Hepatitis B e Antigen-Negative Single Hepatocyte Analysis Shows Transcriptional Silencing and Slow Decay of Infected Cells With Treatment

Chloe L. Thio, Maraake Taddese, Yasmeen Saad, Kristina Zambo, Ruy M. Ribeiro, Tanner Grudda, Mark S. Sulkowski, Richard K. Sterling, Yang Zhang, Eric D. Young, Hyon S. Hwang, Ashwin Balagopal

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Nucleos(t)ide analogues (NUCs) rarely cure chronic hepatitis B (CHB) because they do not eliminate covalently closed circular deoxyribonucleic acid, the stable replication template. In hepatitis B e antigen (HBeAg)-positive CHB during NUCs, HBV-infected cells decline slowly and are transcriptionally silenced. Whether these occur in HBeAg-negative CHB is unknown. Methods. Using paired liver biopsies separated by 2.7–3.7 years in 4 males with HIV and HBeAg-negative CHB at both biopsies and 1 male with HIV who underwent HBeAg seroconversion between biopsies, we quantified amounts of viral nucleic acids in hundreds of individual hepatocytes. Results. In the 4 persistently HBeAg-negative participants, HBV-infected hepatocytes ranged from 6.2% to 17.7% (biopsy 1) and significantly declined in 3 of 4 by biopsy 2. In the HBeAg seroconverter, the proportion was 97.4% (biopsy 1) and declined to 81.9% at biopsy 2 (P < .05). We extrapolated that HBV eradication with NUCs would take >100 years. At biopsy 1 in the persistently HBeAg-negative participants, 23%–56.8% of infected hepatocytes were transcriptionally inactive—higher than we observed in HBeAg-positive CHB—and significantly declined in 1 of 4 at biopsy 2. Conclusions. In HBeAg-negative CHB on NUCs, the negligible decline in infected hepatocytes is similar to HBeAg-positive CHB, supporting the need for more potent therapeutics to achieve functional cure.

Original languageEnglish (US)
Pages (from-to)1219-1226
Number of pages8
JournalJournal of Infectious Diseases
Volume228
Issue number9
DOIs
StatePublished - Nov 1 2023

Keywords

  • HBV decay
  • HBV transcription
  • HBeAg negative
  • cccDNA
  • ddPCR

ASJC Scopus subject areas

  • General Medicine

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