Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. \ua9 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved

Expression of proliferating cell markers in normal and diseased human hearts.

Proliferating cell nuclear antigen (PCNA) myocyte expression and histopathologic features related to its occurrence were investigated in normal and diseased hearts of adult humans using both immunohistochemical and Western blotting techniques. Ki67 Western blotting was also performed in the same samples used for PCNA blotting. Two hundred seventy-one endomyocardial biopsies, and 15 adult, 1 embryonic and 2 fetal hearts were studied. The biopsies were from normal donor hearts (n = 71), patients with cardiomyopathy and myocarditis (n = 64), and patients with transplantation with (n = 106) and without (n = 30) acute rejection of any grade. The 15 hearts were from 1 heart donor, and from patients with cardiomyopathy (n = 5), valvular heart disease (n = 2), ischemic heart disease (n = 4), amyloidosis (n = 1) and transplantation with acute rejection (n = 2). The PCNA labeling index was plotted against myocyte hypertrophy, inflammatory infiltrates and binucleation index. The PCNA labeling index ranged from 2 to 9% in embryonic and fetal hearts. PCNA was expressed by 1 to 2% of myocyte nuclei in 12% of normal heart biopsies, 1 to 5% of myocyte nuclei in 28% of cardiomyopathy and myocarditis biopsies, and by up to 8% of myocyte nuclei in 53% of biopsies of patients with transplantation, independently of the presence and degree of acute rejection. In the latter biopsies and in myocarditis, some inflammatory cells also showed PCNA expression. PCNA positive myocytes were both mono- and binucleated, and there was no correlation between binucleation and PCNA labeling indexes. Ki67 and PCNA blotting confirmed immunohistochemical results

Glucose plasma levels and pregnancy outcomes in women with HIV

There is limited information on the relation between glucose levels in pregnancy and adverse perinatal outcomes in HIV-infected pregnant women

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents.

OBJECTIVES: To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents. DESIGN: Phase I, nonrandomized, open-label study in two stages. METHODS: Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen. RESULTS: Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration-time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses. CONCLUSION: Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials

Development and validation of a scoring system to predict response to obeticholic acid in primary biliary cholangitis

Background & aims: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. Methods: We used data from the Italian RECAPITULATE (N 441) and the IBER-PBC (N 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS), or also after 6 months of treatment (ORS+). Multivariable Cox's regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (ALP/ULN<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or NORMAL RANGE criteria (NR: normal ALP, ALT and bilirubin) up to 24 months. Results: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were of 0.75, 0.78 and 0.72 for POISE, ALP/ULN<1.67 and NR response, which raised to 0.83, 0.88, 0.81 with ORS+, respectively. The respective performances in validation were of 0.70, 0.72 and 0.71 for ORS, and 0.80, 0.84, 0.78 for ORS+. Results were consistent across groups with mild/severe disease. Conclusions: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC