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

作者：David Z. Pan, Cameron M. Soulette, Abhishek Aggarwal, Dong Han, Nicholas van Buuren, Peiwen Wu, Becket Feierbach, Jaw‐Town Lin, Cheng‐Hao Tseng, Chi-Yi Chen, Bryan Downie, Hongmei Mo, Lauri Diehl, Li Li, Simon P. Fletcher, Scott Balsitis, Ricardo Ramírez, Vithika Suri, Yao‐Chun Hsu · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2024-332526 · 被引用次数：17 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Liver Diseases and Immunity

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...