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Objective To study the role of silent mating type information regulation 2 homolog1 (SIRT1)-adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in hepatitis C virus core protein (HCV-core) induced energy metabolism disorders of hepatocytes.Methods HepG2 cells were transfected with recombined expressed plasmid pcDNA3.1-core.The level of reactive oxygen species (ROS),value of ATP/ADP and activity of AMPK α-2,and nicotinamide adenine dinucleotide (NAD)+/NADH in HepG2 cells expressing HCV-core were detected by flow cytometry,liquid scintillation counter and chromatometry,respectively.The activity of SIRT1 was detected with a fluorometric assay kit.Reverse transcription polymerase chain reaction (RT-PCR) and Western blot assay were performed to examine the expression of SIRT1 and AMPK α-2.Quantitative data were analyzed by t-test.Results It was confirmed by Western blot assay that HepG2 cells expressed HCV-core with relative molecular weight of 22 000.Compared to HepG2 cells,the level of ROS in HepG2 cells expressing HCV-core was significantly increased (1.0 ±0.1 vs 4.0±0.5,t=14.411,P＜0.01),the values of ATP/ADP were similar (8.2±2.2 vs 9.3±2.8,t=0.757,P＞0.05),AMPK α-2 (0.8±0.2 vs 0.2±0,t=7.345,P＜0.01),the values of NAD+/NADH (0.08±0.02 vs 0.02±0,t=7.348,P＜0.01),the activity of SIRT1 [(0.30±0.05) pmol· μg-1 · min-1 vs (0.15±0.04) pmol · μg 1 · min 1,t=5.738,P＜0.01] and the mRNA levels of SIRT1 (0.8±0.2 vs 0.4±0.1,t=4.382,P＜0.01) and AMPK α-2 mRNA (0.9±0.3 vs 0.2±0,t=5.715,P＜0.01),and the expression of SIRT1 (0.8±0.2 vs 0.3±0,t=5.941,P＜0.01) and phosphorylated AMPK protein (0.5±0.1 vs 0.1±0,t=9.608,P＜0.01) were all significantly decreased.Conclusion HCV core protein induces energy metabolism disorders of hepatocytes by down-regulation of SIRT1-AMPK signaling pathway.
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ObjectiveTo investigate the effect of adding metformin to peginterferon alfa-2a and ribavirin on the efficacy in patients with genotype 1 chronic hepatitis C and insulin resistance.Methods Ninety-eight patients with genotype 1 chronic hepatitis C and insulin resistance were randomized into the treatment group (n=49) and the control group (n=49).The patients in the control group were treated with peginterferon alfa-2a and ribavirin,and those in the treatment group were treated with metformin in addition to peginterferon alfa-2a and ribavirin. The virologic response rate,the homeostasis model assessment for insulin resistence index (HOMA-IR) and incidence of side effects were compared between two groups.The related factors of sustained virological response (SVR) were studied by multivariate logistic regression analysis.ResultsThe SVR rate of the patients in the treatment group was significantly higher than that of the control group (59.2％ vs 38.8％; x2 =4.083,P=0.043).The HOMA-IR of patients in the treatment group at week 12,24,48 of treatment and week 24 of follow-up were 3.00±0.65,1.90±0.45,1.75±0.40 and 1.60±0.35,respectively,which were all lower than those in the control group (3.50±0.72,2.90±0.64,2.74± 0.48 and 2.60±0.55,respectively) (t=3.610,8.947,11.091 and 10.738,respectively; all P＜ 0.01).The incidence of diarrhea in the treatment group was higher than the control group (28.6％ vs 10.2％ ; x2 =5.288,P=0.021).In multivariate logistic regression analysis,the independent factors associated with SVR were metformin treatment (P =0.009) and HOMA-IR＜ 2 at week 24 of treatment (P=0.011 ). Conclusion The combination of metformin,peginterferon alfa-2a and ribavirin improves insulin sensitivity and increases SVR rate of patients with hepatitis C genotype 1 and insulin resistance with good safety profile.
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Objective To investigate the corelation between neutropenia (ANC) incidence and infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C.Methods A retrospective cohort study of 399 patients treated with peginterferon and ribavirin derived from database of Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University was conducted.The incidence of infections and their relation with ANC were investigated.Potential risk factors for infection were identified by multivariate analysis.Results During treatment,neutropenia (ANC ＜ 1.50 ×109/L) occurred in 251 patients.Among which,mild neutropenia [ANC: ( ＞ 0.75-＜ 1.50) x 109/L],moderate neutropenia [ANC: ( 0.50-0.75 ) × 109/L]and severe neutropenia ( ANC ＜ 0.50 × 109/L)occurred in 132 patients,103 patients and 16 patients,respectively.A total of 80 infections (20.1％ )occurred,among which,14 infections were defined as severe.There was no significant difference in infection rate between patients with and without neutropenia ( 19.9％,50/251 vs 20.3％,50/251 ; x2 =0.007,P =0.933).There was no significant difference in infection rate between patients with and without peginterferon dose reduction ( 21.5％,31/144 vs 19.2％,49/255 ; x2 =0.307,P =0.580 ).In multivariate logistic regression analysis,the independent factors associated with infection were age (P =0.021),diabetes (P =0.004) and cirrhosis (P =0.012).Conclusions Infections during treatment with peginterferon alfa and ribavirin for chronic hepatitis C are irrelevant to neutropenia.The independent factors associated with infection are age,diabetes and cirrhosis.
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Objective To study the impact of ribavirin cumulative dose on virological response rates in genotype 1 hepatitis C virus(HCV)infected patients.Methods The medical records of 225 genotype 1 chronic hepatitis C(CHC)patients treated with peginterferon α-2a plus ribavirin were retrospectively analyzed.These patients were divided into four groups according to ribavirin cumulative dose:>97%,80%-97%,60%-79%and97%(65.6%,84/128),80%-97%(60.5%,26/43),60%-79%(58.3%,21/36)(x2=9.538,P=0.023).The relapse rate was 61.5%(8/13)in group of ribavirin cumulative dose97%(20.0%,21/105),80%-97%(23.5% ,8/34),60%-79%(27.6%,8/29)(x2=10.837,P-0.013).Among patients achieved rapid virological response(RVR),SVR in groups of ribavirin cumulative dose>97%,80%-97%,60%-79%and<60 % of standard dose were 92.0%(23/25),88.9%(8/9),85.7%(6/7)and 75.0%(3/4),respectively(x2=1.098,P=0.778).Conclusiom Mlid reduction of ribavirin dose not affect SVR of genotype 1 HCV infected patients.However,the relapse rate is high and SVR is low in patients treated with ribavirin cumulative dose<60% of standard dose.
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ObjectiveTo investigate the impact of age and sex on virologic responses rates to peginterferon alfα-2a and ribavirin treatment in patients with chronic hepatitis C.MethodsThe medical records of 449 chronic hepatitis C patients,treated with peginterferon and ribavirin in Department of Infectious Diseases,the Second Affiliated Hospital,Harbin Medical University,were retrospectively analyzed.These patients were divided into three groups according to age:patients ＜40 years (n =131 ),patients 40-50 years ( n =131 ) and patients ＞ 50 years ( n =187 ).The virologic response rates,the incidences of side events,and the rates of patients receiving ≥ 80％ of planned peginterferon alfα-2a or ribavirin dose were compared between male and female patients in the three groups.The influential factors on sustained virologic response (SVR) of patients were studied by multivariate analysis.Results For genotype 1,in patients ＜ 40 years group,the SVR rate of female was significantly higher than that of male (75.0％,30/40 vs 54.0％,27/50; P ＜0.05 ) ; in patients 40-50 years group,there was no significant difference in the SVR rate between male and female (51.0％,25/49 vs 53.7％,22/41 ; P ＞ 0.05 ) ; in patients ＞50 years group,the SVR rate of female was significantly lower than that of male (31.1％,19/61 vs 50.7％,34/67; P ＜0.05).For genotype 2,there were no significant differences in virologic response rates between male and female in the three groups.The incidence of adverse events of patients aged ＜ 40 years group,40-50 years group,＞ 50 years group,were 51.1％ (67/131),51.1％ (67/131),and 70.6％ (132/187),respectively,and the incidence of adverse events of patients aged ＞ 50 years was significantly higher than those of other groups ( P ＜ 0.001 ).For genotype 1,in patients ＞ 50 years group,the rate of patients receiving ≥80％ of planned ribavirin dose of female was significantly lower than that of male (42.6％,26/61 vs 62.7％,42/67; P ＜ 0.05).In multivariate analysis,the independent factors associated with SVR of patients aged ＞ 50 years were sex ( P =0.013 ),genotypes ( P =0.002 ),cirrhosis ( P =0.004 ),≥ 80％ of planned ribavirin dose ( P =0.008 ) and presence of rapid virologic response (RVR) ( P =0.001 ).ConclusionsFor genotype 1 patients,in patients ＜ 40 years group the SVR rate of female is higher than that of male; in patients 40-50 years group,male and female share similar SVR rates;in patients ＞ 50 years group the SVR rate of female is lower than that of male.Age and sex has no impact on virologic responses rates for genotype 2 patients.