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1.
Effect of sofosbuvir and daclatasvir on lipid profile, glycemic control and quality of life index in chronic hepatitis C, genotype 3 patients.
Jain, A, Kalra, BS, Srivastava, S, Chawla, S
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2019;(1):39-43
Abstract
OBJECTIVES The management of hepatitis C has progressed from interferon-based therapy to oral direct acting antiviral therapy. Deranged lipid levels (total cholesterol, triglyceride) after treatment with interferon-based therapy are well known. There is a paucity of data on changes in lipid profile, glycemic parameters and alteration in quality of life with the newer regimen. This study was designed to assess the changes in lipid profile, glycemic parameters, quality of life in chronic hepatitis C patients with genotype 3 after treatment with sofosbuvir and daclatasvir. METHODS The study was a single-centre, prospective study, conducted at tertiary care hospital from January 2017 to December 2017. Fifty patients, who received sofosbuvir (400 mg) and daclatasvir (60 mg) orally once daily for a period of 12 weeks for chronic hepatitis C and genotype 3, were recruited. RESULTS Total cholesterol levels (166.9 ± 23.8 to 192.4 ± 34.5 mg/dL, p-value < 0.0001) and low-density cholesterol (LDL) levels (100.9 ± 22.8 to 121.6 ± 37.2, p-value < 0.0001) were elevated after the treatment. A significant decrease in median levels of glycated hemoglobin (HbA1c) was observed (5.57% to 5.41%, p-value < 0.002). Quality of life markedly improved in all domains, i.e. physical, physiological, environmental, and social relationships according to an abbreviated form of World Health Organization quality of life assessment named WHOQOL-BREF questionnaire. Treatment was found to be effective with sustained virological response (SVR) achieved in 94% patients. CONCLUSIONS Our study reports a substantial increment in total cholesterol, and low-density lipoprotein with sofosbuvir and daclatasvir treatment though it achieved SVR in 94% of patients and improved their quality of life.
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2.
Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells.
Gerresheim, GK, Roeb, E, Michel, AM, Niepmann, M
Cells. 2019;(11)
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the "Warburg Effect" and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
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3.
Antioxidants benefits in hepatitis C infection in the new DAAs era.
Lozano-Sepúlveda, SA, Rincón-Sanchez, AR, Rivas-Estilla, AM
Annals of hepatology. 2019;(3):410-415
Abstract
Some of the evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory. Here we perform a descriptive analysis of the available data in vivo and in vitro of the possible antiviral action and controversy of several antioxidant molecules against HCV.
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4.
Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.
Evon, DM, Sarkar, S, Amador, J, Lok, AS, Sterling, RK, Stewart, PW, Reeve, BB, Serper, M, Reau, N, Rajender Reddy, K, et al
Journal of hepatology. 2019;(3):486-497
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Abstract
BACKGROUND & AIMS A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.
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New insights into the rational use of HCV+ organs worldwide.
Morales, JM, Sawinski, D
Clinical transplantation. 2019;(12):e13739
Abstract
Hepatitis C (HCV) is a worldwide health problem. Effective therapies for HCV infection, coupled with an increase in deceased donors due to the opioid epidemic, have led to the broader availability and the use of HCV-infected donor organs, including HCV nucleic acid test-positive (NAT+) donors in HCV-negative recipients. In this review, we discuss the prevalence of HCV infection, trends in the use of HCV-infected donors, and outcomes for those who receive HCV-seropositive or HCV NAT+ donor organs. We discuss management considerations such as hepatitis B reactivation, selection of the optimal direct-acting antiviral regimen, and potential complications. We also present a framework for the rational use of HCV-infected donor organs in the future.
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SEC14L2, a lipid-binding protein, regulates HCV replication in culture with inter- and intra-genotype variations.
Costa, R, Todt, D, Zapatero-Belinchón, F, Schenk, C, Anastasiou, OE, Walker, A, Hertel, B, Timmer, L, Bojkova, D, Ruckert, M, et al
Journal of hepatology. 2019;(4):603-614
Abstract
BACKGROUND & AIMS The lipid-binding protein, SEC14L2, is crucial for the efficient viral replication of clinical hepatitis C virus (HCV) isolates in cell culture. Given the role of SEC14L2 in HCV replication, we aimed to study a large number of HCV positive sera carrying genotypes 1-4, to identify viral factors associated with efficient replication in culture. Additionally, we investigated whether 13 single nucleotide polymorphisms (SNPs) of SEC14L2 have an impact on RNA replication of naturally occurring HCV isolates. METHODS We generated Huh-7.5 cell lines overexpressing SEC14L2 or 13 coding SNPs and tested 73 different HCV positive sera for in vitro replication. Furthermore, we genotyped a cohort of 262 patients with chronic HCV for the common SNP (rs757660) and investigated its effect on the clinical phenotype. RESULTS HCV isolates from genotype 1, 2, 3 and 4 replicate in Huh-7.5 cells overexpressing SEC14L2. Interestingly, only subgenomic replicons from genotypes 1 and 3 showed enhanced replication whereas genotypes 2 and 4 remained unaffected. Furthermore, replication was independent of viral load. Importantly, all tested SNPs supported HCV RNA replication in vitro, while 1 SNP was associated with decreased SEC1L2 expression and viral RNA. All SNPs exhibited comparable cellular cholesterol and vitamin E abundance in naïve Huh-7.5 cells. CONCLUSIONS This large screen of natural HCV isolates of 4 genotypes underscores the relevance of SEC14L2 as an in vitro HCV host factor. Additionally, SEC14L2 variants appear to recapitulate the wild-type enhancement of HCV replication. Variant rs191341134 showed a decreased effect due to lowered stability, whereas variant rs757660, a high prevalence mutant, showed a similar phenotype to the wild-type. LAY SUMMARY Until the year 2015, consistent replication of patient-derived isolates of hepatitis C virus (HCV) in an in vitro model remained a limitation in HCV research. In 2015 a group of authors identified a protein named SEC14L2 that enabled the replication of HCV isolates in cell culture. We performed a large screen encompassing 73 isolates of 4 different HCV genotypes. Additionally, we replaced the natural SEC14L2 with 13 different mutants to test if the protein variation significantly altered its HCV replication enhancing functions. We showed that different genotypes of HCV react differently to the presence of this protein and the variants of the protein mimic the behavior of the wild-type.
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Interaction of antivirals with a heptameric bundle model of the p7 protein of hepatitis C virus.
Dahl, SL, Kalita, MM, Fischer, WB
Chemical biology & drug design. 2018;(4):942-950
Abstract
A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel-forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock, MOE, LeadIT). Three protein regions are defined to which the ligands are placed, the loop region and the site with the termini as well as the mid-region which is supposed to track poses inside the putative pore. A common feature is that the loop sites and poses either within the pore or at the intermonomer space of the bundle are preferred for all ligands with proposed binding energies smaller than -10 kJ/mol. BIT225, benzamine, amantadine, and NN-DNJ show good overall scoring.
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Efficacy of vitamin D supplementation in combination with conventional antiviral therapy in patients with chronic hepatitis C infection: a meta-analysis of randomised controlled trials.
Kim, HB, Myung, SK, Lee, YJ, Park, BJ, ,
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2018;(2):168-177
Abstract
BACKGROUND Although a contributory role of vitamin D levels for the development of chronic hepatitis C has been suggested, the efficacy of vitamin D supplementation in combination with conventional antiviral therapy consisting of pegylated interferon-α (Peg-IFN-α) injection and oral ribavirin (RBV) remains unclear. We investigated its efficacy in the treatment of chronic hepatitis C via a meta-analysis of randomised controlled trials. METHODS We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov and the bibliographies of relevant articles to locate additional publications in September 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. RESULTS Of 522 articles meeting our initial criteria, a total of seven open-label, randomised controlled trials involving 548 participants, were included in the final analysis. Vitamin D supplementation in combination with Peg-IFN-α injection and oral RBV significantly increased the rate of viral response for hepatitis C at 24 weeks after treatment in a random-effects meta-analysis (relative risk = 1.30; 95% confidence interval = 1.04-1.62; I2 = 75.9%). Also, its significant efficacy was observed in patients with hepatitis C virus genotype 1, which is known to be refractory to antiviral therapy. CONCLUSIONS In summary, we observed that additional use of vitamin D has a positive effect on sustained viral response rates of patients with chronic hepatitis C infection. However, we cannot establish the efficacy because of substantial heterogeneity, a small sample size and a low methodological quality.
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Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options.
Loggi, E, Vukotic, R, Andreone, P
Expert review of anti-infective therapy. 2018;(11):833-838
Abstract
Direct acting antivirals have completely changed the landscape of the treatment of chronic hepatitis C. The management of the few patients who relapse to direct acting antivirals requires a careful analysis of the chances to achieve therapeutic success with a second antiviral course. In this context, the usefulness of viral resistances testing, able to detect resistance-associated substitutions in the viral sequence, is at present a matter of debate. Areas covered: The role of resistance associated substitutions is examined through the evaluation of the data from clinical trials that have assessed the impact of viral resistances on the treatment outcome. Special attention has been paid on the data from re-treatment studies. Expert commentary: The treatment failure in chronic hepatitis C is still a possible event. Therefore, additional real-world clinical data on relapse rates and on the relapse management are welcome to definitely address the clinical guidelines. At present, the testing of viral resistances is an exquisite tool for the choice of the re-treatment schedule. In the near future, widespread use of the most recently registered direct acting antivirals with high barrier to resistance will probably weaken the need of resistance testing as a support in clinical decisions.
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Molecular profile of mannan-binding lectin in hepatitis C patients with MBL gene polymorphisms by a modified mannan-coated nitrocellulose assay.
Albuquerque, DAP, Cavalcanti, IT, Vasconcelos, LRS, Montenegro, F, Pereira, LMMB, Cavalcanti, MSM, Moura, P, Júnior, LBC, de Almeida, SMV, Beltrão, EIC
Journal of immunological methods. 2018;:101-106
Abstract
The aim of this study was to develop an assay to analyze the serum profile of Mannose-binding lectin (MBL) through a simple and "in-house" method (called "dot-N-man"). Furthermore, the study attempted to associate molecular masses of MBL to the profile of MBL gene polymorphisms in patients with hepatitis C. Heterogeneity in molecular masses of MBL is due to the impairment of oligomers formation, which is linked to genetic polymorphisms in the MBL gene. Individuals with AA genotype (wild-type) produce high-molecular-mass proteins, whereas AO and OO individuals produce intermediate and low-molecular-mass proteins, respectively. Sera of thirty patients carrying the hepatitis C virus (HCV) were investigated using MBL binding assay with mannan-coated nitrocellulose (dot-N-man). Purified MBL was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Dot-N-Man assay yielded MBL with molecular masses ranging between 55 and 320 kDa, comparable to low and high molecular mass forms of MBL. Nonreducing SDS-PAGE showed high molecular mass bands in all AA individuals while bands of 270 and 205 kDa were observed in sera for a number of patients with AO and OO genotypes, respectively. Immunoblotting confirmed the MBL samples obtained from the dot-N-man. These results provide new insights to understand the MBL molecular forms profile in patients infected with HCV- which could be useful in future investigations on the influence of the MBL structure/genotype on both the progression of infection and the response to hepatitis C therapy.