Efficacy and safety of long-term nucleos(t)ide analogue initial treatment in patients with chronic hepatitis B / 中华临床感染病杂志

Objective To evaluate the efficacy and safety of long-term nucleos (t) ide analogue treatment in patients with chronic hepatitis B (CHB).Methods Two hundred and two initially treated patients with CHB admitted in Zhejiang Provincial People's Hospital during March 2013 and August 2016 were enrolled in the study.Patients were divided into six groups according to the different antiviral therapy:adefovir group (ADV,n =43),entecavir group (ETV,n =44),lamivudine group (LAM,n =25),telbivudine group (LDT,n =23),LDT + ADV group (n =22),and LAM + ADV group (n =45).HBV DNA negative conversion rate,HBeAg serological conversion rate and estimated glomerular filtration rate (eGFR) at baseline and at 48th,96th,144th wk of treatment were measured.Chi-square test and repeated measure of ANOVA were used to analyze the data.Multivariate Logistic regression analysis was applied to detect the relevant risk factors of renal dysfunction in CHB patients.Results After treatment for 144 wks,the HBV DNA negative conversion rates in ETV and LDT group were higher than that in ADV group (both P ＜ 0.01),the levels of eGFR in ADV,ETV,LAM and LAM + ADV group were declined with time,while the eGFR levels in LDT and LDT + ADV group were increased with time (Ftime =3.939,Fgroup =3.983,P ＜0.01 or ＜0.05).After treatment for 96 wks and 144 wks,the levels of eGFR were higher in LDT and LDT + ADV group than those in other groups,respectively (all P ＜ 0.05).Multivariate Logistic regression analysis showed that age ≥40 (x2 =16.145,OR =4.452,95 ％ CI 2.149-9.223,P ＜ 0.05),mild abnormality of eGFR at baseline (x2 =16.449,OR =4.336,95％ CI 2.144-8.891,P ＜ 0.05),and ADV treatment (x2 =5.837,OR =5.280,95％ CI 1.369-20.365,P ＜ 0.05) were independent risk factors of renal dysfunction in CHB patients.Conclusion LDT long-term monotherapy or combination with ADV may improve renal function for patients with CHB,which provides a reference for long-term treatment of CHB patients with nucleos(t) ide analogues.

Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular carcinoma cell activity in vitro and in vivo.

Recent studies have indicated that mammalian target of rapamycin (mTOR) signaling has a critical role in the pathogenesis of hepatocellular carcinoma (HCC). In the current study, we investigated the activity of KU-0063794, a novel mTOR kinase inhibitor, against HepG2 HCC cells. Our results demonstrated that KU-0063794 blocked mTOR complex 1/2 (mTORC1/2) activation, and downregulated mTOR-regulated genes (Cyclin D1 and hypoxia-inducible factor 1α) in HepG2 cells. Consequently, KU-0063794 induced significant anti-survival and pro-apoptotic activities against HepG2 cells. When analyzing the possible KU-0063794-resistance factors, we showed that KU-0063794 induced cyto-protective autophagy activation in HepG2 cells, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 degradation, Beclin-1 expression and LC3B-I to LC3B-II conversion. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine (3-MA) and chloroquine, dramatically enhanced KU-0063794-induced cytotoxicity against HepG2 cells. Further, RNAi knockdown of Beclin-1 also increased KU-0063794 sensitivity in HepG2 cells. In vivo, oral administration of KU-0063794 repressed HepG2 xenograft growth in severe combined immunodeficient (SCID) mice, and its activity was further enhanced with co-administration of the autophagy inhibitor 3-MA. In summary, KU-0063794 inhibits HepG2 cell growth in vitro and in vivo, its activity could be further enhanced with autophagy inhibition.

The association of primary liver cancer with the mutations in basic core promoter and precore genes of hepatitis B virus / 中华临床感染病杂志

Objective To investigate the association of primary liver cancer(PLC)with the mutations of HBV precore and basic core promoter(BCP)genes.Methods The serum markers of hepatitis B and the quantities of serum HBV DNA were detected in 144 HBsAg-positive PLC patients.The precore and BCP gene mutations in patients with HBeAg-negtive and HBV DNA-positive were detected by real-time PCR.One hundred and twenty chronic hepatitis B(CHB)patients were randomly selected to serve as the conol.Results There were 46(3 1.94%)patients with HBeAg-positive and 98(68.06%)patients with HBeAg-negative.In 98 HBeAg-negative patients,56(57.14%)were HBV DNA-positive,in which 43 (76.79%)were with precore 1896 gene mutations,50(89.29%)were with BCP1762/1764 gene mutations.and 38(67.86%)were with both gene mutations.Precore 1896 and BCP1762/1764 gene mutation rates in PLC patients were much higher than those in CHB patients(χ2=9.36 and 5.77,P＜0.05).Conclusion PLC may be associated with the mutations of HBV precore anti BCP genes.