Sofosbuvir/Velpatasvir for the treatment of Hepatitis C Virus infection

Hepatitis C Virus (HCV) infection is major health problem worldwide, with 150 million infected people according to recent epidemiologic estimations. The introduction of direct-acting antivirals made a revolutionary change in the management of HCV infected patients with surprisingly high rates of antiviral response, improved tolerability and reduced time of treatment. Sofosbuvir, in combination with different partner drugs, has been the molecule that led this incredible change. The last generation of SOF-based regimens, namely Sofosbuvir/Velpatasvir, represents a single tablet, once a day, pangenotypic and pan-fibrotic combination, demonstrated to be safe and effective in almost all type of HCV infected individuals. This review overviews the main clinical data of SOF/VEL registration trials, underlying the key features of this combination in terms of efficacy, safety and Patients Reported Outcomes obtained in more than 1800 HCV chronically infected subjects

Mapping the dielectric properties of unknown targets by using a network of microwave sensors: A proof-of-concept

The subject of this paper is the possible use of a network of microwave sensors to achieve a map of the electromagnetic properties of unknown targets. The basic idea is to use a set of microwave sensors to illuminate a region of interest and to measure the resulting axial component of the electric field. Measurements are then processed by means of a technique based on inverse-scattering, which provides an estimate map of the dielectric values of the area under examination, allowing to discriminate among possible targets. In order to initially evaluate the feasibility of the proposed approach, numerical results in a simulated environment are preliminarily considered and discussed. Furthermore, an initial test on experimental data in a simplified configuration is also presented

Selectively charged and zwitterionic analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies are still required. In this context, the preparation of two cationic, an anionic, as well as two zwitterionic tetrasaccharide analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14 (SP14) capsular polysaccharide are presented. By exploiting a block strategy, the negative charge has been installed on the non-reducing end of the lactose unit of the tetrasaccharide and the positive charge either on the non-reducing end of the lactosamine moiety or on an external linker. These structures have then been tested by competitive ELISA, showing that the structural variations we made do not modify the affinity of the neutral compound to binding to a specific antibody. However, lower efficacies than the natural SP14 compound were observed. The results obtained, although promising, point to the need to further elongate the polysaccharide structure, which is likely too short to cover the entire epitopes

IgG cryoglobulinemia

OBJECTIVE: Mixed Cryoglobulinemia is the most well-known Hepatitis C Virus (HCV)-associated extrahepatic manifestation. MC is both an autoimmune and B-lymphoproliferative disorder. Cryoglobulins (CGs) are classified into three groups according to immunoglobulin (Ig) composition: type I is composed of one isotype or Ig class. Type II and type III mixed CGs are immune complexes composed of polyclonal IgGs acting as autoantigens and mono, polyclonal or oligoclonal IgM with rheumatoid factor activity. IgG1 and IgG3 are the predominant subclasses involved. This study shows the simultaneous presence of IgG-RF and IgG3, supporting the hypothesis of an involvement of this subclass in the initiation of early stages of CGs. PATIENTS AND METHODS: We describe a case series of six HCV-positive patients, all of whom had peripheral neuropathy and transient ischemic attacks, presenting cryoprecipitates formed by IgG3 and IgG1. Cryoprecipitate IgG subclass research was carried out by immunofixation electrophoresis by using antisera against IgG1, IgG2, IgG3, and IgG4. RESULTS: Our six patients presented with an immunochemical pattern characterized by the mere presence of IgG1 and IgG3 subclasses with probable RF activity and one of these six patients exhibited monoclonal IgG3 in his cerebrospinal fluid. CONCLUSIONS: We can hypothesize that the IgG passage through the blood-brain barrier could have contributed to the cause of TIAs, through a mechanism involving the precipitation of circulating immune complexes formed by the two subclasses in the intrathecal vessels

Hepatitis B virus-infection related cryoglobulinemic vasculitis. Clinical manifestations and the effect of antiviral therapy: A review of the literature

Objective: Hepatitis B virus (HBV) infection causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, about 20% of the patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV), polyarteritis nodosa, non-rheumatoid arthritis, glomerulonephritis and non-Hodgkin lymphoma. This review analyzed literature data on clinical manifestations of HBV-related CV and the impact of antiviral therapy with analoques nucleotide. Methods: A PubMed search was performed to select eligible studies in the literature, up to July 2022. Results: Some studies have analyzed clinical manifestations in HBV-related CV and have investigated the role of antiviral therapy with nucleotides analogues (NAs). Clinical manifestations of CV vary from mild to moderate (purpura, asthenia and arthralgias) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, and non-Hodking lymphoma). NAs therapy leads to suppression of HBV-DNA; therefore, it is capable of producing clinical response in the majority of patients with mild to moderate symptoms. Conclusion: Antiviral therapy with NAs is the first choice for HBV suppression and control of mild to moderate disease. In severe vasculitis (glomerulonephritis, progressive peripheral neuropathy and leg ulcers), rituximab alone or with plasma-exchange is always indicated in combination with antiviral therapy

B-cell activating factor (BAFF), BAFF promoter and BAFF receptor allelic variants in hepatitis C virus related Cryoglobulinemic Vasculitis and Non-Hodgkin's Lymphoma

Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%–10% of cases evolves into a B cell Non-Hodgkin's Lymphoma (NHL). B-cell activating factor (BAFF) is a key regulator in B-cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF-receptor (BAFF-R) polymorphisms in order to determine if they predispose to HCV-related CV and NHL. The analysis was performed on 416 HCV-chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV-CV) and 114 HCV with NHL (HCV-NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF-R and rs12428930 on the BAFF gene were evaluated by Real-Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV-CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV-CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV-NHL versus HCV. T minor allele was more frequent in HCV-NHL and HCV-CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV-CV and HCV-NHL than in HCV. Genotyping of rs61756766 on BAFF-R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV-NHL versus 3% in HCV. The T minor allele frequency was higher in HCV-NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF-R genetic pattern has a role in the pathogenesis of HCV-related lymphoproliferations. BAFF/BAFF-R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF-R genetic profile assessment could potentially contribute to tailoring anti-BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial

Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis

Background and Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome. Approach and Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively). Conclusions: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up