{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:06:30Z","timestamp":1793387190711,"version":"4.5.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Chronic Hepatitis B Virus (HBV) infection remains a formidable global health challenge, driving severe liver complications such as hepatocellular carcinoma (HCC) and pyogenic liver abscesses (PLA). At the core of HBV persistence lies covalently closed circular DNA (cccDNA), a viral reservoir that fuels ongoing infection despite antiviral treatments. This review highlights molecular mechanisms governing cccDNA formation, maintenance, and clearance, spotlighting innovative therapeutic strategies to disrupt this key viral element. We explore cutting-edge approaches, including epigenetic modulation to silence cccDNA, RNA interference (RNAi) for viral RNA degradation, and CRISPR\/Cas genome editing to excise cccDNA directly. Additionally, emerging antiviral therapies and immunotherapies, such as therapeutic vaccines and immune checkpoint inhibitors, offer new avenues for enhanced treatment efficacy. Special attention is given to the clinical complexities of managing HBV in patients with co-morbid conditions like HCC and PLA, emphasizing the necessity of a multidisciplinary approach. The interplay between antibacterial and antiviral therapies in PLA-associated HBV cases is critically examined to prevent treatment antagonism, ensuring optimal patient outcomes. Advanced therapeutic strategies, including nucleos(t)ide analogs, interferon therapy, and novel genomic interventions, are explored in both isolated HBV infection and PLA co-infections. Personalized regimens remain pivotal in enhancing therapeutic efficacy and long-term disease control. Current review advocates for a shift toward precision medicine, highlighting the critical need for interdisciplinary collaboration to bridge molecular discoveries with clinical innovations. Ultimately, these advancements promise to revolutionize the management of chronic HBV, paving the way for potential cures and improved patient outcomes.<\/jats:p>","DOI":"10.3389\/fmed.2025.1504736","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T06:47:27Z","timestamp":1742194047000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Cracking the code of HBV persistence: cutting-edge approaches to targeting cccDNA in chronic hepatitis B with or without pyogenic liver Abscesses"],"prefix":"10.3389","volume":"12","author":[{"given":"Umar","family":"Saeed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra Zahid","family":"Piracha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmood","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Nouman","family":"Tariq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Shayan","family":"Gilani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakshana","family":"Munusamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen","family":"Bose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilber Uzun","family":"Ozsahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130lker","family":"\u00d6z\u015fahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya M.","family":"Nauli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"B1","year":"2022","journal-title":"Global Hepatitis Report."},{"key":"B2","year":"2023","journal-title":"Viral Hepatitis National Progress Report."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1126\/science.1243462","article-title":"Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.","volume":"343","author":"Lucifora","year":"2014","journal-title":"Science."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e572","DOI":"10.1128\/JVI.00572-18","article-title":"Hepatitis B virus genome recycling and de novo secondary infection events maintain stable cccDNA levels.","volume":"92","author":"Ko","year":"2018","journal-title":"J Virol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cld.2012.09.009","article-title":"Molecular virology of hepatitis B virus for clinicians.","volume":"17","author":"Block","year":"2013","journal-title":"Clin Liver Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.virol.2015.02.031","article-title":"Molecular biology of hepatitis B virus infection.","author":"Seeger","year":"2015","journal-title":"Virology."},{"key":"B7","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.jhep.2022.11.013","article-title":"Histone deacetylase inhibitors suppress hepatitis B virus transcription by altering cccDNA structure.","volume":"78","author":"Li","year":"2023","journal-title":"J Hepatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/s41467-022-27859-y","article-title":"Methylation in the regulation of hepatitis B virus cccDNA transcription.","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat Commun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1053\/j.gastro.2023.11.018","article-title":"Interference targeting cccDNA-derived transcripts reduces viral replication and hepatocellular carcinoma risk.","volume":"126","author":"Liu","year":"2024","journal-title":"Gastroenterology."},{"key":"B10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1128\/JVI.01819-14","article-title":"Inhibiting DNA ligase I and topoisomerase I can significantly reduce cccDNA formation in vitro.","volume":"89","author":"Cui","year":"2015","journal-title":"J Virol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1016\/S0140-6736(07)60752-5","article-title":"Chronic hepatitis B.","volume":"369","author":"Ghany","year":"2007","journal-title":"Lancet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1172\/JCI58847","article-title":"IFN-\u03b1 inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome.","volume":"122","author":"Belloni","year":"2012","journal-title":"J Clin Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1840","DOI":"10.1128\/JVI.01840-18","article-title":"Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and upregulate Hepatitis B virus replication from cccDNA to virion in an HBx-dependent manner.","volume":"93","author":"Saeed","year":"2019","journal-title":"J Virol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"795047","DOI":"10.3389\/fmicb.2021.795047","article-title":"The HBV core protein and core particle both bind to the PPiase Par14 and Par17 to enhance their stabilities and HBV replication.","volume":"12","author":"Saeed","year":"2021","journal-title":"Front Microbiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1016\/j.jhep.2020.07.026","article-title":"Histone deacetylase inhibitors suppress cccDNA transcription by altering its chromatin structure.","volume":"73","author":"Zhang","year":"2020","journal-title":"J Hepatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e926","DOI":"10.1128\/JVI.00926-20","article-title":"An alternatively spliced Sirtuin 2 Isoform 5 inhibits hepatitis B virus replication from cccDNA by repressing epigenetic modifications made by Histone Lysine Methyltransferases.","volume":"94","author":"Piracha","year":"2020","journal-title":"J Virol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1002\/hep.30158","article-title":"DNA methylation leads to cccDNA silencing.","volume":"69","author":"Tang","year":"2019","journal-title":"Hepatology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.antiviral.2017.05.016","article-title":"The role of histone deacetylase inhibitors (HDACis) in suppressing HBV transcription by altering the chromatin structure of cccDNA.","volume":"144","author":"Zhong","year":"2017","journal-title":"Antiviral Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8520","DOI":"10.3748\/wjg.v21.i27.8520","article-title":"Effects of DNA methyltransferase inhibitors on hepatitis B virus replication in hepatoma cells and mice.","volume":"21","author":"Guo","year":"2015","journal-title":"World J Gastroenterol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1007296","DOI":"10.1371\/journal.ppat.1007296","article-title":"Alpha-interferon suppresses hepadnavirus transcription by altering epigenetic modification of cccDNA minichromosomes.","volume":"14","author":"Liu","year":"2018","journal-title":"PLoS Pathogens."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1136\/gutjnl-2020-321585","article-title":"Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones.","volume":"70","author":"Pollicino","year":"2021","journal-title":"Gut."},{"key":"B22","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1159\/000430394","article-title":"Histone deacetylase inhibitors decrease DNA methylation of HBV cccDNA and inhibit HBV replication.","volume":"37","author":"Liang","year":"2015","journal-title":"Cell Physiol Biochem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1016\/j.bbrc.2016.12.059","article-title":"Histone deacetylase inhibitor sodium butyrate suppresses proliferation and promotes apoptosis in hepatocellular carcinoma cells by regulation of the MDM2-p53 signaling pathway.","volume":"482","author":"Wang","year":"2017","journal-title":"Biochem Biophys Res Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/hep.28210","article-title":"Inhibition of Tyrosyl-DNA phosphodiesterase 2 disrupts the repair process necessary for cccDNA formation.","volume":"63","author":"Levrero","year":"2016","journal-title":"Hepatology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.3389\/fphar.2018.01494","article-title":"Small molecules targeting histone and DNA methylation for cancer treatment.","volume":"9","author":"Kong","year":"2018","journal-title":"Front Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1016\/j.drudis.2020.06.014","article-title":"Advances in targeting bromodomain-containing protein 4 (BRD4) in cancer.","volume":"25","author":"Ren","year":"2020","journal-title":"Drug Discov Today."},{"key":"B27","doi-asserted-by":"publisher","first-page":"677838","DOI":"10.3389\/fmicb.2021.677838","article-title":"Therapeutic approaches targeting the epigenetic regulation of cccDNA in chronic hepatitis B virus infection.","volume":"12","author":"Zhao","year":"2021","journal-title":"Front Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"156","DOI":"10.3389\/fimmu.2019.00156","article-title":"RNA interference as a powerful tool for silencing hepatitis B virus in chronic hepatitis B patients: Current status and prospects.","volume":"10","author":"Su","year":"2019","journal-title":"Front Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"eaan0241","DOI":"10.1126\/scitranslmed.aan0241","article-title":"RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated HBV DNA is a source of HBsAg.","volume":"9","author":"Wooddell","year":"2017","journal-title":"Sci Transl Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41572-020-0190-9","article-title":"Hepatitis B virus infection.","volume":"6","author":"Yuen","year":"2020","journal-title":"Nat Rev Dis Primers."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1080\/10717544.2021.1992671","article-title":"Nanoparticle-based delivery systems for RNAi therapy in the treatment of hepatitis B virus infection.","volume":"28","author":"Zhang","year":"2021","journal-title":"Drug Delivery."},{"key":"B32","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.tibs.2017.03.005","article-title":"DNA damage-induced immune response: Micrornas as new players.","volume":"42","author":"Wang","year":"2017","journal-title":"Trends Biochem Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/v14010004","article-title":"Recent progress and future prospective in HBV cure by CRISPR\/cas.","volume":"14","author":"Yang","year":"2021","journal-title":"Viruses."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e301","DOI":"10.1038\/mtna.2016.55","article-title":"Targeting hepatitis B virus with CRISPR\/Cas9.","volume":"5","author":"Seeger","year":"2016","journal-title":"Mol Thera Nucleic Acids."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-38269-8","article-title":"\/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus.","volume":"8","author":"Ramanan","year":"2020","journal-title":"Sci Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"651678","DOI":"10.3389\/fcimb.2021.651678","article-title":"Development of CRISPR\/Cas9 system with enhanced targeting precision for HBV treatment.","volume":"11","author":"Liu","year":"2021","journal-title":"Front Cell Infect Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.ymthe.2019.01.020","article-title":"In vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models.","volume":"27","author":"Yin","year":"2019","journal-title":"Mol Therapy."},{"key":"B38","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/jmv.27589","article-title":"Combination of CRISPR\/Cas9 and RNA interference for synergistic therapy against hepatitis B virus.","volume":"94","author":"Chen","year":"2022","journal-title":"J Med Virol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/S2468-1253(19)30119-0","article-title":"A global scientific strategy to cure hepatitis B.","volume":"4","author":"Revill","year":"2019","journal-title":"Lancet Gastroenterol Hepatol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1111\/j.1440-1746.2008.05459.x","article-title":"Treatment of chronic hepatitis B: Evolution over two decades.","volume":"23","author":"Yuen","year":"2008","journal-title":"J Gastroenterol Hepatol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1053\/j.gastro.2004.03.018","article-title":"Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.","volume":"126","author":"Werle-Lapostolle","year":"2004","journal-title":"Gastroenterology."},{"key":"B42","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1002\/hep.28264","article-title":"Long-term tenofovir disoproxil fumarate therapy results in the regression of liver fibrosis and continued histological improvement in patients with chronic hepatitis B.","volume":"63","author":"Chang","year":"2016","journal-title":"Hepatology."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.3390\/v13091777","article-title":"Inhibition of hepatitis B virus cccDNA formation: An emerging paradigm for chronic HBV therapy.","volume":"13","author":"Guo","year":"2021","journal-title":"Viruses."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/JVI.00301-19","article-title":"RNA interference-based therapeutics for the treatment of HBV infection in animal models.","volume":"93","author":"Liang","year":"2019","journal-title":"J Virol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.omtn.2021.03.019","article-title":"Development of a novel siRNA delivery system enhances the stability and uptake of siRNAs in hepatocytes, improving the efficiency of HBV transcript targeting.","volume":"24","author":"Zhang","year":"2021","journal-title":"Mol Ther Nucleic Acids."},{"key":"B46","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.jhep.2022.01.010","article-title":"Enhancing the host immune response to clear HBV-infected cells harboring cccDNA: A promising approach to combating chronic HBV infection.","volume":"76","author":"Zhou","year":"2022","journal-title":"J Hepatol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.jhep.2017.01.020","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study.","volume":"66","author":"Gane","year":"2017","journal-title":"J Hepatol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.3390\/microorganisms11122826","article-title":"Immunoinformatics and evaluation of peptide vaccines derived from global hepatitis B viral HBx and HBc proteins critical for covalently closed circular DNA integrity.","volume":"11","author":"Saeed","year":"2023","journal-title":"Microorganisms."},{"key":"B49","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.jhep.2017.01.011","article-title":"HBV-specific T-cell therapy and therapy-induced T-cell reactivity in chronic hepatitis B.","volume":"66","author":"Bertoletti","year":"2017","journal-title":"J Hepatol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1053\/j.gastro.2013.02.032","article-title":"Antiviral effect and virus-specific T cell responses in hepatitis B virus-infected chimpanzees treated with interferon-\u03b1 and\/or ribavirin.","volume":"144","author":"Lanford","year":"2013","journal-title":"Gastroenterology."},{"key":"B51","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.jhep.2015.01.002","article-title":"The dynamics of HBV infection: Mechanisms of viral persistence and immune response.","volume":"62","author":"Zoulim","year":"2015","journal-title":"J Hepatol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"108730","DOI":"10.1016\/j.clim.2021.108730","article-title":"Combining immune checkpoint inhibitors with therapeutic vaccines to enhance HBV treatment efficacy.","volume":"226","author":"Zhang","year":"2021","journal-title":"Clin Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1002\/hep.23190","article-title":"Chronic hepatitis B: Update 2009.","volume":"50","author":"Lok","year":"2009","journal-title":"Hepatology."},{"key":"B54","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.","volume":"67","year":"2017","journal-title":"J Hepatol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/ajg.2009.612","article-title":"population-based study of pyogenic liver abscesses in the United States: Incidence, mortality, and temporal trends.","volume":"105","author":"Meddings","year":"2010","journal-title":"Am J Gastroenterol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1159\/000490633","article-title":"Therapy of liver abscesses.","volume":"34","author":"L\u00fcbbert","year":"2018","journal-title":"Visc Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial.","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1016\/j.jhep.2014.01.024","article-title":"Bacterial infections in liver cirrhosis: A position statement based on the EASL Special Conference 2013.","volume":"60","author":"Reig","year":"2014","journal-title":"J Hepatol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1159\/000485500","article-title":"One-year multicenter prospective study on the clinical outcomes of bacterial infections in cirrhotic patients.","volume":"97","author":"Lee","year":"2018","journal-title":"Digestion."},{"key":"B60","first-page":"61","article-title":"Coordinated antibacterial and antiviral treatments in patients with PLA and HBV: Effectiveness in managing both conditions without compromising treatment efficacy.","volume":"45","author":"Wang","year":"2021","journal-title":"J Clin Infect Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"921653","DOI":"10.3389\/fmicb.2023.921653","article-title":"PIN1 and PIN4 inhibition via parvulin impeders Juglone, PiB, ATRA, 6,7,4\u2019-THIF, KPT6566, and EGCG thwarted hepatitis B virus replication.","volume":"14","author":"Saeed","year":"2023","journal-title":"Front Microbiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"e955","DOI":"10.1128\/JVI.00955-18","article-title":"Sirtuin 2 Isoform 1 enhances hepatitis B virus RNA transcription and DNA synthesis through the AKT\/GSK-3\u03b2\/\u03b2-Catenin signaling pathway.","volume":"92","author":"Piracha","year":"2018","journal-title":"J Virol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1234903","DOI":"10.3389\/fcimb.2023.1234903","article-title":"Decoding the multifaceted interventions between human sirtuin 2 and dynamic hepatitis B viral proteins to confirm their roles in HBV replication.","volume":"13","author":"Piracha","year":"2024","journal-title":"Front Cell Infect Microbiol."},{"key":"B64","doi-asserted-by":"crossref","first-page":"e385","DOI":"10.1016\/S2214-109X(23)00007-4","article-title":"Global investments in pandemic preparedness and COVID-19: Development assistance and domestic spending on health between 1990 and 2026.","volume":"11","year":"2023","journal-title":"Lancet Global Health."},{"key":"B65","doi-asserted-by":"crossref","first-page":"726263","DOI":"10.3389\/fcimb.2022.726263","article-title":"SARS CoV-2 induced hepatic injuries and liver complications.","volume":"12","author":"Saeed","year":"2022","journal-title":"Front Cell Infect Microbiol."},{"key":"B66","first-page":"e119590","article-title":"SARS-CoV-2-associated CRP, DD, FER, HBA1c, IL6, LDH, PBNP, and PCT biomarkers and high-resolution computed tomography during the first three waves of COVID-19 in Pakistan (2019).","volume":"15","author":"Saeed","year":"2023","journal-title":"Jundishapur J Microbiol."},{"key":"B67","first-page":"209","article-title":"Evaluation of SARS-CoV-2 spike antibody levels among Sputnik V first dose vaccinated people in Pakistan: Formulation of national anti-COVID-19 mass vaccination strategy.","volume":"6","author":"Saeed","year":"2023","journal-title":"Arch Clin Biomed Res."},{"key":"B68","first-page":"209","article-title":"Effectivity analysis of COVID-19 vaccines against emerging variants of SARS-CoV-2.","volume":"6","author":"Saeed","year":"2023","journal-title":"Arch Clin Biomed Res."},{"key":"B69","first-page":"82","article-title":"Contemplating SARS-CoV-2 infectivity with respect to ABO blood groups.","volume":"5","author":"Saeed","year":"2023","journal-title":"Int J Clin Virol."},{"key":"B70","first-page":"41","article-title":"SARS-CoV-2 infection and incidence of mucormycosis.","volume":"6","author":"Marghoob","year":"2023","journal-title":"Arch Clin Biomed Res."},{"key":"B71","first-page":"217","article-title":"Impact of SARS-CoV-2 on onset of diabetes and associated complications.","volume":"6","author":"Piracha","year":"2023","journal-title":"Arch Clin Biomed Res."},{"key":"B72","first-page":"072","article-title":"SARS-CoV-2 infection-associated detrimental effects on the various human organs.","volume":"5","author":"Nadeem","year":"2023","journal-title":"Int J Clin Virol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"e0241524","DOI":"10.1128\/mbio.02415-24","article-title":"Augmented epigenetic repression of hepatitis B virus covalently closed circular DNA by interferon-\u03b1 and small-interfering RNA synergy.","volume":"15","author":"Hu","year":"2024","journal-title":"mBio."},{"key":"B74","doi-asserted-by":"publisher","first-page":"101215","DOI":"10.1016\/j.gendis.2024.101215","article-title":"Epigenetic regulation and its therapeutic potential in hepatitis B virus covalently closed circular DNA.","volume":"12","author":"Ren","year":"2024","journal-title":"Genes Dis."},{"key":"B75","doi-asserted-by":"publisher","first-page":"e284361","DOI":"10.1590\/1519-6984.284361","article-title":"Unveiling diagnostic prowess: A comparative study of exercise treadmill test and CT coronary in coronary artery disease detection in Pakistan (2021-2023).","volume":"84","author":"Saeed","year":"2024","journal-title":"Braz J Biol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.3390\/v16111667","article-title":"SMC5\/6-mediated transcriptional regulation of hepatitis B virus and its therapeutic potential.","volume":"16","author":"B\u00e4cher","year":"2024","journal-title":"Viruses."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1270018","DOI":"10.3389\/fmicb.2023.1270018","article-title":"Crisis averted: A world united against the menace of multiple drug-resistant superbugs -pioneering anti-AMR vaccines, RNA interference, nanomedicine, CRISPR-based antimicrobials, bacteriophage therapies, and clinical artificial intelligence strategies to safeguard global antimicrobial arsenal.","volume":"14","author":"Saeed","year":"2023","journal-title":"Front Microbiol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.2217\/fmb-2023-0110","article-title":"Antimicrobial susceptibility and clinical characteristics of multidrug-resistant polymicrobial infections in Pakistan, A retrospective study 2019-2021.","volume":"18","author":"Qamar","year":"2023","journal-title":"Future Microbiol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.3390\/v16111710","article-title":"Evaluation of interfering RNA efficacy in treating hepatitis B: Is it promising?","volume":"16","author":"Angelice","year":"2024","journal-title":"Viruses."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s00127-023-02587-w","article-title":"Drug-use disorders in the Eastern mediterranean region: A glance at GBD 2019 findings.","volume":"59","author":"Amirkafi","year":"2024","journal-title":"Soc Psychiatry Psychiatr Epidemiol."},{"key":"B81","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1016\/S0140-6736(24)01548-4","article-title":"National-level and state-level prevalence of overweight and obesity among children, adolescents, and adults in the USA, 1990-2021, and forecasts up to 2050.","volume":"404","year":"2024","journal-title":"Lancet."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1016\/S0140-6736(24)01925-1","article-title":"Global, regional, and national stillbirths at 20 weeks\u2019 gestation or longer in 204 countries and territories, 1990-2021: Findings from the Global burden of disease study 2021.","volume":"404","year":"2024","journal-title":"Lancet."},{"key":"B83","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/S2468-1253(24)00157-2","article-title":"Trends and levels of the global, regional, and national burden of appendicitis between 1990 and 2021: Findings from the Global Burden of Disease Study 2021.","volume":"9","year":"2024","journal-title":"Lancet Gastroenterol Hepatol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1016\/S0140-6736(24)00933-4","article-title":"Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: A systematic analysis for the Global burden of disease study 2021.","volume":"403","year":"2024","journal-title":"Lancet."},{"key":"B85","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1016\/S0140-6736(24)00757-8","article-title":"Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: A systematic analysis for the Global Burden of disease study 2021.","volume":"403","year":"2024","journal-title":"Lancet."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1016\/S0140-6736(24)00476-8","article-title":"Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950-2021, and the impact of the COVID-19 pandemic: A comprehensive demographic analysis for the Global burden of disease study 2021.","volume":"403","year":"2024","journal-title":"Lancet."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.4103\/jcrt.jcrt_105_22","article-title":"Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is downregulated in Invasive ductal carcinoma and potential prognostic marker of breast cancer.","volume":"19","author":"Piracha","year":"2023","journal-title":"J Cancer Res Ther."},{"key":"B88","doi-asserted-by":"publisher","first-page":"znad421","DOI":"10.1093\/bjs\/znad421","article-title":"Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: Multispecialty, prospective cohort study in 25 countries.","volume":"111","year":"2024","journal-title":"Br J Surg."},{"key":"B89","doi-asserted-by":"publisher","first-page":"1394164","DOI":"10.3389\/fpubh.2024.1394164","article-title":"Effectiveness of financial incentives for control of viral hepatitis among substance users: A systematic review and meta-analysis.","volume":"12","author":"Wang","year":"2024","journal-title":"Front Public Health."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.3390\/vaccines12111254","article-title":"Hepatitis B virus-related cirrhosis and hepatocellular carcinoma hospital discharge rates from 2005 to 2021 in Spain: Impact of universal vaccination.","volume":"12","author":"Dom\u00ednguez","year":"2024","journal-title":"Vaccines (Basel)."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1504736\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T06:47:34Z","timestamp":1742194054000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1504736\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,17]]},"references-count":90,"alternative-id":["10.3389\/fmed.2025.1504736"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1504736","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,17]]},"article-number":"1504736"}}