Dataset Information

Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse.

ABSTRACT: Purpose:A detailed analysis of hepatitis C virus (HCV) resistance-associated substitutions (RASs) is required to understand why people fail direct-acting antiviral therapies. This study was conducted to assess RASs in an analysis of 2 trials evaluating the second-generation NS3/4A protease inhibitor grazoprevir (GZR) in combination with peginterferon/ribavirin. Patients and methods:From a total of 113 participants with HCV genotype 1 infection, RASs were evaluated in 25 patients who relapsed and 6 patients with on-treatment virologic breakthrough using consensus Sanger and clonal sequence analysis of NS3/NS4a genes, with in vitro testing of replicon mutants. Next-generation sequencing (NGS) was used in a subset of participants to assess minority variants and the evolution of the whole viral genome. Results:Baseline RASs did not predict treatment failure. Relapse was most commonly associated with RASs at D168, although additional RASs (Y56, R155 and A156) were also detected, particularly in participants with on-treatment breakthrough. Treatment-emergent RASs usually reverted to wild-type (WT), suggesting these mutations were associated with a negative fitness cost (confirmed using in vitro assays). NGS was the most sensitive assay for the detection of minor variants. Significant viral sequence divergence (up to 5.9% codons) was observed across whole genomes in association with the acquisition and reversion of RASs. Conclusion:Relapse with GZR and peginterferon/ribavirin is commonly associated with single RASs in NS3 that generally revert to WT, while breakthrough follows more complex patterns of viral resistance. NGS suggests that large diverse pools of viral quasispecies that emerge with RASs facilitate rapid viral evolution.

SUBMITTER: Bonsall D

PROVIDER: S-EPMC6089106 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse.

Bonsall David D Black Stuart S Howe Anita Ym AY Chase Robert R Ingravallo Paul P Pak Irene I Brown Anthony A Smith David A DA Bowden Rory R Barnes Eleanor E

Infection and drug resistance 20180808

<h4>Purpose</h4>A detailed analysis of hepatitis C virus (HCV) resistance-associated substitutions (RASs) is required to understand why people fail direct-acting antiviral therapies. This study was conducted to assess RASs in an analysis of 2 trials evaluating the second-generation NS3/4A protease inhibitor grazoprevir (GZR) in combination with peginterferon/ribavirin.<h4>Patients and methods</h4>From a total of 113 participants with HCV genotype 1 infection, RASs were evaluated in 25 patients w ...[more]

PMID: 30127629

Similar Datasets

Project description:Purpose:People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. Patients and methods:PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. Results:There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. Conclusion:This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. Clinicaltrialsgov Identifier:NCT02358044.

Project description:UnlabelledChronic hepatitis B (CHB) is prevalent worldwide. The infectious agent, hepatitis B virus (HBV), replicates via an RNA intermediate and is error prone, leading to the rapid generation of closely related but not identical viral variants, including those that can escape host immune responses and antiviral treatments. The complexity of CHB can be further enhanced by the presence of HBV variants with large deletions in the genome generated via splicing (spHBV variants). Although spHBV variants are incapable of autonomous replication, their replication is rescued by wild-type HBV. spHBV variants have been shown to enhance wild-type virus replication, and their prevalence increases with liver disease progression. Single-molecule deep sequencing was performed on whole HBV genomes extracted from samples, including the liver explant, longitudinally collected from a subject with CHB over a 15-year period after liver transplantation. By employing novel bioinformatics methods, this analysis showed that the dynamics of the viral population across a period of changing treatment regimens was complex. The spHBV variants detected in the liver explant remained present posttransplantation, and a highly diverse novel spHBV population as well as variants with multiple deletions in the pre-S genes emerged. The identification of novel mutations outside the HBV reverse transcriptase gene that co-occurred with known drug resistance-associated mutations highlights the relevance of using full-genome deep sequencing and supports the hypothesis that drug resistance involves interactions across the full length of the HBV genome.ImportanceSingle-molecule sequencing allowed the characterization, in unprecedented detail, of the evolution of HBV populations and offered unique insights into the dynamics of defective and spHBV variants following liver transplantation and complex treatment regimens. This analysis also showed the rapid adaptation of HBV populations to treatment regimens with evolving drug resistance phenotypes and evidence of purifying selection across the whole genome. Finally, the new open-source bioinformatics tools with the capacity to easily identify potential spliced variants from deep sequencing data are freely available.

Project description:Objective This study aims to systematically review recent economic evaluations of elbasvir/grazoprevir (EBR/GZR) for chronic hepatitis C (CHC), to critically appraise the reporting quality and to summarize the results. Methods A literature search was undertaken using Medline, Embase, the Cochrane Library, EconLit, China National Knowledge Infrastructure, Wanfang Data, and Chongqing VIP to identify original articles containing economic evaluations of EBR/GZR for CHC published between 1 January 2000 and 31 December 2020. The Consolidated Health Economic Evaluation Reporting Standards statement was used to assess the quality of reporting of the articles. Results Of 93 articles identified, 13 studies fulfilled the inclusion criteria. These studies were conducted in 4 countries, and 8 active interventions were assessed. The target population was patients infected with CHC genotype 1 infection in all studies. Eight out of 13 studies that compared EBR/GZR vs. other direct antiviral agents suggested that EBR/GZR was generally more cost-effective or dominant than daclatasvir/asunaprevir (DCV/ASV), sofosbuvir/velpatasvir (SOF/VEL), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir (3D) but not more cost-effective than glecaprevir/pibrentasvir (GLE/PIB). Two studies from China and one study from the USA that compared EBR/GZR vs. pegylated interferon and ribavirin (PegIFN/RBV) consistently indicated that EBR/GZR was generally more cost-effective than PegIFN/RBV. One study from Italy compared EBR/GZR with SOF + PegIFN/RBV and suggested that EBR/GZR had a lower cost and higher effectiveness. One study from France and one study from the USA confirmed that compared with non-therapy for patients with chronic kidney disease, EBR/GZR was cost-effective at commonly accepted current standards. All included studies were of good quality of reporting, with an average score of 21.9 (range 19–23). Conclusion EBR/GZR for CHC genotype 1 might be cost-effective or dominant compared with PegIFN/RBV and other direct antiviral agents (SOF/VEL, 3D, DCV/ASV, LDF/SOF) or non-therapy. However, under certain assumptions, EBR/GZR was not a cost-effective alternative for CHC patients vs. GLE/PIB.

Dataset Information

Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse.

Publications

Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets