Revisiting the Paradox of Interferon‐Stimulated Gene Expression as a Predictor of Hepatitis C Virus Treatment Response, a Decade Later

Golden-Mason, Lucy; Rosen, Hugo R.

doi:10.1002/hep.30195

Cited by 3 publications

(2 citation statements)

References 10 publications

(25 reference statements)

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“…HBV reactivation can occur through removal or attenuation of anti-HBV immunity: rituximab by B-cell depletion, steroid-containing or steroid-free chemotherapies by a global immune suppression (T cells depletion mainly), and biologics (for example, anti-tumor necrosis factor alpha) by anticytokines [ 21 ]. The mechanism for post-DAA HBV reactivation is unknown but may be due to attenuation of interferon-related immune responses after the start of DAA therapy [ 22 , 23 ]. To address this issue, a study in cooperation with the National Institutes of Health found that in HCV and HBV coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment

Liu

Sheen

Chen

et al. 2021

Clinical Infectious Diseases

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Background For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. Methods In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once-daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either <lower limit of quantification (LLOQ, 20 IU/mL) to ≥LLOQ or ≥LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2x upper limit of normal (ULN). Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. Results All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12 while clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and HBsAg levels were associated with HBV virologic reactivation and baseline ALT, HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. Conclusion Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy.

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Section: Discussionmentioning

confidence: 99%

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment

Liu

Sheen

Chen

et al. 2021

Clinical Infectious Diseases

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“…Hepatitis C viral RNA is recognized by innate pattern recognition receptors (PRRs) residing within the cytoplasmic or endosomal compartments, including retinoic acid inducible gene-I (RIG-I), Nod-like receptors, and endosomal Toll-like receptor-3 [ 31 ]. Activation of PRRs by HCV leads to IFN regulatory factor (IRF)3 phosphorylation, dimerization, and nuclear translocation inducing transcription of type I and III interferon genes.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes

Burchill¹,

Salomon

Golden-Mason

et al. 2021

PLoS Pathog

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Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine responsiveness, and development of complications such as hepatocellular carcinoma. Highly effective direct-acting antiviral (DAA) therapy has revolutionized the management of chronic HCV, with expected cure rates exceeding 95%. DAA treatment represents a unique opportunity to investigate to what extent elimination of viral replication and chronic antigen stimulation can restore immunologic phenotype. In this study we interrogated the global transcriptional profile of isolated peripheral blood T cells before, during and after IFN-free DAA therapy using single-cell mRNA sequencing. Our results demonstrate that T cells mapped at single-cell resolution have dramatic transcriptomic changes early after initiation of DAA and many of these changes are sustained after completion of DAA therapy. Specifically, we see a significant reduction in transcripts associated with innate immune activation and interferon signaling such as ISG15, ISG20, IFIT3, OAS and MX1 in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, DUSP1, in circulating T cells. Conclusion: This study provides the first in-depth transcriptomic analysis at the single-cell level of patients undergoing DAA therapy, demonstrating that IFN-free antiviral therapy in chronic HCV infection induces hitherto unrecognized shifts in innate immune and interferon signaling within T cell populations early, during, and long-term after treatment. The present study provides a rich data source to explore the effects of DAA treatment on bulk T cells.

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Role of Genetic and Epigenetic Modifications in the Progression of Hepatocellular Carcinoma in Chronic HCV Patients

Syyam

Akbar

Jilkova

et al. 2023

Livers

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Globally, hepatocellular carcinoma (HCC) is a significant cause of mortality and morbidity among chronically infected HCV patients. It is established that HCV is a primary risk factor for HCC progression. The treatment of HCV infection has been transformed by the introduction of DAAs with high rates of virological clearance. The reduction in cirrhosis-related consequences, particularly HCC, is the long-term objective of DAAs therapy for HCV. Although the risk of developing HCC is decreased in HCV patients who achieve a disease-sustaining virological response, these patients are nevertheless at risk, especially those with severe fibrosis and cirrhosis. Previous studies have shown that HCV induce several mechanisms of hepatocarcinogenesis in the host’s hepatic micro- and macro-environment, which leads to HCC progression. In an HCV-altered environment, compensatory liver regeneration favors chromosomal instability and irreversible alterations, which encourage hepatocyte neoplastic transformation and the development of malignant clones. These mechanisms involve a series of genetic and epigenetic modifications including host genetic factors, dysregulation of several signaling pathways, histone, and DNA modifications including methylation and acetylation. This review highlights the genetic and epigenetic factors that lead to the development of HCC in chronic HCV-infected individuals and can be targeted for earlier HCC diagnosis and prevention.

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Revisiting the Paradox of Interferon‐Stimulated Gene Expression as a Predictor of Hepatitis C Virus Treatment Response, a Decade Later

Cited by 3 publications

References 10 publications

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment

Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes

Role of Genetic and Epigenetic Modifications in the Progression of Hepatocellular Carcinoma in Chronic HCV Patients

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