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.

Short- and Long-Term Immunological Responses in Chronic HCV/HIV Co-Infected Compared to HCV Mono-Infected Patients after DAA Therapy

“…Brochado-Kith et al showed that following DAA therapy in HCV/HIV co-infected patients (n = 33) at 36 weeks after SVR, patients with advanced cirrhosis had 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. However, normalization of the biomarker values was not achieved, as observed by comparison with HCV (n = 9) and HIV (n = 26) mono-infected patients [17].…”

“…Conversely, a larger study reported a reduction in total activated (HLA-DR+ and CD38+) CD4+ and CD8+ T cells in both groups of patients one-year post SVR [16]. A more recent study showed a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs in HCV/HIV-co-infected patients; however, complete normalization of the immune system was not achieved, as observed by comparison with HCV and HIV mono-infected patients [17]. The studies mentioned above evaluated the effects of treat-ments on T-cell activation and immune system-related plasma biomarkers at SVR or for short time follow-up with discordant results.…”

“…During chronic HCV/HIV coinfection, expression of inflammatory biomarkers has been found to correlate with clinical outcomes because of the influence of both viruses on the progression of the disease [13][14][15][16][17][18]. Among these, IDO activity has been considered an inflammation-related marker for HCV and HIV-1 disease progression [19][20][21][22][23].…”

“…Nowadays, little is known about whether and to what extent immunological alterations induced by HCV are fully reversible upon virus clearance by DAA therapy in HCV mono-as compared to HCV/HIV co-infected patients [15][16][17]. An early report showed that in HCV mono-and HCV/HIV co-infected patients, the frequency of total CD4+ and CD8+ T cells producing IFN-gamma, IL-17, and IL-22 decreased 12 weeks after DAA treatment, whereas no change in T-cell activation was observed at the same time point compared to the baseline [15].…”

Reinfection of Transplanted Livers in HCV- and HCV/HIV-Infected Patients Is Characterized by a Different MicroRNA Expression Profile

“…The introduction of direct-acting antiviral agents (DAAs) against HCV has significantly improved the prognosis of HCV/HIV co-infected patients undergoing liver transplantation for end stage liver disease (ESLD) [ 7 , 8 , 9 , 10 , 11 ]. However, recent studies have suggested that DAA-mediated HCV eradication could represent an impediment to HIV reservoir elimination in coinfected patients [ 4 , 12 ], and that DAA treatment does not completely normalize immune and liver functions as well as the risk of hepatocellular carcinoma development [ 13 , 14 ].…”