Detection of residual HCV-RNA in patients who have achieved sustained virological response is associated with persistent histological abnormality

Abstract

Background Whether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. Methods Subjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous resolution, were subjected to detect HCV-RNA in liver by robust RNAscope assay and PBMC by qPCR. Paired liver biopsies at baseline and at SVR24 were analyzed. Results OCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. In DAA-based subgroups, the incidence of OCI was gradually increased in group of solely DAA(s) therapy, combining DAA and PR therapy and combining DAA and ribavirin therapy. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis and active inflammation at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation ( P = .022) and fibrosis regression ( P = .015). Importantly, we found HCV relapse in one of the OCI patients at 48 weeks after the end of PR treatment. Conclusions HCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients who achieved spontaneous or treatment-induced HCV RNA clearance from serum and associated with persistent histological abnormality. Our findings provide new insights into cure of HCV and could influence the following-up scenario after SVR.

Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

“…Follow-up studies with HCV-infected patients up to 1 year after DAA treatment were found to have a minimal or zero decrease in HCC [94,95,96]. The occurrence of occult HCV infection (OCI) was detected in 15.0% of the DAA-based group and was more frequent in patients with genotype 3 [97]. OCI was significantly connected with severity of fibrosis and active inflammation post-SVR.…”

Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response

“…80%) of patients of their status. In addition, there is a lot of evidence showing that HCV can remain in the liver cells and peripheral blood mononuclear cells (PBMC) of patients after the disappearance of viral RNA in serum, thus establishing occult infection [16,17]. Such ongoing viral replication in hepatocytes can lead to continuous liver injury and may underlie the absence of improvement in clinical outcomes after a sustained virological response achieved in a majority of patients [16].…”

Silent damage? Occult HCV replication and histological disease may occur following apparent HCV clearance

“…Wang and colleagues [4] also showed that protracted hepatic inflammation and severe fibrosis score after SVR was associated with OCI compared to fibrosis regression in non OCI patients. The presence of residual RNA/ongoing viral replication in the liver leads to continuous liver injury and does not improve clinical outcomes following HCV clearance.…”

“…Due to limited availability of liver biopsies in nontransplant patients, the clinical significance of these occult HCV infections and their impact on hepatic and extra-hepatic complications have been less well studied in immunocompentent patients post-SVR. A new study by Wang et al [4] assesses the prevalence of occult HCV infection (OCI) in liver and PBMC of patients following SVR24 achieved with DAA and pegylated ribavarin (PR) treatments and in naturally resolving infections. HCV RNA was observed in approximately 11% of patients by in-situ detection of HCV RNA, namely RNAscope assay of liver biopsies either following DAA and PR at SVR24 or after spontaneous resolution.…”

“…Overall, the study by Wang et al [4] has underscored the clinical relevance of OCI and the importance of longitudinal monitoring of patients after SVR and DAA. In addition, it is important to highlight that these findings were seemingly not associated with re-infections which generally result in a similar occult replication and serum clearance, although multiple studies suggest re-infection after SVR and DAA are possible and could mimic these occult pathologies [5].…”