Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 as biomarkers of ulcerative colitis activity

AIM:Overexpression of mucosal metalloproteinases(MMP) has been demonstrated recently in inflammatory bowel disease.Their activity can be counterbalanced by the tissue inhibitor of metalloproteinases(TIMP).The aim of this study was to evaluate the effect of ulcerative colitis(UC)on MMP- 1 and TIMP-1 plasma concentrations,as two possible biomarkers of the disease activity. METHODS:MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 16 patients with endoscopically confirmed active UC. RESULTS:Plasma concentrations of both MMP-1(13.7±0.2 ng/ml)and TIMP-1(799±140 ng/ml)were significantly elevated in UC patients in comparison to healthy controls (11.9±0.9 ng/ml and 220±7 ng/ml respectively).There was no correlation between TIMP-1 and MMP-1 concentrations (r=0.02).TIMP-1 levels revealed significant positive correlations with scored endoscopic degree of mucosal injury, disease activity index and clinical activity index values as well as C-reactive protein concentration.There was no correlation between MMP-1 and laboratory,clinical or endoscopic indices of the disease activity.CONCLUSION: These results confirm the role of both MMP- 1 and TIMP-1 in the pathogenesis of ulcerative colitis. However only TIMP-1 can be useful as a biomarker of the disease activity, demonstrating association with clinical and endoscopic pictures.

High concentration of antimitochondrial antibodies predicts progressive primary biliary cirrhosis

AIM： To evaluate the serum concentration of antimitochondrial antibodies （AMAs） as a prognostic indicator of progressive primary biliary cirrhosis （pPBC）. METHODS： Serum concentrations of AMA subtypes （anti-M2, anti-M4, and anti-M9）, biochemical indices of liver function and Mayo risk factor （MRF） were determined in 30 women with diagnosed primary biliary cirrhosis （PBC） selected among 348 females with elevated alkaline phosphatase but without signs of hepatic decompensation. They were followed up for 5 years for possible development of hepatic decompensation. RESULTS： Anti-M2 concentration was significantly correlated with bilirubin and albumin levels as well as MRF, whereas anti-M4 was significantly correlated with albumin level, prothrombin time and MRF. During the 5-year follow-up, progressive PBC （pPBC） was diagnosed in 3 among 23 patients available for evaluation. These 3 patients were positive for both anti-M2 and anti-M4. Anti-M2 serum concentration exceeded 1 300 RU/mL in patients with pPBC and only in 1 among 20 non-progressive PBC persons （5%）. Anti-M4 serum concentration exceeded 400 RU/mL in 2 of the progressive patients and none in the non-progressive group. In contrast, anti-M9 serum concentration was below 100 RU/mL in all patients with pPBC, and higher than 100 RU/mL in 11 women （55%） among the non-progressive group. CONCLUSION： Females with elevated alkaline phosphatase and high anti-M2 and anti-M4 concentrations are at a high risk for developing pPBC. Quantitative AMA detection should be considered as a method for early diagnosis of pPBC. 2005 The WJG Press and Elsevier Inc. All rights reserved.

Effect of lamivudine treatment on plasma levels of transforming growth factor β_1,tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B

AIM: Transforming growth factor (TGF)-β1, metalloproteinase (MMP)-1 and its tissue inhibitor (TIMP)-I are considered predictive biomarkers of chronic hepatitis activity and fibrosis.The aim of this study was to evaluate the effect of lamivudine treatment on the plasma levels of these peptides in patients with chronic hepatitis B.METHODS: TGF-β1, MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 40 patients treated with lamivudine for 48 wk. Elimination of HBV-DNA and HBV antigens was evaluated 24 wk after treatment completion.RESULTS: Baseline TGF-β1(29.6±2.2 ng/mL) and TIMP-1(1 578±93 ng/mL) significantly exceeded normal values(18.3±1.6 ng/mL and 1 102±67 ng/mL respectively). Lamivudine treatment resulted in a significant decrease of TGF-β1 and TIMP-1 during treatment with an increase after 24 wk of treatment. Pretreatment MMP-1 levels (6.7±0.7 ng/mL) were significantly lower than normal values (11.9±0.9 ng/mL) and increased during treatment and follow-up. A significant correlation was noted between TGF-β1 or TIMP-1 and aminotransferases as well as fibrosis scored in liver biopsy specimens. There were no statistically significant differences of TGF-β1, TIMP-1 and MMP-1 between four groups at baseline, 24 and 48 wk of treatment. TGF-β1 and TIMP-1 levels increased significantly in non-responders and normalized in responders at wk 72. MMP-1 also normalized in responders and decreased to values significantly lower than normal in non-responders.CONCLUSION: These findings support the role of TGF-β1,TIMP-1 and MMP-1 in the pathogenesis of chronic hepatitis B.Because of their association with hepatic injury and antiviral treatment efficacy, determination of these peptides may be useful in disease management.

Effect of pegylated interferon alpha 2b plus ribavirin treatment on plasma transforming growth factor-β1,metalloproteinase-1,and tissue metalloproteinase inhibitor-1 in patients with chronic hepatitis C

AIM： To evaluate the effect of antiviral treatment on plasma levels of transforming growth factor-β1 （TGF-β1）, metalloproteinase 1 （MMP-1）, and tissue inhibitor of metaUoproteinase-1 （TIMP-1） in patients with chronic hepatitis C. METHODS： TGF-β1, MMP-1, and TIMP-1 plasma concentrations were measured by an enzyme immunoassay in 28 patients, during 48 wk of treatment with pegylated interferon-alpha 2b （PEG-IFN-α2b） plus ribavirin （RBV） and after 24 wk of follow-up. Patients were divided into two groups： responders （R） and non-responders （NR） related to achieved sustained virologic response. Normal values were evaluated in plasma samples of 13 healthy volunteers. RESULTS： Baseline plasma concentrations of TGF-β1 and TIMP-1 （30.9±3.7 and 1 506±61 ng/mL respectively） measured in all subjects significantly exceeded the normal values （TGF-β1： 18.3±1.6 ng/mL and TIMP-1： 1 102±67 ng/mL）. In contrast, pretreatment MMP-1 mean level （6.5±0.9 ng/mL） was significantly lower than normal values （11.9±0.9 ng/mL）. Response to the treatment was observed in 12 patients （43%）. TGF-β1 mean concentration measured during the treatment phase decreased to the control level in both groups. However at wk 72, values of NR patients increased and became significantly higher than in R group. TIMP-1 concentrations in R group decreased during the treatment to the level similar to normal. In NR group, TIMP-1 remained significantly elevated during treatment and follow-up phase and significant difference between both groups was demonstrated at wk 48 and 72. MMP-1 levels were significantly decreased in both groups at baseline. Treatment caused rise of its concentration only in the R group, whereas values in NR group remained on the level similar to baseline. Statistically significant difference between groups was noted at wk 48 and 72. CONCLUSION： These findings support the usefulness of TGF-β1, TIMP-1, and MMP-1 in the management of chronic hepatitis C. Elevated TIMP-1 and low MMP-1 plasma concentrations during antiviral therapy may indicate medication failure.

Role of cannabinoids in chronic liver diseases

Cannabinoids are a group of compounds acting pri-marily via CB1 and CB2 receptors.The expression of cannabinoid receptors in normal liver is low or absent.However,many reports have proven up-regulation of the expression of CB1 and CB2 receptors in hepatic myofibroblasts and vascular endothelial cells,as well as increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases.It has been shown that CB1 receptor signalling exerts profibrogenic and proinflammatory effects in liver tis-sue,primarily due to the stimulation of hepatic stellate cells,whereas the activation of CB2 receptors inhibits or even reverses liver fibrogenesis.Similarly,CB1 re-ceptor stimulation contributes to progression of liver steatosis.In end-stage liver disease,the endocannabi-noid system has been shown to contribute to hepatic encephalopathy and vascular effects,such as portal hypertension,splanchnic vasodilatation,relative pe-ripheral hypotension and probably cirrhotic cardiomy-opathy.So far,available evidence is based on cellular cultures or animal models.Clinical data on the effects of cannabinoids in chronic liver diseases are limited.However,recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis.Moreover,controlling CB1 or CB2 signal-ling appears to be an attractive target in managing liver diseases.

Signal transduction pathways in liver and the influence of hepatitis C virus infection on their activities

In liver,the most intensively studied transmembrane and intracellular signal transduction pathways are the Janus kinase signal transduction pathway,the mitogen-activated protein kinases signal transduction pathway,the transforming growth factor β signal transduction pathway,the tumor necrosis factor α signal transduction pathway and the recently discovered sphingolipid signal transduction pathway.All of them are activated by many different cytokines and growth factors.They regulate specific cell mechanisms such as hepatocytes proliferation,growth,differentiation,adhesion,apoptosis,and synthesis and degradation of the extracellular matrix.The replication cycle of hepatitis C virus(HCV) is intracellular and requires signal transduction to the nucleus to regulate transcription of its genes.Moreover,HCV itself,by its structural and non-structural proteins,could influence the activity of the second signal messengers.Thus,the inhibition of the transmembrane and intracellular signal transduction pathways could be a new therapeutic target in chronic hepatitis C treatment.

Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation

AIM: To analyze the effectiveness and safety of lamivudine treatment in patients with chronic HBV infection undergoing hemodialysis or after kidney transplantation, and to study the frequency of tyrosine - methionine - aspartate - aspartate (YMDD) mutation occurrence after lamivudine treatment. METHODS: We analyzed 91 patients with chronic hepatitis B, among whom, 16 patients underwent hemodialysis, 7 patients had kidney transplantation and 68 patients had normal function of kidney. The hemodialysis patients were treated by lamivudine 300 mg/wk. patients after kidney transplantation and patiente with normal function of kidney were treated with lamivudine 100 mg/d. Therapy lasted for 12 mo. HBV-DNA, HBsAg, HBeAg and anti-HBe, and anti-HCV antibodies were assessed in sera of patients. The analysis was performed before and 6 mo after the end of lamivudine treatment. Before, during and after the lamivudine therapy, the number of erythrocytes, leukocytes, platelets and hemoglobin concentration, ALT and AST activity, as well as bilirubin, urea and creatinine concentrations were analyzed in sera from patients. RESULTS: After the 12-mo lamivudine treatment, elimination of HBV - DNA was observed in 56% patients undergoing hemodialysis and in 53% patients with normal kidney function. Only 1 from 7 (14%) kidney-transplanted patients eliminated HBV-DNA. Furthermore, HBeAg elimination was observed in 36% hemodialysis patients, in 51% patients with normal function of kidneys and in 43% kidney transplanted patients. Among the patients undergoing dialysis, no YMDD mutation was found after 12 mo of therapy, while it was detected in 9 patients (13%) with normal function of kidney and in 2 kidney-transplanted patients (29%, P<0.006). We did not observe significant side effecte of lamivudine treatment in studied patiente. CONCLUSION: Effectiveness of lamivudine therapy in dialysis patients is comparable with that in patiente with normal function of kidney. Lamivudine treatment is well tolerated and safe in patiente with renal insufficiency undergoing hemodialysis and kidney-transplantation. However, in the latter group, high incidence of YMDD mutation after lamivudine treatment was observed.

Epidemiological characteristics of inflammatory bowel disease in North-Eastern Poland

AIM:To provide the clinical and epidemiological data of inflammatory bowel disease (IBD) patients of North-Eastern Poland. METHODS: A total of 248 IBD patients diagnosed and hospitalized in the Department of Infectious Diseases in Bialystok between 1990 and 2003 were included in the study. We analyzed age, sex, education, characteristics of job, type of the environment, discontinuation of employment due to IBD, colitis extent, need of surgical treatment, and coexistence of other diseases. RESULTS: Two hundred and thirty-three IBD patients (94%) were diagnosed as ulcerative colitis (DC), and only 15 (6%) were diagnosed as Crohn's disease (CD). Patients with CD were significantly younger at the time of diagnosis and male predominance was observed. The mean age of the patients at the time UC diagnosis was 44.9±1.1 years. Histogram of the age of patients showed the characteristic biphasic distribution with two peaks between 20 and 40 years and between 60 and 70 years. The predominant form of UC was left sided colitis, which affected almost 80% of the studied population. The most extensive form - pancolitis was present in 34 patients (15%). Only 6% of UC patients required surgery, whereas 36% of CD patients underwent surgery (P<0.005). Among coexisting disorders, cholelithiasis was the most prevalent and demonstrated in 35 patients (14%), pulmonary disorders were diagnosed in 2%, and psoriasis in 1.4%. Since 1998, the number of admitted IBD patients has slightly increased. CONCLUSION: Occurrence of UC in Poland is much higher than that of CD. The majority of UC cases are diagnosed in young people (20-40 years) with the predominance of male patients. The most common clinical form of UC is left sided colitis.

Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C

AIM: To assess serum concentrations of prohepcidin in chronic hepatitis C individuals and evaluate their associations with disease activity and efficacy of pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. METHODS: Prohepcidin was measured in sera of 53 chronic hepatitis C patients. Concentrations of prohepcidin and other iron metabolism markers were analyzed at 9 time points before, during and after the end of antiviral therapy. RESULTS: In hepatitis C virus (HCV) genotype 1-infected individuals, a gradual decrease of prohepcidin during antiviral therapy was observed in responders (88.8 ± 14.7 ng/mL before therapy vs 60.6 ± 0.3 ng/mL in the 48th wk, P = 0.04). In contrast, no decrease was observed in non-responders. A similar association was observed in HCV genotype 3a individuals, with a statistically significant decline in serum prohepcidin only in the responder group (99.5 ± 5.2 ng/mL at baseline vs 72.7 ± 6.1 ng/mL in the 24th wk, P = 0.01). Moreover, HCVRNA at week 12 of therapy was positively correlated with baseline (R = 0.63, P < 0.005) and week 12 (R = 0.60, P = 0.01) serum prohepcidin concentrations in HCV genotype 1 infection. CONCLUSION: Successful PEG-IFN/RBV therapy results in a decline of serum prohepcidin concentration in chronic hepatitis C, which may suggest a direct effect of HCV on iron metabolism at the prohormonal level of hepcidin.

Specifically targeted antiviral therapy for hepatitis C virus

Hepatitis C virus （HCV） infection affects 180 million people worldwide with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. Standard anti-HCV therapy currently aims to enhance natural immune responses to the virus, whereas new therapeutic concepts directly target HCV RNA and viral enzymes or influence host-virus interactions. Novel treatment options now in development are focused on inhibitors of HCV- specific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV （STAT-C）. STAT-C is an attractive strategy in which the main goal is to increase the effectiveness of antiviral responses across all genotypes, with shorter treatment duration and better tolerability. However, the emergence of resistant mutations that limit the use of these compounds in monotherapy complicates the regimens. Thus, a predictable scenario for HCV treatment in the future will be combinations of drugs with distinct mechanisms of action. For now, it seems that interferon will remain a fundamental component of any new anti-HCV therapeutic regimens in the near future; therefore, there is pressure to develop forms of interferon that are more effective, less toxic, and more convenient than pegylated interferon.

Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C

Chronic infection with the hepatitis C virus(HCV)remains a major health problem affecting approximately 58 million people worldwide.In the era of interferon(IFN)-based regimens,patients particularly infected with genotypes 1 and 4 achieved a low response rate.The implementation of direct-acting antivirals changed the landscape of HCV treatment.The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030.In the following years,there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution.The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time.Patients treated with antiviral therapies were younger in successive periods,less burdened with comorbidities and comedications,more frequently treatment-naïve and had less advanced liver disease.Before the IFN-free era,specific subpopulations such as patients with HCV/HIV coinfection,those with a history of previous treatment,patients with renal impairment or with cirrhosis had lower chances for a virologic response.Currently,these populations should no longer be considered difficult to treat.Despite the high effectiveness of HCV therapy,there is a small percentage of patients with treatment failure.However,they can be effectively retreated with pangenotypic rescue regimens.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype(GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin < 10 g/d L) and rashrelated events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the GT1 b and GT1 a groups, respectively) than in the telaprevir groups(2.2% and 3.0%). Among GT1 binfected patients, daclatasvir plus peg IFN/RBV was noninferior to telaprevir plus peg IFN/RBV for SVR12 [85%(228/268) vs 81%(109/134); difference, 4.3%(95%CI:-3.3% to 11.9%)]. Anemia(hemoglobin < 10 g/d L) was significantly less frequent with daclatasvir than with telaprevir [difference,-29.1%(95%CI:-38.8% to-19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1 ainfected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28 B non-CC and cirrhosis- factors known to affect response to peg IFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients d e m o n s t ra t e d t h a t S V R 1 2 wa s a s s o c i a t e d w i t h IL28 B host genotype(CC vs non-CC, P = 0.011) and cirrhosis status(absent vs present, P = 0.031). NS5 A polymorphisms associated with daclatasvir resistance(at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4%(229/268) in the daclatasvir group, and by 85.1%(114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2%(90/134) and 69.7%(46/66), respectively. Discontinuations(of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus peg IFN/RBV demonstrated noninferiority to telaprevir plus peg IFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1 binfected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Changes in characteristics of patients with hepatitis C virus-related cirrhosis from the beginning of the interferon-free era

BACKGROUND Nearly 290000 patients with chronic hepatitis C die annually from the most severe complications of the disease.One of them is liver cirrhosis,which occurs in about 20%of patients chronically infected with the hepatitis C virus(HCV).Direct-acting antivirals(DAAs),which replaced interferon(IFN)-based regimens,significantly improved the prognosis of this group of patients,increasing HCV eradication rates and tolerability of therapy.Our study is the first to assess changes in patient profile,effectiveness,and safety in the HCV-infected cirrhotic population in the IFN-free era.AIM To document changes in patient characteristics and treatment regimens along with their effectiveness and safety profile over the years.METHODS The studied patients were selected from 14801 chronically HCV-infected individuals who started IFN-free therapy between July 2015 and December 2021 in 22 Polish hepatology centers.The retrospective analysis was conducted in real-world clinical practice based on the EpiTer-2 multicenter database.The measure of treatment effectiveness was the percentage of sustained virologic response(SVR)calculated after excluding patients lost to follow-up.Safety data collected during therapy and the 12-wk post-treatment period included information on adverse events,including serious ones,deaths,and treatment course.RESULTS The studied population(n=3577)was balanced in terms of gender in 2015-2017,while the following years showed the dominance of men.The decline in the median age from 63 in 2015-2016 to 61 years in 2021 was accompanied by a decrease in the percentage of patients with comorbidities and comedications.Treatment-experienced patients dominated in 2015-2016,while treatment-naive individuals gained an advantage in 2017 and reached 93.2%in 2021.Genotype(GT)-specific options were more prevalent in treatment in 2015-2018 and were supplanted by pangenotypic combinations in subsequent years.The effectiveness of the therapy was comparable regardless of the period analyzed,and patients achieved an overall response rate of 95%,with an SVR range of 72.9%-100%for the different therapeutic regimens.Male gender,GT3 infection,and prior treatment failure were identified as independent negative predictors of therapeutic success.CONCLUSION We have documented changes in the profile of HCV-infected cirrhotic patients over the years of accessibility to changing DAA regimens,confirming the high effectiveness of IFN-free therapy in all analyzed periods.

Best therapy for the easiest to treat hepatitis C virus genotype 1binfected patients

BACKGROUND The revolution in treatment of patients with chronic hepatitis C virus(HCV)infection dates back to the introduction of direct-acting antivirals(DAAs).The increase in efficacy was most pronounced in patients infected with genotype(GT)1b,as this was the most poorly responsive population to treatment during the interferon era.AIM To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response.METHODS This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database.Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses(SVR).Assessment of the safety was based on the evaluation of the course of therapy,the occurrence of adverse events including serious ones,deaths during treatment and in the post 12-wk follow-up period.RESULTS The studied population consisted of 11385 patients with a mean age of 53±14.8 years and a female predominance(53.4%).The majority of them were treatment-naïve(74.6%)and patients with cirrhosis accounted for 24.3%.Of the DAA regimens used,76.9%were GT-specific with ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin being the most used option(32.4%).A total of 10903 patients responded to treatment resulting in a 98.1%in the per-protocol analysis after excluding 273 patients without SVR data.The effectiveness of all regimens exceeded 90%and the highest SVR of 98.9%was achieved in patients treated with a combination of glecaprevir/pibrentasvir.Logistic regression analyses showed that the virologic response was independently associated with female sex[odds ratio(OR)=1.67],absence of decompensated cirrhosis at baseline(OR=2.42)and higher baseline platelets(OR=1.004 per 1000/μL increase),while the presence of human immunodeficiency virus(HIV)coinfection significantly decreased the odds of response(OR=0.39).About 95%-100%of patients completed therapy irrespective of the drug regimen.At least one adverse effect occurred in 10.9%-36.3%and most of them were mild.No treatment related deaths have been reported.CONCLUSION We documented very high effectiveness and a good safety profile across all DAA regimens.Positive predictors of SVR were female sex,absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.

Factors influencing the failure of interferon-free therapy for chronic hepatitis C:Data from the Polish EpiTer-2 cohort study

BACKGROUND The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C,making it highly effective and safe for patients.However,few researchers have analyzed the factors causing therapy failure in some patients.AIM To analyze factors influencing the failure of direct antiviral drugs in the large,multicenter EpiTer-2 cohort in a real-world setting.METHODS The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020.Data collected from the online EpiTer-2 database included the following:hepatitis C virus(HCV)genotype,stage of fibrosis,hematology and liver function parameters,Child-Turcotte-Pugh and Model for End-stage Liver Disease scores,prior antiviral therapy,concomitant diseases,and drugs used in relation to hepatitis B virus(HBV)and/or human immunodeficiency virus(HIV)coinfections.Adverse events observed during the treatment and follow-up period were reported.Both standard and machine learning methods were used for statistical analysis.RESULTS During analysis,12614 patients with chronic hepatitis C were registered,of which 11938(mean age:52 years)had available sustained virologic response(SVR)data[11629(97%)achieved SVR and 309(3%)did not].Most patients(78.1%)were infected with HCV genotype 1b.Liver cirrhosis was diagnosed in 2974 patients,while advanced fibrosis(F3)was diagnosed in 1717 patients.We included patients with features of hepatic failure at baseline[ascites in 142(1.2%)and encephalopathy in 68(0.6%)patients].The most important host factors negatively influencing treatment efficacy were liver cirrhosis,clinical and laboratory features of liver failure,history of hepatocellular carcinoma,and higher body mass index.Among viral factors,genotype 3 and viral load also exerted an influence on treatment efficacy.Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex,which was not confirmed by the multivariate analysis using the machine learning algorithm(random forest).Coinfection with HBV(including patients with on-treatment reactivation of HBV infection)or HIV,extrahepatic manifestations,and renal failure did not significantly affect the treatment efficacy.CONCLUSION In patients with advanced liver disease,individualized therapy(testing for resistance-associated variants and response-guided treatment)should be considered to maximize the chance of achieving SVR.

Specific ssDNA concentration in liver tissue as an index of apoptosis in hepatitis C virus-infected patients

AIM. To evaluate bhe activity of apoptosis in liver tissue and explore its possible association with hepatic necroinflammarion and fibrosis as well as serum hepatitis C virus （HCV） load. METHODS： The studied population included 50 chronic hepatitis C patients （20 women and 30 men, aged 18-66 years）. HCV-RNA quantification was performed by two-step real-time quantitative RT-PCR mebhod using the TaqMan technology （reagents of Applera Corporation firm, USA）. The morphology of liver tissue was assessed descriptively and scored （necroinflammatory activity and fibrosis）. The early apoptosis activity in liver tissue was examined by ssDNA apoptosis ELISA kit, （Chemicon, Germany）. RESULTS： The correlation between apoptosis and fibrosis in liver tissue was observed. High intensification of apoptosis was proportional to the increase of fibrosis （ssDNA： 16.65×10^-5μg/g; 12.71×10^-5μg/g）, however, bhis difference was not statistically significant （P〉0.05）. Activity of apoptosis in the liver tissue, expressed by ssDNA concentration did not depend on hepatic necroinflammatory changes, HCVRNA viral load, ALT, and AST activity as well as prothrombin time and INR index. CONCLUSION： Fibrosis in the tissue is closely associated with early apoptosis in HCV-infected patients.

Real-world effectiveness and safety of direct-acting antivirals in hepatitis C virus patients with mental disorders

BACKGROUND It is estimated that 58 million people worldwide are infected with the hepatitis C virus(HCV).Patients with severe psychiatric disorders could not be treated with previously available interferon-based therapies due to their unfavorable side effect profile.This has changed with the introduction of direct-acting antivirals(DAA),although their real-life tolerance and effectiveness in patients with different psychiatric disorders remain to be demonstrated.AIM To evaluate the effectiveness and safety of DAA in patients with various mental illnesses.METHODS This was a retrospective observational study encompassing 14272 patients treated with DAA for chronic hepatitis C in 22 Polish hepatology centers,including 942 individuals diagnosed with a mental disorder(anxiety disorder,bipolar affective disorder,depression,anxiety-depressive disorder,personality disorder,schizophrenia,sleep disorder,substance abuse disorder,and mental illness without a specific diagnosis).The safety and effectiveness of DAA in this group were compared to those in a group without psychiatric illness(n=13330).Antiviral therapy was considered successful if serum ribonucleic acid(RNA)of HCV was undetectable 12 wk after its completion[sustained virologic response(SVR)].Safety data,including the incidence of adverse events(AEs),serious AEs(SAEs),and deaths,and the frequency of treatment modification and discontinuation,were collected during therapy and up to 12 wk after treatment completion.The entire study population was included in the intent-to-treat(ITT)analysis.Per-protocol(PP)analysis concerned patients who underwent HCV RNA evaluation 12 wk after completing treatment.RESULTS Among patients with mental illness,there was a significantly higher percentage of men,treatmentnaive patients,obese,human immunodeficiency virus and hepatitis B virus-coinfected,patients with cirrhosis,and those infected with genotype 3(GT3)while infection with GT1b was more frequent in the population without psychiatric disorders.The cure rate calculated PP was not significantly different in the two groups analyzed,with a SVR of 96.9% and 97.7%,respectively.Although patients with bipolar disorder achieved a significantly lower SVR,the multivariate analysis excluded it as an independent predictor of treatment non-response.Male sex,GT3 infection,cirrhosis,and failure of previous therapy were identified as independent negative predictors.The percentage of patients who completed the planned therapy did not differ between groups with and without mental disorders.In six patients,symptoms of mental illness(depression,schizophrenia)worsened,of which two discontinued treatments for this reason.New episodes of sleep disorders occurred significantly more often in patients with mental disorders.Patients with mental illness were more frequently lost to follow-up(4.2%vs 2.5%).CONCLUSION DAA treatment is safe and effective in HCV-infected patients with mental disorders.No specific psychiatric diagnosis lowered the chance of successful antiviral treatment.

Known and probable risk factors for hepatitis C infection:A case series in north-eastern Poland

AIM： To describe the risk profile of patients in hospita with hepatitis C virus （HCV） infection in Poland. METHOD： Using a structured questionnaire, all patients with confirmed HCV infection were interviewed about the risk factors. RESULTS： Among the 250 patients studied, transfusion before 1993 was the primary risk factor in 26%, intravenous drug use setting in 9% and occupational exposure in health-care in 9%. Women were more likely to have a history of occupational exposure or transfusion before 1993 and less likely to undergo minor surgery. Known nosocomial risk factors （transfusion before 1993, dialysis） were responsible for 27% of infections, probable nosocomial factors （transfusions after 1992, minor surgery） for 14% and further 9% were occupationally acquired infections. CONCLUSION： A careful history investigation can identify a known or probable risk factor for HCV acquisition in 59% of patients with HCV infection. Preventive activities in Poland should focus on infection control measures in health-care setting.