The presence of resistance mutations to protease and polymerase inhibitors in Hepatitis C virus sequences from the Los Alamos databank.

Several new direct-acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3-NS4A serine protease and the NS5B RNA-dependent RNA polymerase have been the major targets. HCV variants displaying drug-resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment-naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low-level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre-existence of HCV variants resistant to first-generation protease inhibitors and to non-nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively.

Prediction of significant liver fibrosis in kidney transplant patients with chronic hepatitis C virus infection: the TX-3 index.

HCV infection is highly prevalent among kidney transplant (KT) recipients. The natural history and management of these patients are controversial. We sought to assess the diagnostic value of noninvasive markers of liver fibrosis in KT HCV-infected patients. This cross-sectional study included 102 KT individuals with positive HCV-RNA. Bivariate and multivariate analyses were used to identify variables associated with significant fibrosis (METAVIR > or = F2). Significant fibrosis was observed in 20 patients (20%). Time after transplantation, AST level, and platelet count were identified as independent predictors of significant fibrosis. Based on the regression model, a simplified index was devised. The AUROC for the TX-3 model was 0.867 +/- 0.081 (0.909, when adjusted by DANA). Values < or =4.0 of TX-3 showed a NPV of 97% and scores >9.6 exhibited a PPV of 71%. If biopsy indication was restricted to scores in the intermediate range of TX-3, this could have been correctly avoided in 68% of cases. The APRI score provided a correct diagnosis in only 47 individuals (46%) and exhibited lower diagnostic indices for both cutoffs, as compared to the TX-3 index. Comparison of AUROCs showed a trend towards superior diagnostic accuracy for TX-3 over APRI, although the difference between AUROCs did not reach statistical significance (0.867 +/- 0.053 vs 0.762 +/- 0.066, respectively, P = 0.064). In conclusion, significant liver fibrosis can be reliably predicted in KT HCV-infected subjects by simple and widely available parameters. If additional studies confirm our results, this model might obviate the requirement for a liver biopsy in a significant proportion of those patients.

Anti-hepatitis C virus-positive blood donors: are women any different?

We sought to assess clinical, epidemiological, biochemical, serological and histological characteristics of anti-hepatitis C virus (HCV)-positive female blood donors and compare them with men. As women are frequently the minority among blood donors, studies evaluating this population usually reflect characteristics of male gender. This retrospective study included 380 blood donors with confirmed positive anti-HCV. The mean age was 36.9 +/- 11.3 years and 33.2% were women. Compared with men, female donors showed higher prevalence of prior transfusion of blood products (P = 0.031) and lower prevalence of intravenous drug use (P = 0.001) and alcohol abuse (P < 0.001). Women exhibited lower medians of alanine aminotransferase (P < 0.001) and gamma-glutamyltransferase (P < 0.001). They also showed higher platelet count (P < 0.001) and prothrombin activity (P = 0.049), and a lower frequency of antibody against core antigen of hepatitis B virus (anti-HBc) positivity (P = 0.032). A higher proportion of spontaneous viral clearance (P = 0.001) and a lower frequency of viraemia (P < 0.001) were observed among women. On liver biopsy, women had lower prevalence of fibrosis stage > or = 2. Multivariate analysis identified age (OR = 1.050, 95% CI: 1.019-1.081, P = 0.001) and anti-HBc positivity (OR = 2.184, 95% CI: 1.010-4.722, P = 0.047) as independent predictors of significant fibrosis. Female blood donors presented higher prevalence of spontaneous viral clearance as well as biochemical and histological evidence of less advanced liver disease. These findings could be because of intrinsic characteristics of female gender or secondary to associated factors such as younger age or anti-HBc positivity.

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

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 >or=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.

[Hereditary hemochromatosis. Case report and review of the literature]. / Hemocromatose hereditária. Relato de caso e revisão da literatura.

BACKGROUND: HFE-associated hemochromatosis is one of the most common inherited liver disease in Caucasian populations and refers to the association of increased iron stores with tissue damage (e.g., cirrhosis, diabetes, cardiomyopathy), which is progressive when diagnosis and treatment are delayed. AIMS: Description of a case of hereditary hemochromatosis in an asymptomatic 44-years-old patient, whose diagnosis was made through casual identification of abnormal iron markers. We will also present a brief review of the literature about the topic. CONCLUSIONS: Hereditary hemochromatosis is an ideal disease for primary prevention since the disease can be detected well before serious complications develop. This intervention has been shown to prevent the manifestations of the disease, altering its natural history.

Fatal evolution of systemic lupus erythematosus associated with Crohn's disease.

The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination. After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies. A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks. Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature.