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

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

doi:10.1093/infdis/jiad124

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

Journal Article · Tue May 02 00:00:00 EDT 2023 · Journal of Infectious Diseases

DOI:https://doi.org/10.1093/infdis/jiad124· OSTI ID:2367489

^[1]; ^[1]; Saad, Yasmeen ^[1]; Zambo, Kristina ^[1]; ^[2]; ^[3]; ^[1]; ^[4]; Zhang, Yang ^[5]; Young, Eric D. ^[1]; ^[1]; Balagopal, Ashwin ^[1]

Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Johns Hopkins Univ., Baltimore, MD (United States)
Virginia Commonwealth Univ., Richmond, VA (United States)
Joint Pathology Center (JPC), Silver Spring, MD (United States)

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). Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2367489

Report Number(s):: LA-UR--22-32178

Journal Information:: Journal of Infectious Diseases, Journal Name: Journal of Infectious Diseases Journal Issue: 9 Vol. 228; ISSN 0022-1899

Publisher:: Infectious Diseases Society of AmericaCopyright Statement

Country of Publication:: United States

Language:: English

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