed to identify predictive factors of immediate mortality after surgical resection for hepatocellular carcinoma (HCC). A total of 535 consecutive HCC patients who had undergone their first surgical resection in Taiwan were enrolled between 2010 and 2014. Clinicopathological data and immediate mortality, defined as all cause-mortality within three months after surgery, were analyzed. The expression of autophagy proteins (LC3, Beclin-1, and p62) in adjacent non-tumor tissues was scored by immunohistochemical staining. Approximately 5% of patients had immediate mortality after surgery. The absence of LC3, hypoalbuminemia (<3.5 g/dl), high alanine aminotransferase, and major liver surgery were significantly associated with immediate mortality in univariate analyses. Multivariate logistic regression demonstrated that absence of LC3 (hazard ratio/95% confidence interval: 40.8/5.14-325) and hypoalbuminemia (2.88/1.11-7.52) were significantly associated with immediate mortality. The 3-month cumulative incidence of mortality was 12.1%, 13.0%, 21.4% and 0.4%, respectively, among patients with absence of LC3 expression, hypoalbuminemia, both, or neither of the two. In conclusion, the absence of LC3 expression in adjacent non-tumor tissues and hypoalbuminemia were strongly predictive of immediate mortality after resection for HCC.

APASL consensus statements and recommendation on treatment of hepatitis C.

The Asian-Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL consensus statements and recommendation on management of hepatitis C" in March, 2015, in order to revise "APASL consensus statements and management algorithms for hepatitis C virus infection (Hepatol Int 6:409-435, 2012)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations on treatment of hepatitis C are presented in this review.

APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing.

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.

Insulin-like growth factor II in hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignant human tumors. Hepatocarcinogenesis is a multistep process with a multifactorial etiology. Chronic hepatitis B and hepatitis C virus infection, alcohol drinking and cirrhosis of any etiology are the major risk factors for hepatocellular carcinoma. Growth factors, their receptors and related proteins are involved in the process of malignant transformation. The IGF axis is involved in the proliferation and differentiation of normal, transformed and malignant hepatocytes. In the context of hepatocarcinogenesis, IGF-II has, in particular, been investigated thoroughly. Increased IGF-II bioavailability, protease activity of IGF-binding proteins and IGF-I receptor expression, decreased expression of IGF-II receptor and IGF-binding proteins are thought to contribute to hepatocellular carcinoma genesis. This review will first focus on the role of the IGF axis in hepatocarcinogenesis. In the second part it will emphasize circulating IGF-II levels in chronic liver disease and hepatocellular carcinoma, and diagnostic application of serum IGF-II level in both small and larger hepatocellular carcinoma.

Pyrolysis mechanism of carbon matrix precursor cyclohexane--the formation of condensed-ring aromatics and the growing process of molecules.

Based on the experiments, the UAM1 method was adopted to investigate benzene condensation of an important intermediate and the molecule growing mechanism during the cyclohexane pyrolysis process. The conclusions were drawn as follows: (1) from the viewpoint of thermodynamics, the condensation of benzene and C4H5* is a spontaneous reaction and the rising temperature will increase the spontaneous tendency of the reaction. (2) From the viewpoint of kinetic, the condensation of benzene and C4H5* is a two-step reaction. The rate-determining step is step 2 of hydrogen removal from intermediate C10H10 (I1) with the activation energy of 350.61 kJ/mol below 1473 K while the rate-determining step is step 1 that free radical C4H5* attacks benzene to form intermediate C10H10 (I1) with the activation energy DeltaE(0)(not equal to theta)=31.74 kJ/mol above 1473 K. (3) The space structure, electronic structure and thermodynamics parameters of molecular reaction of dense-ring aromatizing compounds can be used to replace the resonance energy and free valence to judge the activation of thermodynamic reaction of compounds. And (4) the analysis of the space structure, electronic structure and thermodynamic parameters show that the growing process of molecules with benzene used as initial reactants becomes more easier as the multi-ring aromatizing molecular system increases.

Treatment of chronic hepatitis C in southern Taiwan.

Chronic hepatitis C virus (HCV) infection may lead to cirrhosis and hepatocellular carcinoma. Interferon (IFN)-alpha is effective in the treatment of chronic hepatitis C. The rate of response to IFN is enhanced by increasing the IFN dose. Extending the treatment duration can reduce the relapse rate. Addition of ribavirin to IFN increases the sustained virological response (SVR). Thus, combination therapy with IFN and ribavirin was adopted for the treatment of chronic hepatitis C in Kaohsiung Medical University Hospital in 1998. Approximately 60% of patients receiving IFN/ribavirin therapy gained SVR. IFN 6 million units three times per week combined with daily ribavirin for 6 months achieved SVR more frequently than combination therapy with 3 million units. Factors for SVR in these combination regimens were HCV genotype, viral load and early virological response. Long-term follow-up of patients treated with IFN has shown that SVR might reduce the risk of progression to cirrhosis and hepatocellular carcinoma. Pegylated (peg)-IFN has a longer half-life and better efficacy. Combination therapy with peg-IFN and ribavirin accomplished higher SVR than conventional IFN and ribavirin. A multicenter clinical trial was conducted in Taiwan to compare the efficacy of combination therapy between peg-IFN/ribavirin and conventional IFN/ribavirin for 6 months. SVR was higher in patients receiving peg-IFN and ribavirin, especially in those infected with HCV genotype 1b. Based on the results obtained, the national health insurance started to sponsor the combination therapy in October 2003, with a suggested duration for 6 months. Some small-scale studies in Taiwan have postulated higher SVR for treatment duration of 12 than of 6 months in patients with genotype 1b. Further investigation should be conducted in the near future.

Continuum and discrete pulsed cavity ring down laser absorption spectra of Br2 vapor.

The absorption cross-sections at room temperature are reported for the first time, of Br2 vapor in overlapping bound-free and bound-bound transition of A(3)pi1u <-- Xsigma(g)+, X(1)pi1u <-- X(1)sigma(g)+ and B(3)pi0u <-- X(1)sigma(g)+, using cavity ring down spectroscopy (CRDS) technique. We reported here, the A(3)pi1u <-- X(1)sigma(g)+, transition is included along with the two stronger X(1)pi1u <-- X(1)sigma(g)+ and B(3)pi0u <-- X(1)sigma(g) transitions of Br2. We obtained discrete absorption cross-section in the rotational structure, the continuum absorption cross-sections, and were also able to measure the absorption cross-section in separate contribution of A(3)pi1u <-- X(1)sigma(g)+, (1)pi1u <-- X(1)sigma(g)+, and B(3)pi0u <-- X(1)sigma(g)+ transitions using CRDS method to use quantum yield of Br*((2)P(1/2)). We obtained absorption cross-section order 10(-19) cm2 and detection 10(13) molecule cm(-3) (1 mTorr) of Br2. The absorption cross-sections are increasing with increasing excitation energy in the wavelength region 510-535 nm.