medwireNews: Early research from Japan suggests that induction of interferon (IFN)-λ3 could be a promising therapeutic strategy in patients with hepatitis B virus (HBV) infection.
IFN-λ3 production was induced selectively by nucleotide, but not nucleoside, analogs in HBV patients, which in turn, induced IFN-stimulated genes and suppressed hepatitis B surface antigen (HBsAg) production, the investigators report in Gut.
“The discovery of this mechanism is a new advancement for HBV treatment, suggesting the possibility of developing an anti-HBV treatment targeting IFN-λ3 induction,” they write.
Using a custom in-house assay, they analyzed serum IFN-λ3 levels among 142 individuals at various stages of HBV infection – including 80 patients with chronic hepatitis, 22 with liver cirrhosis, and 40 with hepatocellular carcinoma – who had received nucleos(t)ide analog therapy.
Serum levels of IFN-λ3 were significantly higher among the 25 patients treated with the nucleotide analogs (adefovir or tenofovir disoproxil fumarate [TDF]) than among the 117 given nucleoside analogs (lamivudine or entecavir), at a median of 27.2 versus 1.4 pg/mL (p<0.001).
These findings were replicated in an analysis of serial serum samples from 19 adefovir-treated participants, one individual given TDF alone, and 20 patients treated with lamivudine and/or entecavir, such that IFN-λ3 levels rose during nucleotide, but not nucleoside therapy, and “strongly suggested that the nucleotide analogues are themselves responsible for the induction of IFN-λ3,” say the study authors.
Furthermore, they note that IFN-λ3 expression was detected in the supernatant of the colon cancer cell lines WiDr and HT-29 treated with the nucleotide analogs, and this supernatant “robustly upregulated” IFN-regulated genes and inhibited the production of HBsAg in various cell lines of hepatic origin.
HBsAg production by the PLC/PRF/5 hepatoma cell line was also suppressed by the administration of recombinant IFN-λ3, and this inhibition was dose-dependent.
Despite this additional effect of nucleotide analogs, clearly single-agent treatment is not sufficient to induce HBsAg loss, as TDF and entecavir both lead to HBsAg loss in a small proportion of patients, observe the researchers. They propose that combining nucleotide analogs with pegylated (PEG)-IFNα “could theoretically be a promising treatment method.”
Indeed, previous reports have suggested a high probability of HBsAg loss when PEG-IFN is co-administered with adefovir or TDF, whereas simultaneous treatment with lamivudine leads to findings similar to those in patients given PEF-IFNα alone.
Masashi Mizokami (National Center for Global Health and Medicine, Ichikawa) and team conclude that “[p]rospective studies to demonstrate the upregulation of [IFN-stimulated genes] in the liver and its association with HBsAg changes during treatment with nucleotide analogues or combination with PEG-IFN-α would be warranted to confirm our hypothesis.”
medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2017