Treatment Efficacy and Safety of Tenofovir-Based Therapy in Chronic Hepatitis B: A Real Life Cohort Study in Korea

<div><p>Background & Aims</p><p>We evaluated the efficacy and safety of Tenofovir disoproxil fumarate (TDF)-based therapy in naïve and treatment-experienced chronic hepatitis B (CHB) patients for 96 weeks in Korean real life practice.</p><p>Methods</p><p>A total of 209 CHB patients with a prescription for TDF at the Seoul and Daejeon St. Mary’s hospitals were enrolled from December 2012 to October 2014. We compared the virological responses and evaluated the renal safety of treatment-naive and treatment-experienced patients.</p><p>Results</p><p>An overall complete virological response (CVR) was achieved in 80.4% and 84.6% of patients at weeks 48 and 96, respectively. In a subgroup analysis, CVR at week 96 was present in 88.4%, 75.0%, 75.5%, and 83.3% of participants in the lamivudine-resistant (LAM-R) group, adefovir-resistant (ADV-R) group, multidrug-resistant (MDR) group, and suboptimal response group, respectively. In a multivariate analysis, ADV-R, MDR, hepatitis B virus DNA, and hepatitis B e antigen were independent predictors for CVR. With regard to renal safety, diabetes mellitus, cirrhosis, and an initial low estimated glomerular filtration rate were independent factors affecting creatinine elevation (≥0.5 mg/dL). Moreover, two patients with DM and cirrhosis experienced TDF-related Fanconi syndrome.</p><p>Conclusions</p><p>TDF-based therapy demonstrated sustained viral suppression and favorable safety during a 2-year treatment period. The LAM-R and suboptimal response groups showed comparable efficacy to the naïve group, while the ADV-R and MDR groups were significantly associated with a low CVR. Close monitoring of renal safety should be mandatory when treating CHB patients receiving TDF, particularly those with DM and cirrhosis.</p></div

Flow chart of the enrolled participants.

<p>CHB, chronic hepatitis B; TDF, tenofovir disoproxil fumarate; HCC, hepatocellular carcinoma; LAM-R, lamivudine-resistant; ADV-R, adefovir-resistant; MDR, multidrug-resistant.</p

Cumulative rates of a complete virological response (CVR) at week 96 according to subgroup.

<p>(A) Comparison of CVR between NA-naïve and LAM-R patients, (91.5% vs. 88.4%, <i>P</i> = 0.677) and between NA-naïve patients and the suboptimal response group (91.5% vs. 83.3%, <i>P</i> = 0.761). (B) Comparison of CVR between NA-naïve and ADV-R patients, (91.5% vs. 75.0%, <i>P</i> = 0.023) and between NA-naïve patients and the MDR group (91.5% vs. 75.5%, <i>P</i> = 0.256). NA, nucleos(t)ide analogue; LAM, lamivudine; R, resistant; ADV, adefovir; MDR, multidrug-resistant.</p

Comparison of subgroup treatment responses at weeks 48 and 96.

<p>Comparison of subgroup treatment responses at weeks 48 and 96.</p

Cumulative rates of a complete virological response (CVR) at week 96 according to HBeAg status.

<p>Comparison of CVR between HBeAg (+) patients and HBeAg (-) patients (80.0% vs. 93.2%, <i>P</i> < 0.001). HBeAg, hepatitis B e antigen.</p

Univariate and multivariate Cox proportional hazard analyses predicting factors for CVR.

<p>Univariate and multivariate Cox proportional hazard analyses predicting factors for CVR.</p

Univariate and multivariate logistic regression analyses predicting factors for creatinine elevation of ≥ 0.5 mg/dL.

<p>Univariate and multivariate logistic regression analyses predicting factors for creatinine elevation of ≥ 0.5 mg/dL.</p

Overexpression of DUSP1 rescues anti-HCV effect by DUSP1 silencing.

<p>LV-shDUSP1 cells were transfected with pcDNA3.1-DUSP1 plasmid. (A) At 72 h post-transfection, the level of HCV proteins were determined by western blot analysis. (B) Localization of STAT1 was detected using immunocytochemistry. Red, anti-STAT1; blue, DAPI. White narrows indicate cytoplasm location of STAT1; original magnification ×200. All data are representative of at least three independent experiments.</p

<i>Aronia melanocarpa</i> Extract Ameliorates Hepatic Lipid Metabolism through PPARγ2 Downregulation

<div><p>Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Studies have demonstrated that anthocyanin-rich foods may improve hyperlipidemia and ameliorate hepatic steatosis. Here, effects of <i>Aronia melanocarpa</i> (AM), known to be rich of anthocyanins, on hepatic lipid metabolism and adipogenic genes were determined. AM was treated to C57BL/6N mice fed with high fat diet (HFD) or to FL83B cells treated with free fatty acid (FFA). Changes in levels of lipids, enzymes and hormones were observed, and expressions of adipogenic genes involved in hepatic lipid metabolism were detected by PCR, Western blotting and luciferase assay. In mice, AM significantly reduced the body and liver weight, lipid accumulation in the liver, and levels of biochemical markers such as fatty acid synthase, hepatic triglyceride and leptin. Serum transaminases, indicators for hepatocyte injury, were also suppressed, while superoxide dismutase activity and liver antioxidant capacity were significantly increased. In FL83B cells, AM significantly reduced FFA-induced lipid droplet accumulation. Protein synthesis of an adipogenic transcription factor, peroxisome proliferator-activated receptor γ2 (PPARγ2) was inhibited <i>in vivo</i>. Furthermore, transcriptional activity of PPARγ2 was down-regulated <i>in vitro</i>, and mRNA expression of PPARγ2 and its downstream target genes, adipocyte protein 2 and lipoprotein lipase were down-regulated by AM both <i>in vitro</i> and <i>in vivo</i>. These results show beneficial effects of AM against hepatic lipid accumulation through the inhibition of PPARγ2 expression along with improvements in body weight, liver functions, lipid profiles and antioxidant capacity suggesting the potential therapeutic efficacy of AM on NAFLD.</p></div

DUSP1 suppression increases STAT1 activity and nuclear translocation.

<p>Phosphorylation (A) and nuclear translocation (B) of STAT1 were assessed by cell-based ELISA and confocal microscopy, respectively. (A) Expression of phospho-STAT1 was normalized to that of STAT1 and then to the ratio in LV-cont-infected cells. (B) Red, anti-STAT1; blue, DAPI. Merged image allows assessment of nuclear localization of STAT1; original magnification ×200. All data are representative of at least three independent experiments.</p