{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:27:30Z","timestamp":1787113650211,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fogarty International Center at the US National Institutes of Health","award":["D43 TW009610"],"award-info":[{"award-number":["D43 TW009610"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1G11TW012503-01"],"award-info":[{"award-number":["1G11TW012503-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1G11TW012503-01"],"award-info":[{"award-number":["1G11TW012503-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Sub-Saharan African Network for TB\/HIV Research Excellence","award":["Del-22-007"],"award-info":[{"award-number":["Del-22-007"]}]},{"name":"Bill &amp; Melinda Gates Foundation","award":["INV-033558"],"award-info":[{"award-number":["INV-033558"]}]},{"award":["INV-033558"],"award-info":[{"award-number":["INV-033558"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Gilead Sciences","award":["19275"],"award-info":[{"award-number":["19275"]}]},{"award":["19275"],"award-info":[{"award-number":["19275"]}],"id":[{"id":"https:\/\/ror.org\/056546b03","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Trials of Excellence in Southern Africa","award":["CSA2020NoE-3104 TESAIII"],"award-info":[{"award-number":["CSA2020NoE-3104 TESAIII"]}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["K43 TW012350"],"award-info":[{"award-number":["K43 TW012350"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"award":["K43 TW012350"],"award-info":[{"award-number":["K43 TW012350"]}],"id":[{"id":"https:\/\/ror.org\/02xey9a22","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>(1) Background: The Hepatitis B virus (HBV) is characterized by extensive genetic diversity, including low-frequency variants that contribute to disease progression. We aimed to characterize low-frequency variants and evaluate their potential clinical impact. (2) Methods: We utilized 104 HBV near-full-length sequences generated using next-generation sequencing (NGS) from people living with HIV (PLHIV). We used an in-house bioinformatics suite (HBVgenomeR v5.9.7) to filter for low-frequency variants (5\u201350%), which were compared to escape and drug resistance mutations (DRMs) and hepatocellular carcinoma (HCC)-associated mutations reported at the consensus level. Unclassified variants were characterized by HBV open reading frames (ORFs) to determine mutation frequency per genomic region. (3) Results: A total of six escape mutations were detected in 8\/104 (7.7%) sequences, with surfaceN131T being the most prevalent (5\/8). We also observed six DRMs in 30\/104 (28.8%), with rtV173L being the most prevalent (21\/30). Truncation mutations were also observed with rtA181T\/sW172* and rtM204I\/sW196L being the most prevalent. A total of 8\/104 (7.7%) sequences had four variants associated with HCC. The xP46S was the highest observed HCC-associated mutation at 5\/8. We report 1152 unique uncharacterized variants across all ORFs, and these were found in 94\/104 (90.4%) sequences. The RNaseH domain had the highest burden (330\/1152, 28.6%). (4) Conclusions: Deep sequencing results identified clinically significant mutations, including those below the 20% detection limit of traditional sequencing, that would go unreported. This highlights the possible underreporting of mutational burden in people living with HBV\/HIV, indicating the importance of deep sequencing to aid in HBV\/HIV understanding and management.<\/jats:p>","DOI":"10.3390\/v18080904","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:42:17Z","timestamp":1786974137000},"page":"904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deep Sequencing of Hepatitis B Virus Reveals Clinically Relevant Low-Frequency Variants Among People Living with HIV in Botswana"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9815-9088","authenticated-orcid":false,"given":"Tsholofelo","family":"Sethibe","sequence":"first","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Biological Sciences, School of Physical and Life Science, Faculty of Natural and Applied Science, University of Botswana, Gaborone Private Bag UB0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7606-0569","authenticated-orcid":false,"given":"Wonderful Tatenda","family":"Choga","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Division of Medical Virology, Microbiology Unit, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare P.O. Box MP167, Zimbabwe"},{"name":"Department of Agricultural Genetics and Cell Technology, Faculty of Agriculture and Technology, National University of Science and Technology, Bulawayo P.O. Box AC 939, Zimbabwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence G.","family":"Gaongalelwe","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0180-2705","authenticated-orcid":false,"given":"Bonolo B.","family":"Phinius","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1153-2480","authenticated-orcid":false,"given":"Gorata G. A.","family":"Mpebe","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Biological Sciences, School of Physical and Life Science, Faculty of Natural and Applied Science, University of Botswana, Gaborone Private Bag UB0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1592-7533","authenticated-orcid":false,"given":"Kabo","family":"Baruti","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Okavango Research Institute, University of Botswana, Maun Private Bag 285, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4069-7176","authenticated-orcid":false,"given":"Chanana Dorcus","family":"Tsayang","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goabaone","family":"Mbae","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basetsana Katlo S.","family":"Phakedi","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"School of Allied Health Professions, Faculty of Medicine and Health Sciences, University of Botswana, Gaborone Private Bag UB0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patience","family":"Motshosi","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Biological Sciences, School of Physical and Life Science, Faculty of Natural and Applied Science, University of Botswana, Gaborone Private Bag UB0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8833-1805","authenticated-orcid":false,"given":"Linda","family":"Mpofu-Dobo","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Biological Sciences and Biotechnology, School of Life Sciences, Botswana International University of Science and Technology, Palapye Private Bag 16, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mosimanegape","family":"Jongman","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Biological Sciences, School of Physical and Life Science, Faculty of Natural and Applied Science, University of Botswana, Gaborone Private Bag UB0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3821-4592","authenticated-orcid":false,"given":"Sikhulile","family":"Moyo","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"School of Allied Health Professions, Faculty of Medicine and Health Sciences, University of Botswana, Gaborone Private Bag UB0022, Botswana"},{"name":"Department of Applied Biology and Biochemistry, National University of Science and Technology, Bulawayo P.O. Box AC 939, Zimbabwe"},{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA"},{"name":"School of Health Systems and Public Health, University of Pretoria, Private Bag X20, Pretoria 0028, South Africa"},{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9974-9684","authenticated-orcid":false,"given":"Motswedi","family":"Anderson","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"},{"name":"Africa Health Research Institute, Private Bag X7, Congella, Durban 4013, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simani","family":"Gaseitsiwe","sequence":"additional","affiliation":[{"name":"Botswana Harvard Health Partnership, Gaborone Private Bag BO320, Botswana"},{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3748\/wjg.v22.i1.145","article-title":"Overview of hepatitis B virus mutations and their implications in the management of infection","volume":"22","author":"Caligiuri","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.cld.2007.08.002","article-title":"Molecular virology of hepatitis B virus for clinicians","volume":"11","author":"Block","year":"2007","journal-title":"Clin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3748\/wjg.v22.i1.126","article-title":"Genetic variation of hepatitis B virus and its significance for pathogenesis","volume":"22","author":"Zhang","year":"2016","journal-title":"World J. 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