Association of Bcr-Abl Tyrosine Kinase Inhibitors With Hepatitis B Virus Reactivation Requiring Antiviral Treatment in Taiwan

Abstract

IMPORTANCE The US Food and Drug Administration (FDA) highlighted the potential risk of hepatitis B reactivation that was associated with Bcr-Abl tyrosine kinase inhibitor (TKI) treatment and has required updated product labels. OBJECTIVE To examine the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs. DESIGN, SETTING, AND PARTICIPANTS This nested case-control study included patients who entered a hepatitis B carrier cohort in Taiwan after January 1, 2005. Patients who received their firstantiviral agents for hepatitis B flare for more than 28 days after the cohort entry date were included as case patients. For each case, a corresponding risk set was formed that included all eligible patients in the study cohort who had the same age (within 1 year), same sex, and were at risk of developing hepatitis B flare at the case date. As many as 10 control patients were randomly selected from the risk set for each case patient. TKIs were evaluated before the hepatitis B flare for case patients and before the corresponding index date for control patients. Data were collected from the Taiwan National

Pharmacology and pharmacovigilance of protein kinase inhibitors

“…Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Recently, a nested casecontrol study which included patients who entered a hepatitis B carrier cohort in Taiwan confirmed this risk [84]. This analysis revealed that BCR-ABL PKIs use during the previous 90 days was independently associated with a 56% higher risk of hepatitis B flare (adjusted rate ratio [aRR], 1.56, CI95% [1.11-2.20]).…”

Sex‐specific incidence of hepatitis B virus flares among Bcr‐Abl tyrosine kinase inhibitor users in Taiwan

“…(2) The Bcr‐Abl TKI users had at least one of the following cancer types before the index date: CML, GIST, monocytic leukemia (ML), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML). If a patient had more than one cancer diagnosis before the index date, the cancer type was determined according to the following hierarchical order: ALL, AML, ML, CML, GIST 11 . (3) The cancer patients using Bcr‐Abl TKIs were chronic HBV carriers, as defined according to the operational definitions described in our previous publication 11 .…”

“…If a patient had more than one cancer diagnosis before the index date, the cancer type was determined according to the following hierarchical order: ALL, AML, ML, CML, GIST 11 . (3) The cancer patients using Bcr‐Abl TKIs were chronic HBV carriers, as defined according to the operational definitions described in our previous publication 11 . The date that a patient was first recognized as HBV carrier could be before or after the index date.…”

“…US Food and Drug Administration highlighted this concern and product labels were updated accordingly 10 . A recent population based case–control study revealed an association between Bcr‐Abl TKI and hepatitis B flare, with the effect modification of sex on this association (rate ratio of 3.20 [1.70–6.03] in females and 1.14 [0.72–1.81] in males) 11 . Growing evidence suggests that Bcr‐Abl TKIs have immunomodulatory effects and dual‐mode of action in vivo, which appears to be mediated by directly or indirectly acting on immune cells 12 …”

Hepatitis B Virus Reactivation Associated With Therapeutic Interventions

“…Two large-scale retrospective studies evaluating the risk of HBV reactivation in TKI-treated CML patients with positive HBsAg reported HBV reactivation rates of 26-34.8% (61,62). More recently, a nationwide nested casecontrol study with 733,691 patients with HBV in Taiwan found that Bcr-Abl TKI use was independently associated with HBV reactivation (aHR, 1.56; 95% CI 1.11-2.20) (63).…”