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Publications

Published: 2 March 2017

Medicines and Hepatitis B Reactivation

Prescriber Update 38(1): 2-3
March 2017

Key Messages

  • Hepatitis B reactivation can occur in patients with a history of hepatitis B infection.
  • Reactivation can occur spontaneously but is more common in the setting of immune suppression or cancer chemotherapy.
  • Patients at risk of hepatitis B reactivation requiring immunosuppression should be screened for hepatitis B virus before immunosuppressive therapy is started.


The natural course of hepatitis B virus (HBV) infection depends on the interaction between viral replication and the host’s immune response. HBV persists in the body even when there is evidence of serological recovery1. Therefore, HBV reactivation can occur in patients with a history of HBV infection. Reactivation can occur spontaneously but is more common in the setting of immune suppression or cancer chemotherapy2. It can also occur in patients undergoing solid organ or haematopoietic stem cell transplantation1.

HBV reactivation is a rare but distinctive syndrome defined by a sudden and marked increase in HBV replication. It is usually accompanied by elevations in serum aminotransferase levels and sometimes by jaundice. Reactivation can be severe causing acute liver failure and death2.

The prevalence of HBV reactivation reported in the literature ranges widely. This is due to most studies being case reports or small case series that use different definitions of HBV reactivation3.

The exact mechanism of HBV reactivation is unclear but the initiating factor is thought to be loss of immune control over viral replication2.

Medicines Implicated in HBV Reactivation

A range of immunosuppressive agents have been implicated in HBV reactivation. Many novel and targeted agents for the treatment of malignant, inflammatory and autoimmune conditions have been associated with clinical evidence of HBV reactivation3.

The risk of HBV reactivation to specific medicine classes has been estimated by the American Gastroenterological Association based on a comprehensive review of the literature (Table 1)3,4,5.

Table 1: Risk estimates of HBV reactivation according to medicine class3,4,5

Risk estimate of hepatitis B reactivation Medicine class Medicine examples Additional information
High
(>10%)
B-cell depleting agents Rituximab Associated with highest risk due to their potent and durable immunosuppressive effect.
Corticosteroids High dose (eg, prednisone ≥20 mg for ≥4 weeks) Directly affect T-cell function and promote HBV DNA replication. Risk varies according to dose, duration and route of administration.
Moderate
(1–10%)
TNFα inhibitors Infliximab
Etanercept
Adalimumab
TNFα is a first line of defence in viral infections. Inhibition of TNFα increases the risk of HBV reactivation.
Cytokine inhibitors and integrin inhibitors Ustekinumab
Natalizumab
Evidence largely based on case reports. The risk may be due to their known relative potency of immunosuppression.
Tyrosine kinase inhibitors Imatinib
Nilotinib
Moderately immunosuppressive. Risk has been associated with the treatment of conditions including chronic myeloid leukaemia and gastrointestinal stromal tumours.
Corticosteroids Moderate dose (eg, prednisone <20 mg for ≥4 weeks)  
Low
(<1%)
Traditional immunosuppression Azathioprine
Mercaptopurine
Methotrexate
Most cases involve co-administration with corticosteroids or other immunomodulators, thereby increasing the risk.
Corticosteroids Low dose (eg, prednisone for <1 week)
Intra-articular corticosteroids
 


The Medicines Adverse Reactions Committee recently reviewed information on the risk of HBV reactivation with the use of direct-acting antivirals (eg, Viekira Pak, Viekira Pak-RBV, Harvoni) for the treatment of hepatitis C6. These data sheets are in the process of being updated to include information on the risk of HBV reactivation.

Prophylaxis of HBV Reactivation

Generally, the outcome is poor when antiviral treatment is started after HBV reactivation is already established3. Therefore, patients at risk of HBV reactivation should be screened for HBV and appropriate antiviral prophylaxis should be considered3.

Cases Reported in New Zealand

The Centre for Adverse Reactions Monitoring (CARM) has received three reports of suspected hepatitis B reactivation. The suspect medicines reported in these cases were normal immunoglobulin in the first case; rituximab, tacrolimus and prednisone in the second case; and abiraterone in the third case.

Please continue to report any suspected adverse reactions and interactions to CARM. Reports can be submitted on paper or electronically (https://nzphvc.otago.ac.nz/).

References
  1. Lok AS, Bonis PA. 2016. Hepatitis B virus reactivation associated with immunosuppressive therapy. UpToDate. URL: www.uptodate.com/contents/hepatitis-b-virus-reactivation-associated-with-immunosuppressive-therapy (accessed 15 December 2016).
  2. Di Bisceglie AM, Lok AS, Martin P, et al. 2015. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 61(2): 703-11.
  3. Pattullo V. 2016. Prevention of Hepatitis B reactivation in the setting of immunosuppression. Clinical and Molecular Hepatology 22(2): 219-37.
  4. Perrillo R, Gish R, Falck-Ytter Y. 2015. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1): 221-44.
  5. Reddy KR, Beavers KL, Hammond SP, et al. 2015. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1): 215-19.
  6. Medsafe. 2016. Safe Prescribing of Direct-Acting Antivirals for Treatment of Hepatitis C - It's Complicated. Prescriber Update 37(4): 50-51.
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