{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T02:05:51Z","timestamp":1779156351503,"version":"3.51.4"},"reference-count":28,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["OD011095"],"award-info":[{"award-number":["OD011095"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["AI138810"],"award-info":[{"award-number":["AI138810"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["AI116269"],"award-info":[{"award-number":["AI116269"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["AI116868"],"award-info":[{"award-number":["AI116868"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK094818"],"award-info":[{"award-number":["DK094818"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sanofi","award":["X"],"award-info":[{"award-number":["X"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,2]]},"abstract":"<jats:p>\n                    There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV\/HIV-coinfected persons who took NUCs over 2\u20134 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.140584","type":"journal-article","created":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T11:01:40Z","timestamp":1601550100000},"source":"Crossref","is-referenced-by-count":31,"title":["Single hepatocytes show persistence and transcriptional inactivity of hepatitis B"],"prefix":"10.1172","volume":"5","author":[{"given":"Ashwin","family":"Balagopal","sequence":"first","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-2753","authenticated-orcid":true,"given":"Tanner","family":"Grudda","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruy M.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA."},{"name":"Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmeen S.","family":"Saad","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyon S.","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-5108","authenticated-orcid":true,"given":"Jeffrey","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-2585","authenticated-orcid":true,"given":"Kathleen","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard K.","family":"Sterling","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-0002","authenticated-orcid":true,"given":"Alan S.","family":"Perelson","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark S.","family":"Sulkowski","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William O.","family":"Osburn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe L.","family":"Thio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2020,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.12.2.351"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309809"},{"issue":"20","key":"B3","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01032-19","article-title":"Revisiting hepatitis B virus: challenges of curative therapies","volume":"93","author":"Hu","year":"2019","journal-title":"J Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27381"},{"key":"B5","unstructured":"Sulkowski MS, et al. Continued therapy with ABI-H0731 + NrtI results in sequential reduction\/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg-positive patients. National AIDS Treatment Advocacy Project. https:\/\/www.natap.org\/2019\/AASLD\/AASLD_59.htm Accessed September 8, 2020"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31026"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2019.07.046"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13195"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13227"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-012-0737-2"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy270"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz607"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.08.034"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003934"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.03.018"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.05.014"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.12.6356-6363.2002"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.12.9392-9399.1997"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.1.311-322.2001"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.05.029"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29872"},{"issue":"1","key":"B22","doi-asserted-by":"crossref","first-page":"P16","DOI":"10.1016\/j.jhep.2017.08.021","article-title":"Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients","volume":"68","author":"Wang","year":"2017","journal-title":"J Hepatol"},{"key":"B23","doi-asserted-by":"crossref","unstructured":"Farag MS, et al. Hepatitis B virus RNA as early predictor for response to PEGylated interferon alfa in HBeAg negative chronic hepatitis B [published online January 8, 2020]. 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