Risk of Reactivation of Hepatitis B Virus (HBV) and Tuberculosis (TB) and Complications of Hepatitis C Virus (HCV) Following Tocilizumab Therapy: A Systematic Review to Inform Risk Assessment in the COVID-19 Era

  1. Cori Campbell
  2. Monique I. Andersson
  3. M. Azim Ansari
  4. Olivia Moswela
  5. Siraj A. Misbah
  6. Paul Klenerman
  7. Philippa C. Matthews

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Abstract

Objectives: Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of severe COVID-19 caused by infection with SARS-CoV-2. However, unintended consequences of TCZ therapy include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), and worsening of hepatitis C virus (HCV). We set out to assimilate existing data for these complications, in order to help inform evidence-based risk assessments for the use of TCZ, and thus to reduce the risk of serious but preventable complications.

Methods: We searched the global WHO database of Individual Case Safety Reports (ICSRs) and adverse drug reactions (ADRs) (“VigiBase”) and undertook a systematic literature review, in accordance with PRISMA guidelines. We generated mean cumulative incidence estimates for infection complications.

Results: Mean cumulative incidence of HBV and TB were 3.3 and 4.3%, respectively, in patients receiving TCZ. Insufficient data were available to generate estimates for HCV. These estimates derive from heterogeneous studies pre-dating SARS-CoV-2, with differing epidemiology and varied approaches to screening and prophylaxis, so formal meta-analysis was not possible.

Conclusions: We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm to guide clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.

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  1. Version published to 10.3389/fmed.2021.706482
  2. ScreenIT

    SciScore for 10.1101/2021.03.22.21254128: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We undertook a systematic literature review (on 25 February 2021), searching Medline, Embase and Web of Science databases using search terms presented in Table S2, in accordance with PRISMA guidelines (Table S3).
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Caveats: Estimates of risk may be biased, with a likelihood of under-estimating true risk based on selection of low-risk study participants, provision of prophylaxis when indicated, short durations of follow-up and reporting population estimates which include individuals without latent infection. We were unable to undertake a formal meta-analysis due to the heterogeneity of data, and the reported mean across studies must be interpreted with caution. Further ‘real world’ data are needed to investigate the impact of TCZ in racially diverse COVID cohorts, in patients with other underlying pathology, and over longer periods of follow-up[1,16], both to determine the subgroups in whom treatment may be of most benefit, and to identify the circumstances in which it carries the most risk. It is notable that many existing publications about the use of TCZ in COVID do not even discuss the potential for these infective complications. Risk appraisal for use of TCZ in COVID is currently based on experience in treating patients with inflammatory and rheumatological disease, who may also be immunosuppressed as a result of their primary condition, and in whom immunosuppressive therapy is prolonged and may involve multiple agents (including steroids, methotrexate and other biological agents). However, although COVID treatment comprises only one or two doses of TCZ, the context of critical illness, universal combination with steroid therapy, and two doses given in quick succession, may inflate ...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.03.22.21254128 on medRxiv