HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

Abstract

Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways ("cytokine-cytokine receptor interaction", "viral protein interaction with cytokine and cytokine receptor", "chemokine signaling pathway", and "hepatitis C"). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.

Keywords: DAA therapy; HIV/HCV coinfection; PBMCs; cirrhosis; gene expression; immune system; plasma biomarkers.

Figure 1

Study design flowchart. RNA sequencing identified a total of 60,623 genes. Of these, we selected 4,723 genes of the immune system from the InnateDB. A total of 4,719 genes were selected for the differential expression analysis. Next, the FilterByExpr function was applied for each comparison: (A) HIV/HCV-f vs. HIV/HCV-b, 3,079 genes were selected, 17 were SDE genes involved in four biological pathways; (B) HIV/HCV-f vs. HCV-mono-f, 2,847 genes were selected, 17 were SDE genes involved in one biological pathway; (C) HIV/HCV-f vs. HIV-mono, 2,779 genes were selected, 46 were SDE genes involved in four biological pathways. HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-f, HIV/HCV-coinfected patients 36 weeks after the sustained virological response (SVR); HCV-mono-f, HCV-monoinfected patients 36 weeks after SVR; HIV-mono, HIV-monoinfected patients; SDE, significantly differentially expressed; GLM, generalized linear model; GLMM, Generalized linear mixed model.

Figure 2

Association between changes in plasma biomarkers and liver disease severity scores (A) [liver stiffness measurement (LSM) and (B) hepatic venous pressure gradient (HVPG)] after successful all-oral direct-acting antiviral treatment in HIV/HCV-coinfected patients with advanced cirrhosis. Data were calculated by GLMM models. Values are expressed as regression coefficient (β) and 95% of confidence interval (95%CI). The statistically significant differences are shown in bold.

Figure 3

Volcano plots showing differentially expressed genes between groups: (A) HIV/HCV-f vs. HIV/HCV-b, (B) HIV/HCV-f vs. HCV-mono-f, and (C) HIV/HCV-f vs. HIV-mono. The vertical lines represent the cut-off of FC=2, and the horizontal line indicates the cut-off of FDR=0.05. FDR, false discovery rate for multiple comparisons using Benjamini and Hochberg procedure; FC, fold-change; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-f, HIV/HCV-coinfected patients 36 weeks after the sustained virological response (SVR); HCV-mono-f, HCV-monoinfected patients 36 weeks after SVR; HIV-mono, HIV-monoinfected patients.

Figure 4

Association between changes in significant differentially expressed (SDE) genes and liver disease severity scores (A) [liver stiffness measurement (LSM) and (B) hepatic venous pressure gradient (HVPG)] after successful all-oral direct-acting antiviral treatment in HIV/HCV-coinfected patients with advanced cirrhosis. Data were calculated by GLMM models. Values are expressed as regression coefficient (β) and 95% of confidence interval (95%CI). The statistically significant differences are shown in bold.