Effects of tenofovir disoproxil fumarate on intrahepatic viral burden and liver immune microenvironment in patients with chronic hepatitis B.

Background: The impact of nucleos(t)ide analogues on intrahepatic viral burden and immune microenvironment in patients with chronic hepatitis B (CHB) is not clear.
Objective: We aimed to characterise the effects of tenofovir disoproxil fumarate (TDF) on intrahepatic viral burden and the liver immune microenvironment in patients with CHB.
Design: Core liver biopsies were collected at baseline and year 3 from patients with CHB with minimally raised serum alanine aminotransferase in a double-blind placebo-controlled trial (NCT01522625). Paired biopsies were analysed by RNA-sequencing (n=119 pairs), a custom multiplex immunofluorescence assay (n=30 pairs), and HBV-targeted long-read DNA sequencing (n=49 pairs).
Results: Both non-integrated and integrated HBV DNA were present in all patients at baseline, with >65% having interchromosomal translocations. Treatment significantly reduced the frequency of HBV core+ hepatocytes and intrahepatic (integrated and non-integrated) HBV DNA, but had no effect on HBsAg+ hepatocytes. Clonally expanded integrations were enriched for HBsAg coding regions and showed dysregulation of nearby genes. At baseline, there was significant enrichment of intrahepatic CD8+ T cell proximity to HBV core+ hepatocytes, but not to HBsAg+ cells. The densities of T cells and B cells were significantly reduced by TDF. Transcriptomic analyses found TDF induced widespread downregulation of immune-related genes including inhibitory and regulatory genes.
Conclusion: TDF significantly reduced intrahepatic integrated and non-integrated HBV DNA, exerting disparate effects on HBV core+ and HBsAg+ cells and on different immune cell subsets. Our data suggest there may be differential cytotoxic T cell-mediated killing of HBV core+ versus HBsAg+ hepatocytes, providing insights for HBV cure strategies.
Competing Interests: Competing interests: DZP, CMS, AA, DH, NvB, PW, BF, BD, LL, LD, HM, SPF, SB, RR and VS were employees and stockholders of Gilead Sciences, Inc. J-TL, C-HT and Y-CH have research support from Gilead Sciences. C-HT and Y-CH are paid lecturers for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme and Novartis. Y-CH is an advisory committee member for Gilead Sciences.
(© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)