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Monitoring reversion of hepatitis C virus-induced cellular alterations by Direct-Acting Antivirals using cryo Soft X-ray Tomography and Infrared Microscopy

ABSTRACT:

SUBMITTER: Ana Joaquina Perez-Berna

PROVIDER: EMPIAR-10789 | biostudies-other |

REPOSITORIES: biostudies-other

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Monitoring reversion of hepatitis C virus-induced cellular alterations by direct-acting antivirals using cryo soft X-ray tomography and infrared microscopy.

Perez-Berna Ana J AJ Benseny-Cases Nuria N Rodríguez María José MJ Valcarcel Ricardo R Carrascosa José L JL Gastaminza Pablo P Pereiro Eva E

Acta crystallographica. Section D, Structural biology 20211027 Pt 11

Hepatitis C virus (HCV) is an enveloped RNA virus. One of the hallmarks of HCV infection is a rearrangement of the host cell membranes, known as the `membranous web'. Full-field cryo soft X-ray tomography (cryo-SXT) in the water-window energy range (284-543 eV) was performed on the MISTRAL beamline to investigate, in whole unstained cells, the morphology of the membranous rearrangements induced in HCV replicon-harbouring cells in conditions close to the living physiological state. All morphologi ...[more]

PMID: 34726165

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Monitoring reversion of hepatitis C virus-induced cellular alterations by direct-acting antivirals using cryo soft X-ray tomography and infrared microscopy

Project description:The study of cells replicating hepatitis C and treated with antiviral compounds by soft X-ray cryo tomography (cryo-SXT) and synchrotron-based infrared microscopy allows correlation of the viral structures resolved by the former with their chemical composition revealed by the latter. The results show the potential of cryo-SXT as a platform to determine the effectiveness of antiviral compounds in infected cells, guiding drug development at a preclinical level. Hepatitis C virus (HCV) is an enveloped RNA virus. One of the hallmarks of HCV infection is a rearrangement of the host cell membranes, known as the ‘membranous web’. Full-field cryo soft X-ray tomography (cryo-SXT) in the water-window energy range (284–543 eV) was performed on the MISTRAL beamline to investigate, in whole unstained cells, the morphology of the membranous rearrangements induced in HCV replicon-harbouring cells in conditions close to the living physiological state. All morphological alterations could be reverted by a combination of sofosbuvir/daclatasvir, which are clinically approved antivirals (direct-acting antivirals; DAAs) for HCV infection. Correlatively combining cryo-SXT and 2D synchrotron-based infrared microscopy provides critical information on the chemical nature of specific infection-related structures, which allows specific patterns of the infection process or the DAA-mediated healing process to be distinguished.

| S-EPMC8561738 | biostudies-literature

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Direct-acting antivirals for chronic hepatitis C.

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Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods.

Project description:AimTo evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs).MethodsNinety-six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated.ResultsA sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05).ConclusionsMonitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective.

| S-EPMC5681287 | biostudies-literature

Clinical utility of hepatitis C virus core antigen assay in the monitoring of direct-acting antivirals for chronic hepatitis C.

Project description:BACKGROUND:Hepatitis C virus core antigen (HCV Ag) assay has been proposed as a more economical alternative to HCV RNA detection. This study aimed to investigate the clinical utility of HCV Ag assay in the monitoring of direct-acting antivirals (DAAs) for chronic hepatitis C patients. METHODS:We analyzed serum samples from 110 patients treated with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin. The levels for both HCV Ag and HCV RNA assessed by COBAS TaqMan HCV (CTM) Test or Abbott RealTime HCV (ART) assay were evaluated at baseline, week 2, 4, and 12 during treatment and 12 weeks after completion. RESULTS:Baseline HCV Ag levels showed good correlations with HCV viral load (r = 0.879; p<0.001); whereas the correlation was slightly stronger with CTM test than with ART assay (p = 0.074). The concordance of HCV Ag and HCV RNA undetectability was significantly better in CTM test than in ART assay at week 2 (p = 0.003) and week 4 (p = 0.003). A sustained viral response 12 weeks off therapy (SVR12) was achieved in 108 patients (98%); the HCV Ag assay identified 99% of these patients. Both undetectability of serum HCV Ag and HCV RNA had high positive predictive value at week 2 (98% vs. 100%) and at week 4 (97% vs. 99%) in predicting SVR12. CONCLUSIONS:HCV Ag assay may be a feasible alternative to HCV RNA for the determination of SVR12 in patients treated with DAAs.

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Project description:Background:Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) results in sustained virologic response (SVR) in > 90% of patients. However, some patients required retreatment with newer DAA options. Treatment was selected after consultation with a clinical pharmacy specialist. Methods:A retrospective chart review of patients at the West Palm Beach Veterans Affairs Medical Center (WPBVAMC) in Florida retreated from January 2015 to December 2019 was conducted. Data collected included HCV genotype, previous therapy, newly prescribed medications, and treatment outcomes. Results:Since 2015, > 900 patients have been treated at WPBVAMC, including 22 patients who had previously failed interferon combined with DAA regimens and 46 patients who needed retreatment after failure with an all-oral therapy. This review documents the outcomes of retreatment with DAA after initial failure to achieve SVR Of 28 patients treated with a boceprevir-based regimen, 10 ended in failure. All 10 were retreated, and all achieved SVR with ledipasvir/sofosbuvir. Of 53 patients treated with a sofosbuvir-based interferon regimen, 12 failed treatment. All 12 were retreated and all achieved SVR. Thirty patients were retreated after failure with an all-oral DAA. Of 27 tested, 21 achieved SVR. All patients who failed therapy again had cirrhosis. Conclusions:Veterans retreated with DAAs for HCV infection had a high success rate. Repeat failures of DAAs were rare, but cirrhosis seems to be common among these patients.

| S-EPMC7473721 | biostudies-literature

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Project description:The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives.

| S-EPMC3820491 | biostudies-literature

Economic Evaluation of Direct-Acting Antivirals for Hepatitis C in Norway.

Project description:PURPOSE:New direct-acting antiviral (DAA) drugs have revolutionized the treatment of hepatitis C in recent years. OBJECTIVE:Our objective was to analyse the cost effectiveness of combinations of different DAAs compared with ribavirin and peginterferon-?-2a, taking into account rebates from tender negotiations. METHODS:We used a compartmental model specifically developed for Norway to simulate hepatitis C and complications with and without different DAAs. All costs were based on Norwegian fees and estimates, estimating healthcare sector costs for the year 2016. We performed Monte Carlo simulations on uncertain input parameters to facilitate probabilistic sensitivity analyses. RESULTS:For patients diagnosed with genotype 1, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost effective compared with eight other available alternatives, given a cost-effectiveness threshold of €70,000 per quality-adjusted life-year. For genotype 2, the combination of sofosbuvir and ribavirin was the most effective and cost-effective alternative for all patients. Among available alternatives for patients with genotype 3, sofosbuvir in combination with peginterferon and ribavirin was the most cost-effective alternative, although the combination of daclatasvir and sofosbuvir was somewhat more effective. CONCLUSIONS:For each of the hepatitis C genotypes 1, 2 and 3, there were combinations of DAAs that were cost effective in a Norwegian setting. As a result of recent tender negotiations in Norway, treating all diagnosed patients with hepatitis C with the most cost-effective DAAs will result in lower total expenditure on these medications compared with 2015.

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Project description: Not available

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