Modulation of the Immune System in Chronic Hepatitis C and During Antiviral Interferon-Free Therapy

Abstract

The treatment of patients with chronic hepatitis C virus (HCV) infection has changed tremendously over the past 2 years, with an increasing variety of all-oral direct-acting antiviral (DAA) treatment regimens available for different HCV genotypes and distinct clinical settings. These treatments have significantly improved safety in patients with advanced liver disease compared with interferon (IFN)-based regimens. HCV modifies the human immune system to escape immunosurveillance via several mechanisms. One of the basic mechanisms of HCV is the ability to “switch” the immune response by reducing the activity of cells responsible for the elimination of virus-infected cells. IFN-free DAA treatment regimens provide a unique opportunity to assess the effect of HCV elimination on the immune system. Abrupt changes in the immune system can in some cases be responsible for two alarming processes: viral reactivation in patients with chronic hepatitis B and recurrence of hepatocellular carcinoma in patients with previous successful cancer treatment.

Differential expression of viral pathogen-associated molecular pattern receptors mRNA in Egyptian chronic hepatitis C virus patients

“…The expression levels of IFN-α were positively correlated with the levels of both TLR3 and TLR7. Moreover, this downregulation in chronic HCV infection, could be one of the mechanisms used by HCV to interfere with an early innate immune response through impairment of the IFNs mediated antiviral mechanisms that may therefore lead to impaired T cell activation, in agreements with previous studies that have reported in mice showing lacking MyD88 as a result of TLR7 signal disturbance [24] that is responsible for the persistent replication and eventually promote disease progression and establishment, a chronic infection in 70-80% of infected patients [19,25].…”

“…Accordingly, several TLR ligands have been studied as a synthetic activator of certain TLRs. For instance, application of the TLR7 agonist ANA773 isatoribine has been shown to markedly enhance viral clearance by the immune system, as monitored by dose-dependent dynamics of immunological biomarkers [24]. In addition, synthetic dsRNA (poly I:C) TLR3 antagonists, such as dsRNA mimic polyinosinic: polycytidylic acid (poly I:C) induced stimulation and reactivation of DCs that could induce the immune responses against HCV infection [32].…”

Hepatitis C and history of FVIII inhibitor development in a long‐term cohort of Brazilian patients with haemophilia A

“…An imbalance between the Th1 and Th2 responses with overactivation of B cells has been suggested. 7 Thus, we hypothesize that the higher inhibitor prevalence in HCV-infected individuals, but mostly in low levels, is a consequence of loss of tolerogenic mechanism, which contributes to trigger the humoral response against FVIII.…”

Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C?

“…The IFN-free direct antiviral agent (DAA) therapy has changed radically antiviral therapy in HCV infection, so that a successful treatment can be reached to practically all patients irrespective of their comorbidity [108]. Actually, 3 classes of DAAs are available, and they differ according to the specific viral protein they target: NS3/4A protease inhibitors (voxilaprevir, simeprevir, glecaprevir, grazoprevir, and paritaprevir); NS5A inhibitors (ombitasvir, ledipasvir, velpatasvir, elbasvir, pibrentasvir, and daclatasvir); and NS5B polymerase inhibitors that block replication of viral RNA (dasabuvir and sofosbuvir) [109]. During DAA treatment, the inhibition of HCV replication leads to reversal of NK cells and phenotypic and functional shifts of CD4 and CD8 T cells typical of CHC, triggering viral reactivation in patients with chronic hepatitis B and recurrence of HCC in some patients with earlier effective cancer treatment [109].…”