Pharmacotherapy-Induced Hepatitis B Reactivation Among Patients With Prior Functional Cure: A Systematic Review

Ann Pharmacother. 2019 Mar;53(3):294-310. doi: 10.1177/1060028018800501. Epub 2018 Sep 11.


Objective: To describe and quantify the incidence and morbidity of hepatitis B reactivation (HBVr) secondary to pharmaceutical agents (eg, rituximab, tumor necrosis factor inhibitors, direct-acting antivirals [DAAs] for hepatitis C) among patients with previously resolved hepatitis B infection.

Data sources: The MEDLINE database was searched from inception through July 2018 using the terms hepatitis B + ( reactivation OR [drug or drug class linked to HBVr]).

Study selection and data extraction: Relevant English-language cohort studies or randomized trials quantifying the incidence of HBVr secondary to pharmacotherapy among patients negative for hepatitis B surface antigen and DNA and positive for hepatitis B core antibody were included.

Data synthesis: Among 2045 articles, 102 met inclusion criteria. Receipt of rituximab was associated with the highest risk of HBVr (for oncological indication: 6.2% rate [225/3601 patients]) and subsequent hepatitis (up to 52.4% of all HBVr cases). Biologic agents for autoimmune disease were uncommonly associated with HBVr (2.4%, 56/2338), with only 4 cases of hepatitis, all attributable to rituximab. Reactivation caused by DAAs was rare (0.3%, 28/8398), with no cases of hepatitis. Relevance to Patient Care/Clinical Practice: This review compares and contrasts the incidence and clinical relevance of HBVr for various pharmacotherapies among patients with functionally cured hepatitis B, with discussion of appropriate risk mitigation strategies.

Conclusions: Among patients with prior functional cure of hepatitis B, prophylactic antiviral therapy is recommended with rituximab administration irrespective of indication because of a high risk for HBVr-associated morbidity. Enhanced monitoring alone is reasonable for patients receiving nonrituximab biologics or DAAs.

Keywords: direct-acting antiviral; drug safety; hepatitis B; immunosuppressant; reactivation; rituximab.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use*
  • Cohort Studies
  • Female
  • Hepatitis B / blood
  • Hepatitis B / drug therapy
  • Hepatitis B / virology*
  • Hepatitis B Core Antigens / blood*
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / immunology
  • Humans
  • Male
  • Middle Aged
  • Virus Activation / drug effects*
  • Virus Activation / immunology


  • Antiviral Agents
  • Hepatitis B Core Antigens