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• W2555096688 abstract "We read with great interest the recently published report ‘Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With Ribavirin’ by Dao Thi et al.1Dao Thi V.L. et al.Gastroenterology. 2016; 150: 82-85Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar The authors suggest that their important in vitro observations require a clinical proof-of-concept study to confirm that sofosbuvir might be considered as therapy for treatment of chronic hepatitis E. We have recently treated a patient with chronic hepatitis C (HCV genotype 3) and hepatitis E (HEV genotype 3) co-infection post liver transplantation (immunosuppressed with tacrolimus and azathioprine) with a 12-week course of daily sofosbuvir (400mg) and daclatasvir (60mg), in view of previous ribavirin intolerance. In contrast with the in vitro observations, we report that sofosbuvir without ribavirin was not effective in treating chronic HEV or restoring HEV specific reactive T cells in an immunocompromised patient. In our patient, after commencing treatment with the above regimen, serum alanine aminotransferase normalized after one week and HCV RNA was undetectable after 4 weeks of treatment. However, anti-viral treatment had negligible effect on HEV viremia, as measured by quantitative HEV RNA in serum (Figure 1A). Variable T-cell immunity to HEV infection has been previously reported; although in one report HEV specific T cell responses could be detected in resolved HEV infection controls, no IFN-γ response was observed in chronic HEV infection when cells were stimulated with ORF-2 and 3 peptides suggesting an impairment of adaptive responses.2Suneetha P.V. et al.Hepatology. 2012; 55: 695-708Crossref PubMed Scopus (137) Google Scholar In our patient, HEV specific T- cell responses were monitored before and during anti-viral treatment using HEV genotype 3 ORF-2 and 3 overlapping peptide stimulation of peripheral blood mononuclear cell (PBMC) cultures overnight and measurement of intracellular IL-2, TNF-α and IFN-γ by flow cytometry. Modest CD4 and CD8 T-cell cytokine responses were detected in response to HEV peptide stimulation. In the pre-treatment samples the relative number of cells found reactive to HEV peptide stimulation was raised in TNF-α secreting CD4 and CD8 T cells and in IL-2 producing CD8 cells. CD4 and CD8 T cells expressing elevated IFN-γ and TNF-α were observed at 1 month of therapy. After 2 months of treatment, cells were non-reactive to HEV peptide stimulation. Alteration in the profile of cytokine response to HEV peptide stimulation over treatment may represent a change in tissue mobilization of reactive T cells with lymphopenia observed, potentially explaining the lack of response at this time point. T-cell naïve and memory subsets in CD4+ and CD8+ T cells pre- and during anti–viral therapy were determined (Figure 1B and C). Anti–viral therapy resulted in a 54.4% reduction of CD4+ central memory cells at the end of treatment compared with pre-therapy levels with modest increases detected in CD4+ naïve, effector memory and terminal effector cells. CD8+ cells showed stable naïve cell numbers throughout the study with modest reductions over the treatment period in the percentage of central memory and effector memory cells. However, a 65.5% increase in the percentage of terminal effector cells was observed compared with pre-therapy levels. A shift from central memory to effector memory populations in CD4+ T cells with a partial reversal of CD8+ T-cell exhaustion phenotype in HCV infection treated with directly acting anti-virals has been reported.3Burchill M.A. et al.J Viral Hepatol. 2015; 22: 983-991Crossref PubMed Scopus (86) Google Scholar We also examined if anti-viral therapy had any effect on the sequence of the ORF-2 region of HEV by phylogenetic analysis. When compared with reference sequences of other HEV subtypes, our patient derived sequences clustered with those from genotype 3c. Sequences from pre-therapy and 2 months on therapy showed little sequence change variation suggesting no obvious immune response to HEV in the ORF-2 region examined. In conclusion, in contrast with the in vitro findings, we have not been able to show that conventional anti-HCV sofosbuvir and daclatasvir treatment (without ribavirin) in an immunosuppressed patient is effective in clearing chronic HEV infection or restoring HEV-specific T cell responses. We agree with the authors that further clinical studies are required to study the effect of sofosbuvir and daclatasvir in the treatment of chronic HEV infection, with or without concomitant ribavirin therapy, as alternative safe and effective treatment options for chronic HEV infection are required. Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With RibavirinGastroenterologyVol. 150Issue 1PreviewInfection with hepatitis E virus genotype 3 may result in chronic hepatitis in immunocompromised patients. Reduction of immunosuppression or treatment with ribavirin or pegylated interferon-α can result in viral clearance. However, safer and more effective treatment options are needed. Here, we show that sofosbuvir inhibits the replication of hepatitis E virus genotype 3 both in subgenomic replicon systems as well as a full-length infectious clone. Moreover, the combination of sofosbuvir and ribavirin results in an additive antiviral effect. Full-Text PDF ReplyGastroenterologyVol. 151Issue 5PreviewWe thank Drs Sookoian and Pirola for their thoughtful comments and interest in our recent work. We appreciate the opportunity to broadly discuss the questions raised. Full-Text PDF" @default.
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• W2555096688 date "2017-01-01" @default.
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• W2555096688 title "Sofosbuvir and Daclatasvir Anti–Viral Therapy Fails to Clear HEV Viremia and Restore Reactive T Cells in a HEV/HCV Co-Infected Liver Transplant Recipient" @default.
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• W2555096688 doi "https://doi.org/10.1053/j.gastro.2016.05.060" @default.
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