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. 2019 Aug:46:227-235.
doi: 10.1016/j.ebiom.2019.07.043. Epub 2019 Jul 23.

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

Yijin Wang  1 , Huiying Rao  2 , Xiumei Chi  3 , Boan Li  4 , Hongyang Liu  1 , Liyuan Wu  1 , Hao Zhang  4 , Shuhong Liu  1 , Gaungde Zhou  1 , Na Li  5 , Junqi Niu  6 , Lai Wei  7 , Jingmin Zhao  8
Affiliations

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

Yijin Wang et al. EBioMedicine. 2019 Aug.

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.

Keywords: Direct-acting antiviral agents; Hepatic pathology; Liver fibrosis; Occult hepatitis C; RNAscope assay.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Histological evaluation at baseline and post-SVR in HCV patients with SVR. HAI (A) and fibrosis (S) (B) score were analyzed at pre- and post-treatment in DAA and PR subgroups. Chi-square test or Fisher's exact test was used to compare pathology between DAA and PR groups. For comparing pathology between pre- and post-treatment, McNemar test was used.
Fig. 2
Fig. 2
Incidence of OCI in patients with treatment-induced or spontaneous HCV resolution. (A) Representative images of HCV-RNA detection by RNAScope assay in one OCI patient. The number of OCI cases in subgroups was showed in (B) (C) (D) and the proportion of OCI was summarized in (E). (F) The ratio of OCI in subsets of peg-IFN-free (including solely DAA and DAA plus ribavirin) (N = 42), combination of PR and DDA (N = 18), and PR (N = 50) treatment groups.
Fig. 3
Fig. 3
Histological evaluation between patients with or without OCI. HAI (A) and S (B) score were analyzed at pre- and post-treatment in patients with and without OCI. (C) and (D) are representative images of liver biopsies from two OCI patients. Chi-square test or Fisher's exact test was used to compare pathology between between OCI and non-OCI groups. For pre- and post-treatment comparison, McNemar test were used.
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