Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection

Abstract

The estimated prevalence of hepatitis C virus infection in the US is approximately 1.8%. Although interferon monotherapy and combination therapy of interferon with ribavirin represent mainstay for treating HCV infection, the rate of sustained virologic response remains suboptimal. The growing evidence suggested that the clinical sequence and treatment response of chronic hepatitis C are determined by a dynamic, complex tripartite relationship among HCV infection, the host immune response, and the effect of different interferon regimens. The treatment response is associated with various viral factors including the pretreatment viral level, dynamic change of viral level during treatment, viral genotype quasispecies and nucleotide mutation in nonstructural protein 5A of hepatitis C virus. Host factors that may affect treatment response include age, gender, race, HLA alleles and the host immune responses. Interferon regimens, including type, dose, frequency and duration of treatment and combination of interferon with other anti-HCV agents also alter the therapeutic response. Understanding these complicated interaction may provide better insights into the mechanism(s) of interferon response, leading to more effective clinical application of interferon therapy.

Hepatitis C virus genetic variability and evolution

“…Unfortunately, to date there is no effective vaccine available [6] . Currently, the standard of care (SOC) therapy involves pegylated interferon α (INF-α-peg) and ribavirin (RBV) [7] . In addition, the new SOC (NSOC) therapy of protease inhibitors boceprevir or telaprevir in combination with INF-α-peg and RBV have been approved for the eradication of HCV genotype 1 in the United States, Europe and Japan [8][9][10][11] .…”

“…Although IFN-α is effective in reducing the viral load, complete eradication of the virus is achieved in less than 20% of patients treated with IFN-α alone [32] . In those patients who initially respond to IFN-α, ribavirin helps increasing the frequency of virus eradication, yet its effect on non-responder patients is still limited [7] . Although viral genotype and viral load, as well as serum HCV RNA clearance during therapy are definitely related to response, further insight into viral factors involved in therapeutic responsiveness is still necessary [27] .…”

Hepatitis C virus inhibits intracellular interferon alpha expression in human hepatic cell lines

“…Most HCV-infected subjects develop chronic infection, suggesting that HCV may have evolved strategies to overcome or evade efficient innate immune responses of the host. [2][3][4][5][6] The innate immune response is the earliest phase of immune defense and also regulates the adaptive immune response. 7 Because the innate immune response of the immune cells or virus-infected cells plays a crucial role in controlling viral infection, damage to the innate immune response may generate a favorable microenvironment for HCV infection and replication.…”

“…[10][11][12][13][14] Virus infection activates IRF-7 through inducible phosphorylation, and phosphorylated IRF-7 participates together with IRF-3 in the transcriptional induction of immediateearly and delayed-type IFN genes. 1,2 Activation of the ISGF3 complex also binds to interferon-stimulated response elements (ISRE) found in hundreds of IFN-stimulated genes (ISGs), including 2Ј-5Ј oligoadenylate synthase (2Ј-5Ј OAS), myxovirus resistance protein (Mx), double-stranded RNA (dsRNA) activated kinase (PKR) and major histocompatibility complex class I, resulting in the induction of proteins that impair viral gene expression and replication. 8,14,15 Clinically, IFN-␣-based treatment combined with ribavirin is the major therapeutic choice available for chronic HCV infection.…”

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

“…Type I includes IFN-␣, IFN-␤, IFN1⍀, and IFN-; type II IFN includes IFN-␥ (Foster, 1997;Maeyer and Maeyer-Guignard, 1998;LaFleur et al, 2001). Most cells in the human body produce type I IFNs within hours of viral infection, with the IFN-␣ family having greater antiviral activity against hepatitis C infection than the others (Hu et al, 2001).…”