Real life results of direct acting antiviral therapy for HCV infection in HIV-HCV-coinfected patients: Epi-Ter2 study.

The aim of this study was to evaluate the baseline demographics and real-life efficacy of direct acting antivirals (DAAs) in HIV-HCV-positive patients as compared to patients with HCV monoinfection. The analysis included 5690 subjects who were treated with DAAs: 5533 were HCV-positive and 157 were HIV-HCV-positive. Patients with HCV-monoinfection were older (p < .0001) and in HIV-HCV group there were more men (p < .0001). Prevalence of genotype 1a (p = .002), as well as of genotypes 3 and 4 (p < .0001) was higher in HIV-HCV-coinfected patients. Genotype 1b was more frequent (p < .0001) in the HCV-mono-infection group. Patients with HCV-monoinfection had a higher proportion of fibrosis F4 (p = .0004) and lower proportion of fibrosis F2 (p < .0001). HIV-HCV-coinfected individuals were more often treatment-naïve (p < .0001). Rates of sustained viral response after 12 weeks did not differ significantly between both groups (95.9% versus 97.3% in coinfection and monoinfection group, respectively; p > .05). They were, however, influenced by HCV genotype (p < .0001), stage of hepatic fibrosis (p < .0001), male sex (p < .0001), BMI (p = .0001) and treatment regimen modifications (p < .0001). Although factors associated with worse response to therapy (male sex, genotype 3) occurred more often in the HIV coinfection group, real-life results of DAAs did not differ significantly between both populations.

Hepatitis C virus (HCV) genotype 1 NS5A resistance-associated variants are associated with advanced liver fibrosis independently of HCV-transmission clusters.

OBJECTIVES: The aim of the study was to characterize the differences in the frequencies of NS3 and NS5A resistance-associated variants (RAVs) among Polish therapy-naive genotype 1 (G1) hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients including clustering patterns and association of RAV frequency with liver fibrosis. METHODS: NS3/NS5A RAVs were identified by population sequencing in 387 directly acting antiviral treatment-naive G1-infected individuals (54 with genotype 1a (G1a) and 333 with genotype 1b (G1b)). Liver fibrosis was assessed based on histopathology or ultrasound elastography. Phylogenetic clusters were identified using maximum likelihood models. For statistics, chi-squared or two-sided Fisher's exact tests and multivariate logistic regression models were used, as appropriate. RESULTS: NS3 RAVs were found in 33.33% (18/54) for G1a and 2.62% (8/297) for G1b whereas NS5A variants were present in 5.55% (3/54) G1a and 9.31% (31/333) G1b sequences. Variations in NS5A 31 and 93 codon positions were found only in G1b (4.2% (14/333) for L31I/F/M and 5.39% (17/333) for Y93H). NS5A RAVs were more frequent among patients with advanced liver fibrosis (17.17% (17/99) for F3-F4 versus 6.94% (17/245) for F0-F2; p 0.004) or liver cirrhosis (20.34% (12/59) for F4 versus 7.72% (22/285) for F0-F3; p 0.003). Liver cirrhosis (F4) was associated with higher odds ratio of the NS5A RAVs among HCV-infected patients (odds ratio 2.34, 95% CI 1.004-5.291; p 0.049). NS5A RAVs were less frequent among sequences forming clusters and pairs (5.16% (8/155) versus 11.21% (26/232); p 0.039). CONCLUSIONS: Presence of NS5A RAVs correlated with progression of liver fibrosis and represents de novo selection of variants rather than transmission of drug resistance. Hence, the presence of NS5A RAVs may be a predictor for a long-lasting HCV infection.

Treatment of HCV infection in Poland at the beginning of the interferon-free era-the EpiTer-2 study.

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections.

The role of endoplasmic reticulum stress in nonimmune diabetes: NOD.k iHEL, a novel model of beta cell death.

The final common pathway in diabetes development is beta cell apoptosis. We herein describe a novel diabetes model based on transgenic NOD.k iHEL mice, wherein male mice develop diabetes due to nonimmune-mediated beta cell death. Histology and electron microscopy confirm endoplasmic reticulum (ER) abnormalities that are consistent with endoplasmic stress caused by the HEL transgene. The NOD.k iHEL model may be particularly useful for studying mechanisms of beta cell death secondary to ER stress and also for testing potential therapies designed to protect beta cells from stress-induced apoptosis. The observation that only male NOD.k iHEL mice develop diabetes and exhibit ER abnormalities is intriguing and suggests these mice may be useful in deciphering the link between hyperandrogenism, insulin resistance, and diabetes.

The role of Fas ligand in beta cell destruction in autoimmune diabetes of NOD mice.

Fas ligand (FasL), a type 2 membrane protein belonging to the TNF family, plays an important role in the induction of cell death. Ligation of Fas receptors by FasL results in apoptosis of the Fas-expressing cell. Autoimmune diabetes results from beta cell destruction by islet-reactive T cells, a process that involves beta cell apoptosis. This raises the question of whether the FasL-Fas pathway plays a major role in beta cell death. To address this issue it is important to know whether beta cells express Fas and/or FasL and, if so, whether induction of these molecules leads to beta cell death. In fact, both Fas and FasL have been demonstrated to be expressed by beta cells in response to cytokine stimulation, although there remains an argument in the literature as to whether beta cells truly express FasL. This is largely because FasL expression has only been demonstrable by immunohistochemistry and not by flow cytometry. Transgenic NOD mice with beta cells expressing a FasL transgene develop an accelerated form of diabetes. We show here that beta cells from FasL transgenic NOD mice are more susceptible to cytokine-induced apoptosis than wild-type beta cells, consistent with the hypothesis that if beta cells express FasL then Fas-FasL interaction on the beta cell surface is able to mediate beta cell self-death in the absence of T cells. Interventions that block the Fas-FasL pathway may be useful, therefore, in the prevention or treatment of type 1 diabetes.

Physical versus chemical defence mechanisms in toxic Gastrolobium.

The degree to which physical defence mechanisms are present in toxic species of Gastrolobium was compared with the known fluoroacetate (the toxic principle) concentrations of these plants using both histological leaf sections prepared from fresh leaves (4 species), and a variety of visual external traits measured from herbarium specimens (28 species). There was a strong negative correlation between the presence of physical deterrents (e.g. area of fibres, number and length of spines) and the fluoroacetate concentration of each species. This suggests that, with respect to their leaves, individual species have established a compromise between producing physical grazing deterrents and the adoption of chemically mediated antiherbivore strategies.