[Show abstract][Hide abstract] ABSTRACT: A simeprevir (SMV)-based regimen has shown promising results in treating chronic hepatitis C virus (HCV) infection. This meta-analysis aimed to assess the efficacy and safety of simeprevir for treating HCV genotype 1 infection.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, along with the reference lists of retrieved articles. The meta-analysis only included randomized controlled trials (RCTs) that compared the efficacy and safety of addition of SMV to peginterferon (PegIFN) and ribavirin (RBV) (triple regimen) with PegIFN/RBV alone (dual regimen) in treating chronic HCV genotype 1 infection.
A total of seven RCTs involving 2,301 patients were included. The triple regimen had a higher pooled sustained virologic response (SVR) rate [odds ratio (OR) = 4.57; 95% confidence interval (CI): 3.34-6.27; p < 0.001)] and lower pooled relapse rate [relative risk (RR) = 0.41; 95% CI: 0.33-0.50; p < 0.001] than the dual regimen had. The pooled incidence of adverse events (AEs) was comparable between the two regimens (RR= 1.01; 95% CI: 0.99-1.03; p = 0.339), whereas the incidence of serious AEs in the triple regimen was lower (RR = 0.7; 95% CI: 0.50-0.98; p < 0.05).
The meta-analysis demonstrates that the addition of SMV to pegIFN and RBV is effective and well-tolerated in treating chronic HCV genotype 1 infection, with a low incidence of AEs.
Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva 07/2015; 107. DOI:10.17235/reed.2015.3840/2015 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypercoagulability, hemodynamic changes, and endothelial injury are the three major contributors to the development of thrombosis. However, the role of hypercoagulability in portal vein thrombosis (PVT) in liver cirrhosis is still controversial. The aim of this study is to elucidate the relationship between procoagulant imbalance and PVT in patients with liver cirrhosis.
This study included 151 patients with cirrhosis with (n=20) or without PVT (n=131). Levels of procoagulant factor (FVIII) and anticoagulants [protein C (PC), protein S (PS), and antithrombin (AT)] were measured. Procoagulant imbalance was also evaluated using a thrombin generation test with/without Protac and the results were expressed as Protac-induced coagulation inhibition percentage (PICI%). The lower the PICI% value, the greater the procoagulant imbalance.
The levels of PC (P<0.001), PS (P<0.05), and AT (P<0.001) decreased progressively from Child-Pugh A to C in all patients, whereas the levels of FVIII did not alter with the severity of cirrhosis (P>0.05), which indicated the balance tilting toward procoagulation in liver cirrhosis. Similarly, the PICI% values decreased from Child-Pugh A to C (P<0.001). However, there were no differences in the levels of PC, PS, AT, FVIII or PICI% between patients with and without PVT (P>0.05), even after stratification by Child-Pugh classification (P>0.05).
Procoagulant imbalance is not associated with the presence of PVT in patients with cirrhosis, although the imbalance worsens with the severity of cirrhosis.
European Journal of Gastroenterology & Hepatology 06/2015; 27(6). DOI:10.1097/MEG.0000000000000352 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is prevalent worldwide and early diagnosis of HCC is critical for effective treatment and optimal prognosis.
Serum was screened first by immunoproteomic analysis for HCC-related tumor associated antigens (TAAs). Selected TAAs were clinically evaluated retrospectively in patients with HCC, liver cirrhosis, chronic hepatitis and healthy controls. Levels of autoantibody to the selected TAAs were measured by protein microarrays containing protein antigens of the candidate TAAs. Analyses were done by using receiver operating characteristics (ROC) to calculate diagnostic accuracy.
Twenty-two candidate TAAs were assessed by protein microarray analysis in 914 participants with serum α-fetoprotein (AFP) available. Twelve candidate TAAs were statistically different in signal intensity between HCC and controls. Among them, CENPF, HSP60 and IMP-2 showed AUC (area under the curve) values of 0.826, 0.764 and 0.796 respectively for early HCC. The highest prevalence of autoantibody positivity was observed in HCC cases with BCLC tumor stage A, well-differentiated histology and Child-Pugh grade C. Specifically, 73.6% or 79.3% cases of early HCC with negative AFP were positive for autoantibody to CENPF or HSP60.
Tumor-associated autoimmune reactions may be triggered by early stage HCCs. Measurement of serum autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC.
[Show abstract][Hide abstract] ABSTRACT: Kupffer cells play critical roles in both progression and resolution of liver fibrosis. Interferon α2b is an important immunoregulator which has anti-fibrotic effect in addition to its antiviral effect. It remained unclear whether the anti-fibrotic effect of interferon α2b is mediated by regulating functions of Kupffer cells.
Primary isolated Kupffer cells were cultured with interferon α2b and the expression of matrix metalloproteinase-13, interleukin-10, transforming growth factor -β1 and tumor necrosis factor-α were measured. To investigate the role of mitogen-activated protein kinase pathways in regulating cytokines production by interferon α2b-stimulated Kupffer cells, inhibitors were given before cells were treated with interferon a2b.
Cell purity was more than 98%. Stimulating Kupffer cells with interferon α2b led to a dramatic increase in matrix metalloproteinase-13 and interleukin-10 expression. In contrast, the values of tumor necrosis factor-α and transforming growth factor -β1 remained unchanged throughout the 24-hour observation period. Inhibited ERK1/2 pathway prevented interferon α2b-triggered matrix metalloproteinase-13 production, while inhibited p38MAPK, ERK1/2 or JNK signaling pathways all blocked interleukin-10 expression.
Interferon α2b may exert anti-fibrotic effect by elevating the level of matrix metalloproteinase-13 and interleukin-10 in Kupffer cells, in a mitogen-activated protein kinase signaling pathways-dependent manner.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Stimulating a successful host immune response may be a promising helpful therapy to achieve elimination of hepatitis B virus (HBV) infection in chronic hepatitis B (CHB). Thymosin α-1 (Tα-1), as an immunomodulatory agent, can enhance T-cell response in CHB patients and has been widely studied either alone or in combination with nucleos(t)ide analogs. This editorial reviews these articles to present the efficacy of Tα-1 in CHB.
English and Chinese articles in MEDLINE, EMBASE, the Cochrane Controlled Trial Registry, Chinese periodical full-text database of science and technology, Chinese periodical full-text database and Wan-fang database by thesis search were collected and reviewed.
In CHB, Tα-1monotherapy is effective in suppressing viral replication compared with untreated control or conventional interferon. Most of the combination therapy of Tα-1 plus either lamivudine or IFN-α showed better effects on HBV DNA suppression and HBeAg seroconversion. Presently, clinical studies of Tα-1 combined with entecavir on the treatment of HBV-cirrhosis are ongoing.
[Show abstract][Hide abstract] ABSTRACT: The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively.
This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay.
At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log10 IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log10 IU/mL and baseline HBV DNA <9 log10 copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p<0.001).
Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Gut 01/2015; DOI:10.1136/gutjnl-2014-308546 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimsTo compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE).Methods
Adult patients without antiviral therapy within 6 months before screening with HBV DNA ≥ 105 copies/mL, ALT 1.3 to 10 times upper limit of normal and compensated HBeAg positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV DNA >1000 copies/mL at week 24) from week 30 to week 104, while patients with early virological response (HBV DNA ≤ 1000 copies/mL at week 24) continued lamivudine monotherapy untill week 104. For all the patients receiving lamivudine monotherapy, ADV would be added if virological breakthrough was confirmed.ResultsAt week 104, more patients in COMBO and OPTIMIZE groups achieved HBV DNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.47%). Patients under lamivudine monotherapy with early virological response showed superior efficacy at week 104 (HBV DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated.Conclusions
Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg positive CHB patients. In lamivudine treated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development.
Journal of Gastroenterology and Hepatology 10/2014; 30(4). DOI:10.1111/jgh.12835 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aimLiver stiffness measurement (LSM) using transient elastography (FibroScan®) is a useful tool to assess fibrosis in various chronic liver diseases. However, studies were mainly performed in Western countries and largely focused on chronic hepatitis C (CHC). We therefore carried out a multi-center study to validate the accuracy of LSM in the assessment of liver fibrosis in a large cohort of Chinese patients with chronic hepatitis B (CHB).Methods
We compared LSM results to histological staging and serum fibrosis markers (5 direct markers, APRI and FIB-4) using Spearman correlation analysis and Area Under ROC Curves (AUROCs).Results469 patients were enrolled and eligible for statistical analysis. LSM in F0 to F4 was 5.5 ±1.7, 5.8 ±2.2, 7.6 ±3.4, 14.5 ±10.8, and 22.3 ±13.6 kPa, respectively (correlation with fibrosis stage r=0.522, p<0.001). AUROC for LSM to correctly allocate patients to histological fibrosis stage ≥F2, ≥F3 and F4 was 0.82, 0.88, and 0.90, respectively. LSM outperformed serum fibrosis markers for detection of fibrosis F≥2 and F4. Patients with ALT levels 1-5x and >5x the upper limit of normal values had significantly higher stiffness values than stage-matched patients with normal ALT.Conclusions
Transient elastography is a reliable non-invasive technique to predict significant liver fibrosis in Chinese patients with CHB, being superior to current biomarker panels. However, enhanced inflammatory activity can lead to elevated stiffness values unrelated to histological fibrosis stage.
Journal of Gastroenterology and Hepatology 10/2014; 30(4). DOI:10.1111/jgh.12840 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The use of serum anti-hepatitis B core antibody (HBc)-positive/hepatitis B surface antigen (HBsAg)-negative liver donors for patients with hepatitis B virus (HBV)-related liver disease (HBRLD) is a promising means of expanding the organ donor pool and does not increase the risk of HBV recurrence. However, whether such donors will compromise the histology of the liver grafts is unclear.
Among 84 patients who underwent transplantation for HBRLD and who did not have post-transplant HBV recurrence (non-detectable serum HBsAg and HBV DNA), 19 underwent liver biopsy (eight received anti-HBc-positive/HBsAg-negative liver grafts; 11 received anti-HBc-negative liver grafts) and were included in the study. Intrahepatic total HBV DNA and covalently closed circular DNA (cccDNA) were detected using real-time polymerase chain reaction; histological characteristics were evaluated with the Batts-Ludwig semi-quantitative scoring system.
Of the 19 recipients, nine (47.4%) were positive for intrahepatic HBV DNA; 82.5% (7/8) received grafts from anti-HBc-positive donors and 18.2% (2/11) received grafts from anti-HBc-negative donors (P=0.003). HBV cccDNA was not detectable in the liver grafts of the 19 recipients. Ten patients had mild inflammation and minimal fibrosis in the portal area: four of the eight in the anti-HBc-positive group and six of the 11 in the anti-HBc-negative group (P>0.05).
Anti-HBc-positive/HBsAg-negative donors for HBRLD pose a higher risk of occult HBV infection post-liver transplant but do not cause liver damage. Thus, anti-HBc-positive grafts may be considered an effective and safe means of expanding the pool of liver donors for patients with HBRLD.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
An optimization strategy based on the Roadmap concept is supposed to improve the clinical outcomes of patients with suboptimal antiviral response. The aim of this study was to prove the concept with a multicenter, open-label, randomized, controlled study. In all, 606 hepatitis B e antigen (HBeAg)-positive, nucleos(t)ide-naive chronic hepatitis B patients were randomized to the Optimize or Mono group. Patients in the Optimize group were treated with telbivudine for 24 weeks, after which those suboptimal responders with HBV DNA ≥300 copies/mL at week 24 received telbivudine plus adefovir until week 104, while the early virological responders continued telbivudine monotherapy. Patients in the Mono group received telbivudine monotherapy. All patients with telbivudine monotherapy had adefovir added if viral breakthrough developed. Sixty-eight percent (204/300) of patients in the Optimize group had adefovir added due to suboptimal response. At week 104, compared to the Mono group, more patients in the Optimize group achieved HBV DNA <300 copies/ml (76.7% versus 61.2%, P < 0.001) with less genotypic resistance (2.7% versus 25.8%, P < 0.001). The rates of HBeAg seroconversion and alanine aminotransferase (ALT) normalization were comparable between the two groups (23.7% versus 22.1%; 80.7% versus 79.2%). For week 24 suboptimal responders, telbivudine plus adefovir showed an additive antiviral potency, with 71.1% achieving virological response at week 104 and only 0.5% developing genotypic resistance, compared with 46.6% who achieved virological response and 37.8% who developed genotypic resistance with telbivudine monotherapy. Both treatment regimens were well tolerated, with an observed persistent increase of the glomerular filtration rate.
For suboptimal virological responders to telbivudine at week 24, adjusting the treatment strategy is recommended. Adding adefovir can benefit these patients with additive antiviral potency and low resistance without increased side effects.
[Show abstract][Hide abstract] ABSTRACT: There is considerable variation in reimbursement policies in Asian countries and this is likely to have an impact on treatment practice for chronic hepatitis B (CHB). Consequently a survey of leading hepatologists was performed to evaluate such policies and their impact on management of CHB in the Asia Pacific region.
A questionnaire was sent to key hepatologists in Asia Pacific for information on CHB reimbursement policy-its nature, coverage, funding source, duration, review strategy and impact on Asia Pacific Association for the Study of the Liver (APASL) CHB guidelines. The results were analysed and described.
Leading hepatologists from 16 Asia Pacific countries responded. Almost all of the countries have reimbursement policies but eligibility varied from only a limited group (e.g. civil servants only) to universal access. In most instances reimbursement was from the central government (except China, Pakistan and Hong Kong). Reimbursement policies were usually created by Ministry of Health committees, who received input from medical professionals, although they may not be aware of the APASL guidelines. Policies were limited by available resources, funds and prioritization. Where there was a regular review this occurred between 1 and 5 years. The quantum of reimbursement varied from 50 % in Singapore to 100 % in the majority of other countries. The criteria for treatment reimbursement were based on doctor's opinion alone (Bangladesh, India, Pakistan, Philippines, Singapore and Vietnam) or specific clinical/laboratory criteria in the rest of the countries. In general, most countries offered unlimited duration for reimbursement except Taiwan, Indonesia and Pakistan. Monitoring tests for treatment response were reimbursed in all countries other than Vietnam. Viral resistance was diagnosed by viral or biochemical breakthrough, and viral resistance testing was uncommon. The main rescue therapy was adefovir.
Reimbursement policies differed from country to country, the quantum and the proportion of patients who received reimbursement also varied significantly. Asia Pacific countries were able to follow APASL guidelines with variable success based on their reimbursement policies.
Hepatology International 01/2014; 9(1):43-51. DOI:10.1007/s12072-014-9593-x · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic hepatitis C virus (HCV) infection is relatively frequent in China. This study investigated the clinical, demographic, and viral and host genetic characteristics that may influence disease manifestations and clinical management.
In this cross-sectional observational study, treatment-naïve Han ethnic adults with recently confirmed chronic HCV infection were enrolled at 28 hospitals across China. HCV genotype and host IL28B genotypes were determined and compared with patient demographic parameters and medical status.
Among the 997 HCV-positive patients analyzed, 56.8% were infected with HCV genotype 1b, followed in prevalence by genotypes 2, 3, and 6, with substantial regional variation. Overall 84.1% of patients were IL28B genotype CC (rs12979860), with little regional variation. Cirrhosis was reported in 10.1% of patients and was significantly associated with hepatitis B virus coinfection, low HCV viral load, low serum alanine aminotransferase, high serum aspartate aminotransferase, diabetes, and high pickled food consumption. Medical procedures were common transmission risk factors; however, lifestyle-associated risk factors, including intravenous drug abuse and tattoos or piercings, were more common in patients with HCV genotype 3 or 6.
Most HCV-infected Han Chinese patients were IL28B genotype CC (rs12979860). HCV genotypes varied by geographic region, and disease characteristics differed according to HCV genotype. Relatively frequent detection of advanced liver disease may reflect limitations on access to antiviral therapy, and suggests that greater awareness of factors that influence HCV-associated disease may help avoid clinical complications and improve patient outcomes.
Journal of Gastroenterology and Hepatology 10/2013; 29(3). DOI:10.1111/jgh.12398 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholestasis represents the consequence of impaired bile formation and decrease in bile flow, generally classified as extra- and intrahepatic. Cholestasis is the pivotal hallmark of the so-called primary cholestatic liver diseases but may also emerge in other forms of chronic liver injury. The aim now was to summarise the current state of knowledge on intrahepatic cholestasis related to chronic liver diseases.
For this overview on intrahepatic cholestasis in chronic liver disorders other than the 'classic' cholestatic liver diseases, selected references were retrieved by literature search in MEDLINE and textbooks were reviewed. All articles were selected that discussed pathophysiological and clinical aspects of intrahepatic cholestasis in the context of alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis B and C virus infections as well as drug-induced and granulomatous liver diseases. Titles referring to primary biliary cirrhosis and sclerosing cholangitis were excluded.
Dependent on the aetiology, intrahepatic cholestasis is present at variable frequencies and in different disease stages in chronic liver diseases. Cholestasis secondary to chronic liver injury may denote a severe disease course and development of end-stage liver disease or specific disease variants. These findings indicate that 'secondary intrahepatic cholestasis' (SIC) can occur in the natural course of chronic liver diseases other than the primary cholestatic diseases, in particular in the setting of advanced disease progression.
European Journal of Clinical Investigation 06/2013; 43(10). DOI:10.1111/eci.12128 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Health care decision makers are increasingly concerned about the value of chronic hepatitis B (CHB) treatments in China. This analysis aims at estimating the relative value of entecavir as a first-line option at treatment initiation and for different treatment durations from a holistic perspective.MethodsCHB was simulated by using a Markov disease transition model with disease states based on available natural history data. The model assumed 5-year treatment duration with entecavir, lamivudine, telbivudine, and adefovir based on published clinical data. The speed of disease progression varies by viral load and hepatitis B “e” antigen status. Direct medical costs included medication and management of liver complications. The primary output was the estimated cost savings of entecavir per patient per day versus the comparator.ResultsFor treatment duration of 5 years and a follow-up period of 30 years, entecavir treatment was translated into specific patient benefit of an estimated cost saving of $2.69 per day compared with no treatment. In addition, long-term usage of entecavir resulted in daily $2.33 and $1.73 cost saving compared with short-term usage (1-year and 2-year, respectively). Among available treatment options in China, entecavir treatment exhibited about $0.90 to $1.81 daily cost saving versus the comparators. The detailed daily cost saving of entecavir is summarized as follows—entecavir versus lamivudine: $1.81, entecavir versus telbivudine: $0.90, entecavir versus adefovir: $2.02, and entecavir versus generic adefovir: $1.37.Conclusions
Long-term usage of entecavir exhibits the characteristics of a favorable CHB treatment, which translates into economic value as opposed to either no treatment or alternative strategies.
[Show abstract][Hide abstract] ABSTRACT: Diethyldithiocarbamate (DDC) could block collagen synthesis in hepatic stellate cells through the inhibition of reactive oxygen species derived from hepatocyte cytochrome P450 2E1 (CYP2E1). However, the effect of DDC on matrix metalloproteinase-1 (MMP-1), which is the main collagen degrading matrix metalloproteinase, has not been reported. In co-culture experiments, we found that DDC significantly enhanced MMP-1 expression in human hepatic stellate cells (LX-2) that were cultured with hepatocyte C3A cells either expressing or not expressing CYP2E1. The levels of both proenzyme and active MMP-1 enzyme were upregulated in LX-2 cells, accompanied by elevated enzyme activity of MMP-1 and decreased collagen I, in both LX-2 cells and the culture medium. H2O2 treatment abrogated DDC-induced MMP-1 upregulation and collagen I decrease, while catalase treatment slightly upregulated MMP-1 expression. These data suggested that the decrease in ROS by DDC was partially responsible for the MMP-1 upregulation. ERK1/2, Akt and p38 were significantly activated by DDC. The ERK1/2 inhibitor (U0126) and Akt inhibitor (T3830) abrogated the DDC-induced MMP-1 upregulation. In addition, a p38 inhibitor (SB203580) improved MMP-1 upregulation through the stimulation of ERK1/2. Our data indicate that DDC significantly upregulates the expression of MMP-1 in LX-2 cells which results in greater MMP-1 enzyme activity and decreased collagen I. The enhancement of MMP-1 expression by DDC was associated with H2O2 inhibition and coordinated regulation by the ERK1/2 and Akt pathways. These data provide some new insights into treatment strategies for hepatic fibrosis.
[Show abstract][Hide abstract] ABSTRACT: Elevated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression contributes to excess production of extracellular matrix in liver fibrosis. Herein, we constructed a recombinant adeno-associated virus (rAAV) carrying siRNA of the TIMP-1 gene (rAAV/siRNA-TIMP-1) and investigated its effects on liver fibrosis in rats. Two models of rat liver fibrosis, the carbon tetrachloride and bile duct ligation models, were treated with rAAV/siRNA-TIMP-1. In the carbon tetrachloride model, rAAV/siRNA-TIMP-1 administration attenuated fibrosis severity, as determined by histologic analysis of hepatic collagen accumulation, hydroxyproline content, and concentrations of types I and III collagen in livers and sera. Levels of mRNA and active matrix metalloproteinase (MMP) 13 were elevated, whereas levels of mRNA and active MMP-2 were decreased. Moreover, a marked decrease was noted in the expression of α-smooth muscle actin, a biomarker of activated hepatic stellate cells (HSCs), and transforming growth factor-β1, critical for the development of liver fibrosis. Similarly, rAAV/siRNA-TIMP-1 treatment significantly alleviated bile duct ligation-induced liver fibrosis. Furthermore, this treatment dramatically suppressed TIMP-1 expression in HSCs from both model rats. These data indicate that the administration of rAAV/siRNA-TIMP-1 attenuated liver fibrosis by directly elevating the function of MMP-13 and diminishing activated HSCs. It also resulted in indirect decreased expression of type I collagen, MMP-2, and transforming growth factor-β1. In conclusion, rAAV/siRNA-TIMP-1 may be an effective antifibrotic gene therapy agent.
American Journal Of Pathology 03/2013; 182(5). DOI:10.1016/j.ajpath.2013.01.036 · 4.59 Impact Factor