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Liver safety assessment in clinical trials of new agents for chronic hepatitis B
dc.contributor.authorFontana, Robert J.
dc.contributor.authorAvigan, Mark I.
dc.contributor.authorJanssen, Harry L. A.
dc.contributor.authorRegev, Arie
dc.contributor.authorMishra, Poonam
dc.contributor.authorGaggar, Anuj
dc.contributor.authorBrown, Nathaniel
dc.contributor.authorWat, Cynthia
dc.contributor.authorMendez, Patricia
dc.contributor.authorAnderson, Ryan T.
dc.contributor.authorGiven, Bruce
dc.contributor.authorMiller, Veronica
dc.contributor.authorBeumont, Maria
dc.date.accessioned2020-02-05T15:04:25Z
dc.date.availableWITHHELD_13_MONTHS
dc.date.available2020-02-05T15:04:25Z
dc.date.issued2020-02
dc.identifier.citationFontana, Robert J.; Avigan, Mark I.; Janssen, Harry L. A.; Regev, Arie; Mishra, Poonam; Gaggar, Anuj; Brown, Nathaniel; Wat, Cynthia; Mendez, Patricia; Anderson, Ryan T.; Given, Bruce; Miller, Veronica; Beumont, Maria (2020). "Liver safety assessment in clinical trials of new agents for chronic hepatitis B." Journal of Viral Hepatitis 27(2): 96-109.
dc.identifier.issn1352-0504
dc.identifier.issn1365-2893
dc.identifier.urihttps://hdl.handle.net/2027.42/153564
dc.description.abstractInvestigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)‐infected hepatocytes are intended to induce a durable off‐treatment 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‐resistant HBV virions, or idiosyncratic drug‐induced 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.
dc.publisherU.S. Food and Drug Administration
dc.publisherWiley Periodicals, Inc.
dc.subject.otherHBV
dc.subject.otherdrug development
dc.subject.othercausality assessment
dc.subject.otherantivirals
dc.subject.otherhepatotoxicity
dc.titleLiver safety assessment in clinical trials of new agents for chronic hepatitis B
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelOncology and Hematology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/153564/1/jvh13223_am.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/153564/2/jvh13223.pdf
dc.identifier.doi10.1111/jvh.13223
dc.identifier.sourceJournal of Viral Hepatitis
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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