Juliana P. Sampaio

Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection.

HCV infection is common among patients with end‐stage renal disease (ESRD) on hemodialysis, and it has been considered an independent risk factor for mortality in this setting. Although liver biopsy in ESRD patients with HCV infection is useful before kidney transplantation, it carries a high risk of complications. We sought to assess the diagnostic value of noninvasive markers to stage liver fibrosis in 203 ESRD HCV‐infected patients. Univariate and multivariate analysis were used to identify variables associated with significant fibrosis (METAVIR F2, F3, or F4 stages). Significant liver fibrosis was observed in 48 patients (24%). Logistic regression analysis identified AST and platelet count as independent predictors of significant fibrosis (P < 0.001 and P = 0.001, respectively). The area under the receiver operating characteristic curve of the AST to platelet ratio index (APRI) for predicting significant fibrosis was 0.801. An APRI < 0.40 accurately identified patients with fibrosis stage 0 or 1 in 93% of the cases (NPV = 93%), and all misclassified subjects were F2. A cutoff ≥ 0.95 to confirm significant fibrosis had a PPV of 66%. If biopsy indication was restricted to APRI scores in the intermediate range (≥0.40 and < 0.95), 52% of liver biopsies could have been correctly avoided. Conclusion: Stage of liver fibrosis can be reliably predicted in ESRD HCV‐infected subjects by simple and widely available blood tests such as AST levels and platelet count. These tests might obviate the requirement for a liver biopsy in a significant proportion of those patients. (HEPATOLOGY 2007.)

Optimized cutoffs improve performance of the aspartate aminotransferase to platelet ratio index for predicting significant liver fibrosis in human immunodeficiency virus/hepatitis C virus co‐infection

Aim: To assess the diagnostic value of modified cutoffs for aspartate aminotransferase to platelet ratio index (APRI) to predict significant liver fibrosis in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) patients.

Serum levels of YKL‐40 and hyaluronic acid as noninvasive markers of liver fibrosis in haemodialysis patients with chronic hepatitis C virus infection

Summary.  Hepatitis C virus (HCV) infection is highly prevalent among end‐stage renal disease (ESRD) patients undergoing haemodialysis and it is an important cause of morbidity and mortality in this population. The aim of this study was to evaluate the diagnostic value of YKL‐40 and hyaluronic acid (HA) as noninvasive markers of liver fibrosis in 185 ESRD HCV‐infected patients. Significant liver fibrosis was defined as METAVIR F2, F3 or F4 stages. Significant fibrosis was observed in 45 patients (24%). By univariate analysis, higher levels of YKL‐40, HA, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma‐glutamyltransferase (GGT) as well as reduced platelet count were associated with fibrosis. However, by multivariate analysis, only AST (P = 0.001), platelet count (P = 0.004) and HA (P = 0.042) were independently associated with significant fibrosis. For the prediction of significant fibrosis, the areas under receiver operating characterictic curve (AUROC) of the regression model (0.798) was significantly higher than the AUROC of YKL‐40 (0.607) and HA (0.650). No difference was noted between the AUROC of the regression model and AST to platelet ratio index (APRI) (0.787). Values <8.38 of the regression model showed a negative predictive value of 94% and scores ≥9.6 exhibited a positive predictive value of 65%. If biopsy indication was restricted to scores in the intermediate range of the regression model, it could have been correctly avoided in 61% of the cases. In conclusion, APRI and a model based on AST, platelet count and HA showed better accuracy than YKL‐40 and HA (when used solely) for the prediction of significant fibrosis in ESRD HCV‐infected patients.

Gender influence on treatment of chronic hepatitis C genotype 1

INTRODUCTION Although various studies have been published regarding the treatment of chronic hepatitis C (CHC) with peginterferon (Peg-IFN) and ribavirin, little is known regarding the real impact of gender on the characteristics that influence the effectiveness and safety of antiviral treatment for CHC patients. The objective of this study was to evaluate the influence of gender on HCV treatment outcomes. METHODS A retrospective analytical study was conducted among selected carriers of CHC genotype 1, who were treated with Peg-IFN alpha-2b at a dose of 1.5 microg/kg or Peg-IFN alpha-2a at a dose of 180 microg/week plus a ribavirin dose of 1,000-1,250 mg/day, according to weight, between 2001 and 2007. RESULTS Among 181 patients undergoing treatment, the mean age was 46.4 +/- 11.0 years and 46% were women. At baseline, 32% of the patients had advanced fibrosis (F3-F4 Scheuer), and 83% of the subjects had viral load > 400,000 IU/ml, without significant difference between the genders (p = 0.428 and p = 0.452, respectively). When compared with men, women had higher incidence of many adverse events such as anemia (p < 0.001) and higher need for dose reduction, for both Peg-IFN (p = 0.004) and ribavirin (p = 0.006). However, the rate of sustained virological response (SVR) did not differ between the genders: 45% (female) vs 41% (male); p=0.464. CONCLUSIONS This study suggests that women and men react differently to combined therapy, especially in relation to the incidence of adverse events and the need for dose modification. Nevertheless, these differences do not influence the SVR rate.

Clinical and histological impact of previous hepatitis B virus infection in patients with chronic hepatitis C

Background: Recent reports suggest that hepatitis C virus (HCV) carriers with serological markers of prior hepatitis B virus (HBV) infection have more advanced liver fibrosis, irrespective of HBV‐DNA detection.

Expanding the applicability of noninvasive fibrosis markers in HIV/HCV co‐infected patients

We read with interest the article by Ikeda et al.1 The authors have elegantly shown that flavustatin, atorvastatin, and simvastatin exert a strong inhibitory effect on HCV replication in their in vitro model. Such an effect was drastically increased when these statins were used in combination with interferon-alpha. The authors report that fluvastatin exhibited the strongest anti-HCV activity, whereas atorvastatin and simvastatin showed moderate inhibitory effects. Ikeda and colleagues argue that these statins might be clinically useful in treatment of HCV infection given that they are commonly used for the treatment of hypercholesterolemia without inducing severe side effects.1 In our opinion, evidence from basic studies needs to be translated into clinical practice with great caution. In particular, we point out that the use of HMG-CoA reductase inhibitors is likely associated with an up-regulation in LDL receptors.2 Given that HCV is deemed to enter the hepatocytes via such LDL receptors,3 it has been speculated that the use of drugs that lower lipid plasma levels might translate into an increased rate of HCV infection,4 which could counterbalance in vivo the antiviral effects observed in vitro.1 Evidence for the close interaction between beta-lipoprotein levels and HCV viremia also comes from a recent retrospective study showing that the higher the cholesterol and LDL levels prior to treatment, the greater the odds of responding to interferon-based antiviral treatment.5 On the other hand, the inverse correlation existing between serum cholesterol levels and hepatic steatosis, which is reversible after effective antiviral treatment,6 suggests that HCV needs fatty substrates to thrive. In the final analysis, lipid-lowering agents might translate into an enhanced entrance rate of HCV into the hepatocytes, which could be balanced by an impaired replication due to the potential “direct” antiviral action. The pharmacokinetic profile also has to be considered. The authors argue that pravastatin, the only hydrophilic statin examined in the index study,1 enters the cells and has the same metabolic effects as the other statins. However, the physicochemical properties, which are dependent on the different chemical structures,7 might affect both the pharmacokinetic features and antiviral properties of different HMG Co-A inhibitors. In particular, statin concentration at the level of hepatic membranes is a critical factor. As pointed out by the authors, plasma concentrations of fluvastatin during treatment with standard therapeutic dosages are lower than those expected to be effective in vitro for a synergistic effect of interferon on HCV replication.1 This makes it very difficult to predict the drug concentration inside liver cells and thus to anticipate antiviral effects in a clinical setting. In conclusion, we suggest that the structure-activity relationship of statins may account for their kinetic and at least a part of their antiviral properties. The complexity of the interaction between HCV and lipoprotein metabolism should discourage immediate extrapolation of basic findings to clinical practice. The safety profile of statins administered to hyperlipidemic individuals does not provide sufficient evidence to suggest their usefulness as antiviral drugs, which should be assessed through ad hoc randomized clinical trials.

Anti-HCV reactive blood donors: clinical and epidemiological factors associated with false-reactive results.

Background In certain clinical settings, false-reactive anti-hepatitis C virus (HCV) results are rare because the majority of persons being tested have evidence of liver disease and the specificity of the screening assays is high. However, among healthy populations, such as blood donors, mainly in regions with a low prevalence of HCV infection, this situation does occur. In this study, we sought to assess clinical, epidemiological, and laboratory characteristics of blood donors with false-reactive anti-HCV screening tests. Methods This retrospective cross-sectional study included 537 anti-HCV reactive blood donors referred to a tertiary care centre for liver diseases. Results The mean age was 36.5±11.2 years and 71.8% were men. Blood donors of older age (P=0.010), history of alcohol abuse (P=0.039), past transfusion (P<0.001), intravenous drug use (P<0.001), and with antibody against core antigen of hepatitis B virus reactivity (P=0.003) were less likely to have a false-reactive anti-HCV result. By multivariate analysis, only the absence of parenteral risk factors (prior transfusion and intravenous drug use) was independently associated with false-reactive anti-HCV tests. Conclusion Blood donors with reactive anti-HCV screening tests with no risk factors for parenterally acquired HCV infection are more likely to present with false-reactive results.

Evidence of a significant role for Fas―mediated apoptosis in HCV clearance during pegylated interferon plus ribavirin combination therapy

BACKGROUND The role of apoptosis in treatment-induced HCV clearance is controversial. We sought to assess the kinetics of serum apoptosis-related cytokines during pegylated interferon-α2a or -α2b plus weight-based ribavirin therapy for genotype 1 chronic HCV infection. METHODS Serum levels of soluble Fas (sFas), soluble Fas ligand (sFasL) and soluble tumour necrosis factor receptor I (sTNF-RI) were measured at baseline, week 12 and 24 weeks after the end of therapy. RESULTS Sustained virological response (SVR) was achieved in 46% of the 164 included patients, 29% had a non-response (NR) and 25% had relapse (RR). NR patients presented with higher levels of sFasL at baseline and lower levels of sTNF-RI at week 12 as compared to RR and SVR patients. Lower concentrations of sFas were observed in SVR patients 24 weeks after treatment as compared to RR and NR patients. An increase in sFas at week 12 followed by a significant drop 24 weeks after therapy was observed among SVR patients. An increase in sFasL during and after treatment was observed in RR and SVR patients. NR patients exhibited an earlier drop in sTNF-RI levels as compared to RR and SVR patients. CONCLUSIONS Virological response during HCV therapy was associated with an increase of sFas and sFasL, and maintenance of increased concentrations of sTNF-RI.