Systematic review with network meta-analysis: Comparative efficacy of oral nucleos(t)ide analogues for the prevention of chemotherapy-induced hepatitis B virus reactivation.

OBJECTIVES: Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection. RESULTS: Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%). MATERIALS AND METHODS: PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes. CONCLUSIONS: Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy.

Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1.

All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea.

Plumbagin Ameliorates CCl 4 -Induced Hepatic Fibrosis in Rats via the Epidermal Growth Factor Receptor Signaling Pathway.

Epidermal growth factor (EGF) and its signaling molecules, EGFreceptor (EGFR) and signal transducer and activator of transcription factor 3 (STAT3), have been considered to play a role in liver fibrosis and cirrhosis. Plumbagin (PL) is an extracted component from the plant and has been used to treat different kinds of cancer. However, its role in regulation of EGFR and STAT3 during liver fibrosis has not been investigated. In this study, the effects of PL on the regulation of EGFR and STAT3 were investigated in carbon tetrachloride (CCl4) induced liver fibrosis and hepatic stellate cells (HSC-T6). PL significantly attenuated liver injury and fibrosis in CCl4 treated rats. At concentrations of 2 to 6 µM, PL did not induce significant cytotoxicity of HSC-T6 cells. Moreover, PL reduced phosphorylation of EGFR and STAT3 in both fibrotic liver and heparin-binding EGF-like growth factor (HB-EGF) treated HSC-T6 cells. Furthermore, PL reduced the expression of α-SMA, EGFR, and STAT3 in both fibrotic liver and HB-EGF treated HSC-T6 cells. In conclusion, plumbagin could ameliorate the development of hepatic fibrosis through its downregulation of EGFR and STAT3 in the liver, especially in hepatic stellate cells.

Mesenchymal stem cells ameliorate experimental autoimmune hepatitis by activation of the programmed death 1 pathway.

Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in many autoimmune diseases. However, few studies have focused on the effects of MSCs on autoimmune hepatitis. In our study, we investigated the therapeutic effects of BMSCs (bone mesenchymal stem cells) transplantation in mouse experimental autoimmune hepatitis (EAH) and explored the potential mechanism. BMSCs were injected intravenously into EAH mice. Then, serum levels of ALT and AST, and pathologic alteration of liver tissue were measured to evaluate the liver function and inflammation degree. The expressions of programmed death ligand 1, IL-17 and IL-23 were detected by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. Upon serum biochemical levels and pathological examination, the BMSCs-treated mice especially with multiple dosing administration showed significantly reduction of liver damage. Moreover, the expression of IL-17 was down-regulated by BMSCs intervention as compared to the model group, whereas the PD-L1 and IL-23 were up-regulated following the administration of MSCs. In conclusion, the results of this study suggest that BMSCs transplantation, especially on multiple dosing, may exert immunosuppression effect to ameliorate EAH through the inhibition of IL-17 and up-regulation of PD-L1.

BMP-7 attenuates liver fibrosis via regulation of epidermal growth factor receptor.

The aim of this study was to elucidate the effect of bone morphogenetic protein-7 (BMP-7) on liver fibrosis induced by carbon tetrachloride (CCl4) in vivo and on the hepatic stellate cells (HSC) activation in vitro. In vivo, thirty male ICR mice were randomly allocated to three groups, the control group (n = 6), the CCl4 group (n = 18) and the BMP-7+CCl4 group (n = 6). The model of liver fibrosis was induced by intraperitoneal injection with CCl4 three times per week lasting for 12 weeks in CCl4 group and the BMP-7+CCl4 group. After 8 weeks injection with CCl4, mice were intraperitoneal injected with human recombinant BMP-7 in BMP-7+CCl4 group. Meanwhile, mice in the CCl4 group were only intraperitoneal injection with equal amount of saline. The degree of liver fibrosis was assessed by HE and Masson's staining. PCR and western blot were used to detect mRNA and protein levels. In BMP-7+CCl4 group, serum levels of alanine aminotransferase (ALT) and aminotransferase (AST) were decreased and serum albumin (Alb) was increased. Meanwhile, the expressions of transforming growth factor-ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) were down-regulated by BMP-7 intervention as compared to the CCl4 group (P < 0.05). Furthermore, BMP-7 also suppressed the expression of epidermal growth factor receptor (EGFR) and phosphorylated-epidermal growth factor receptor (pEGFR). HE and Masson stain showed that liver damage was alleviated in BMP-7+CCl4 group. In vitro study, expression of EGFR, TGF-ß1 and α-SMA were down regulated by BMP-7 dose-dependently, indicating it might effect on suppression of HSC activation. Therefore, our data indicate BMP-7 was capable of inhibiting liver fibrosis and suppressing HSCs activation, and these effects might rely on its crosstalk with EGFR and TGF-ß1. We suggest that BMP-7 may be a potential reagentfor the prevention and treatment of liver fibrosis.