Predicting Early Viral Control under Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus Using Pretreatment Immunological Markers

Hutchinson, James A.; Weigand, Kilian; Adenugba, Akinbami; Kronenberg, Katharina; Haarer, Jan; Zeman, Florian; Riquelme, Paloma; Hornung, Matthias; Ahrens, Norbert; Geissler, Edward K.; Werner, Jens

doi:10.3389/fimmu.2018.00146

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…Higher serum levels of type 1 or 2 cell associated cytokines/chemokines are present in patients with rapid virologic response (4). Similarly, frequencies of baseline CD3 + and naive CD8 + T lymphocytes reliably identified patients that achieve rapid reduction in viremia following DAA therapy (5). While these studies suggest host immunity affects response to DAA, rapid viral load decline does not lead to SVR and these immune biomarkers cannot be applied to selecting potential responders to short duration therapy.…”

Section: Introductionmentioning

confidence: 99%

Peripheral PD-1+ T Cells Co-expressing Inhibitory Receptors Predict SVR With Ultra Short Duration DAA Therapy in HCV Infection

et al. 2019

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Direct acting antiviral (DAA) regimens of 12 weeks result in HCV clearance in vast majority of patients across genotypes. We previously demonstrated an ultra-short regimen of 4 weeks DAA cleared HCV in a subset of patients. Here, we hypothesized that individual level of antiviral immunity differentially influenced viral clearance and investigated biomarkers of a successful response. Cohorts of HCV patients treated for 4 weeks with DAA therapy who either achieved sustained virologic response (SVR) or relapsed were compared at baseline and at end of therapy (EOT) for immune cell phenotypes and HCV specific immunity. Higher levels of PD-1 + CD8 + and CD4 + T lymphocytes co-expressing inhibitory receptors (IR) were present at baseline and at EOT in HCV patients who eventually achieved SVR compared with those who relpased. HCV specific CD8 + T cells were predominantly contained within these IR expressing PD-1 + subsets. Patients in the SVR group had significantly higher CD8 + T cell degranulation in response to HCV peptides at baseline and higher levels of cytokine producing T cells at EOT time-point, relative to those who relapsed. In ex vivo cultures, PD-1 + CD160 + CD8 + T cells had higher HCV specific degranulation and PD-1 + 2B4 + CD8 + T cells had higher cytokine expression (IFNγ + TNFα + or IFNγ + CD107a + ) compared with single or no IR expressing subsets, indicating higher virus specific functional capacity of these subsets. Receiver operating characteristics curve (ROC) for baseline circulating frequencies of PD-1 + CD160 + , PD-1 + Tim-3 + CD8 + T cells and PD-1 + CD160 + , PD-1 + Blimp-1 + , PD-1 − CTLA4 + CD4 + T cells respectively, had associated C-statistics of 0.8214 and 0.9451 for discriminatin of patients who successfully cleared HCV with 4 weeks treatment. Thus, PD-1 + virus-specific CD8 + T cell subsets with cytotoxic capacity are present in a subset of chronic HCV infected individuals that associate with ability to achieve SVR, indicating role of immunity in DAA mediated viral clearance with short duration therapy.

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Section: Introductionmentioning

confidence: 99%

Peripheral PD-1+ T Cells Co-expressing Inhibitory Receptors Predict SVR With Ultra Short Duration DAA Therapy in HCV Infection

et al. 2019

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“…27,28 By contrast, nonspecific and systemic CD8 + T cell activation is related to a longer time to viral clearance. 29 Nevertheless, these immune indexes are not routinely determined in clinical laboratory tests. In another study conducted in northern China, baseline ALT or AST was not related to DAA treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

Xie

Deng

Yang

et al. 2022

Journal of Medical Virology

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The data on direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients in southern China with multiple genotypes circulating are limited. This study aims to evaluate the efficacy and safety of DAA regimens among CHC patients in Guangdong, China. A total of 220 patients receiving a variety of DAA were enrolled. The primary outcome was sustained virologic response (SVR) at 12 weeks. Resistance associated substitutions (RASs) were evaluated by deep sequencing. The overall SVR rate was 96.4%, and was 97.7% for genotype 1, 100% for genotype 2, 91.9% for genotype 3, 95.7% for genotype 6, and 100% for untyped. The overall incidence of adverse events (AEs) was 8.2% (18/220) and all the AEs were mild. Nonstructural proteins 5A RAS, 30K/31M, and Y93H were most prevalent at baseline and the end of treatment in non-SVR patients, respectively. Logistics regression showed that elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at baseline were specifically associated with non-SVR in patients with genotype 3 and 6 infections (p = 0.029 and p = 0.017) but not genotype 1 infection (p = 0.746 and p = 0.971), and baseline AST was the best predictor for SVR in genotypes 3 and 6 patients (area under curve = 0.890). Our studies demonstrated all DAA regimens achieved ideal SVR and

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“…With this study, we aimed also at investigating whether chronic HCV infection, and DAA treatment, could affect the overall T cell compartment. HCV-infected individuals show reduced numbers of naïve T cells and a proportional increase of memory subpopulations in both CD4 + and CD8 + T cells, and the magnitude of these alterations predicts response to therapy (Shen et al, 2010, 2011; Hutchinson et al, 2018). In agreement, we observed reduction of N CD4 + T cells and increase of CM CD8 + T cells in NT subjects.…”

Section: Discussionmentioning

confidence: 99%

In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment

Telatin

Nicoli

Frasson

et al. 2019

Front. Cell. Infect. Microbiol.

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Chronic HCV infection is characterized by several immunological alterations, such as the accumulation of suppressor cells and of hyperactivated T lymphocytes. However, it is unclear whether direct-acting antiviral (DAA)-mediated HCV clearance restores immune dysfunctions. We performed a phenotypic characterization by flow cytometry of different immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSCs) and T lymphocytes in 168 patients with persistent HCV infection not treated, under DAA therapies and sustained virological responders. Chronic HCV infection prompted the accumulation of M-MDSCs independently of patient and clinical characteristics, and altered their metabolic properties. HCV RNA was undetectable in the majority of patients just after few weeks of DAA therapy, whereas M-MDSC levels normalized only 6 months after therapy. In addition, HCV infection deeply perturbed the T cell compartment since a re-distribution of memory CD4 + and CD8 + T cells was observed at the expenses of naïve cells, and memory T lymphocytes displayed increased activation. Notably, these features were only partially restored by DAA therapies in the CD4, but not in the CD8, compartment as high immune activation levels persisted in the terminally differentiated memory CD8 + T cells even more than 1 year after sustained virological response. Together, these results suggest that successful DAA therapies do not lead to full immunological reconstitution as fast as viral clearance.

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Predicting Early Viral Control under Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus Using Pretreatment Immunological Markers

Cited by 9 publications

References 21 publications

Peripheral PD-1+ T Cells Co-expressing Inhibitory Receptors Predict SVR With Ultra Short Duration DAA Therapy in HCV Infection

Peripheral PD-1+ T Cells Co-expressing Inhibitory Receptors Predict SVR With Ultra Short Duration DAA Therapy in HCV Infection

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment

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