{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:31:48Z","timestamp":1788960708605,"version":"build-2803163510"},"reference-count":58,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008897","name":"Janssen Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Viral Hepatitis"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Investigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)\u2010infected hepatocytes are intended to induce a durable off\u2010treatment clearance of hepatitis B surface antigen (HBsAg) (referred to as functional cure). The aim of this paper was to highlight challenges in interpreting liver safety data in clinical trials of these agents when given alone or in combination regimens. The incidence, grading and management of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed along with a summary of serum ALT flares observed during the registration trials for peginterferon and nucleos(t)ide reverse transcriptase inhibitors. Recommendations regarding the detection, management and interpretation of liver safety biomarker data in future clinical trials as well as suggested inclusion and exclusion criteria for phase 1\/2 vs phase 3 studies are provided. Criteria to help classify liver safety signals as being due to the intended therapeutic response, emergence of drug\u2010resistant HBV virions, or idiosyncratic drug\u2010induced liver injury are provided along with a review of the role of an expert hepatic adjudication panel in assessing a compound's hepatotoxicity profile. Finally, an algorithmic approach to the differential diagnosis and recommended medical evaluation and management of individual clinical trial patients that develop a liver safety signal is provided along with the rationale to collect and test research blood samples for future mechanistic studies.<\/jats:p>","DOI":"10.1111\/jvh.13223","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T04:39:47Z","timestamp":1576125587000},"page":"96-109","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Liver safety assessment in clinical trials of new agents for chronic hepatitis B"],"prefix":"10.1111","volume":"27","author":[{"given":"Robert J.","family":"Fontana","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I.","family":"Avigan","sequence":"additional","affiliation":[{"name":"Office of Surveillance and Epidemiology Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry L. A.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Toronto Centre for Liver Disease University Health Network Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Regev","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Mishra","sequence":"additional","affiliation":[{"name":"Division of Antiviral Products Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuj","family":"Gaggar","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Brown","sequence":"additional","affiliation":[{"name":"Hepatitis B Foundation Doylestown PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Wat","sequence":"additional","affiliation":[{"name":"Roche Products Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Mendez","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc. Warminster PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3175-545X","authenticated-orcid":false,"given":"Ryan T.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Forum for Collaborative Research University of California Berkeley"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Given","sequence":"additional","affiliation":[{"name":"Arrowhead Pharmaceuticals, Inc Pasadena CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6543-3224","authenticated-orcid":false,"given":"Veronica","family":"Miller","sequence":"additional","affiliation":[{"name":"Forum for Collaborative Research University of California Berkeley"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Beumont","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development Janssen Pharmaceutica NV Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,11]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.11.062"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.05.008"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29800"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-11-165"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2018.04.006"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.22461"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-2980.2011.00540.x"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2012.07.107"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(83)80114-0"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23190"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27805"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1621"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.033"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2019.02.005"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.27834"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.33638"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2017.04.009"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.16333"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(01)00266-5"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2000.8559"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28438"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix690"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy350"},{"key":"e_1_2_14_25_1","volume-title":"Guidance for Industry: Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment","author":"FDA","year":"2018"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.05.039"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.07.012"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.04.029"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26549"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29640"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29821"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28323"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28813"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23696"},{"key":"e_1_2_14_35_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.03.012"},{"key":"e_1_2_14_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2010.02.008"},{"key":"e_1_2_14_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23577"},{"key":"e_1_2_14_38_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200932010-00005"},{"key":"e_1_2_14_39_1","volume-title":"Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver","author":"Zimmerman HJ","year":"1999"},{"key":"e_1_2_14_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20800"},{"key":"e_1_2_14_41_1","volume-title":"Guidance for Industry Drug\u2010Induced Liver Injury: Premarketing Clinical Evaluation","author":"FDA\/CDER\/CBER","year":"2009"},{"key":"e_1_2_14_42_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2017.274977"},{"key":"e_1_2_14_43_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.10.026"},{"key":"e_1_2_14_44_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802878"},{"key":"e_1_2_14_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-014-0183-6"},{"key":"e_1_2_14_46_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402454"},{"key":"e_1_2_14_47_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.03.016"},{"key":"e_1_2_14_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30825"},{"key":"e_1_2_14_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2893.2010.01275.x"},{"key":"e_1_2_14_50_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v16.i5.554"},{"key":"e_1_2_14_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00074-2"},{"issue":"1","key":"e_1_2_14_52_1","first-page":"27","article-title":"Hepatitis B virus co\u2010infection in human immunodeficiency virus\u2010infected subjects","volume":"4","author":"Puoti M","year":"2002","journal-title":"AIDS Rev"},{"key":"e_1_2_14_53_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.1.74"},{"key":"e_1_2_14_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290321"},{"key":"e_1_2_14_55_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.10.010"},{"key":"e_1_2_14_56_1","volume-title":"Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA\/BE Studies","author":"FDA","year":"2012"},{"key":"e_1_2_14_57_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.165.12.1363"},{"key":"e_1_2_14_58_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.12.032"},{"key":"e_1_2_14_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.632"}],"container-title":["Journal of Viral Hepatitis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvh.13223","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvh.13223","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jvh.13223","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvh.13223","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T12:19:44Z","timestamp":1694089184000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jvh.13223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,11]]},"references-count":58,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1111\/jvh.13223"],"URL":"https:\/\/doi.org\/10.1111\/jvh.13223","archive":["Portico"],"relation":{},"ISSN":["1352-0504","1365-2893"],"issn-type":[{"value":"1352-0504","type":"print"},{"value":"1365-2893","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,11]]},"assertion":[{"value":"2019-06-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}