Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies

Abstract

Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.

Changes in serum hepatitis B surface and e antigen, interferon‐inducible protein 10, and aminotransferase levels during combination therapy of immune‐tolerant chronic hepatitis B

“…As a major aim of the study was to account for factors that might underlie variability in response to therapy, IFN lambda 4 (IFNL4; IL‐28B) genotype was also analyzed because this has previously been shown to be a predictive factor for response to PegIFN treatment in chronic hepatitis C virus infection although less well established for hepatitis B. [ 16,17 ]…”

“…As a major aim of the study was to account for factors that might underlie variability in response to therapy, IFN lambda 4 (IFNL4; IL-28B) genotype was also analyzed because this has previously been shown to be a predictive factor for response to PegIFN treatment in chronic hepatitis C virus infection although less well established for hepatitis B. [16,17] This secondary analysis of the treatment trials allowed comparison of differences in the magnitude of virologic response with inflammatory indicators (ALT, IP-10, IL-18) in children and adults and assessment of possible interrelationships between levels of IFNinducible cytokines, ALT elevations, achievement of primary efficacy endpoints, degree of HBV DNA decline, and decrease in HBsAg and HBeAg concentrations. The investigators evaluated the relationship to changes in HBV RNA as a direct measure of transcription from circular covalently closed circular HBV DNA (cccDNA).…”

Expression Profiles of Hepatic Immune Response Genes in HEV Infection

“…Similarly, TNFs and interferon receptors facilitate the initiation of cell pathways associated with infections [ 31 , 32 , 33 ]. These genes were previously studied concerning HBV, HCV, liver diseases, and viral-induced cancers [ 34 , 35 , 36 ], but no study showed this gene with expression profiles in HEV infections. The expression of the seven immune response genes CCL2, CCL5, CXCL10, CXCL15, TNF, IFNGR1, and SAMSN1 was evaluated through a real-time PCR.…”

Interferon and Hepatitis B: Current and Future Perspectives

“…In addition to type I IFN, type III IFNs, consisting of four IFN-λ subtypes (IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4), has been considered as an alternative in treatment of CHB ( 142 ). IFN-III signals through a heterodimeric receptor composed of IFN-λ receptor-1 (IFNLR1) and interleukin-10 receptor subunit beta (IL10RB) ( 143 ).…”