Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: A systematic review, meta-analysis, and expert opinion
July 15, 2022 - George V. Papatheodoridis1,†, Vasileios Lekakis1,†, Thodoris Voulgaris1,†, Pietro Lampertico2,3, Thomas Berg4, Henry L.Y. Chan5, Jia-Horng Kao6, Norah Terrault7, Anna S. Lok8,*,#, K. Rajender Reddy9,*,#
Summary
HBV reactivation (HBVr) can be prevented by nucleos(t)ide analogues (NAs). We conducted a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressive and immunomodulatory therapies and developed guidance on NA prophylaxis. An expert panel reviewed the data and categorised the risk of HBVr associated with each class of drugs into low (<1%), intermediate (1-10%), and high (>10%). Our search uncovered 59 studies, including 3,424 HBsAg+ and 5,799 HBsAg-/anti-HBc+ patients, which met our eligibility criteria. Based on medium-high quality evidence, immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids were associated with high HBVr risk in HBsAg+ patients; cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids with intermediate risk in HBsAg-/anti-HBc+ patients; and anti-tumour necrosis factor agents and immune checkpoint inhibitors with low risk in HBsAg-/anti-HBc+ patients. Provisional recommendations are provided for drugs with low quality evidence. NA prophylaxis is recommended when using drugs associated with a high HBVr risk, while monitoring with on-demand NAs is recommended for low-risk drugs – either approach may be appropriate for intermediate-risk drugs. Consensus on definitions and methods of reporting HBVr, along with inclusion of HBsAg+, and HBsAg-/anti-HBc+ patients in clinical trials, will be key to gathering reliable data on the risk of HBVr associated with immunosuppressive or immunomodulatory therapies.
Introduction
HBV reactivation (HBVr) is a serious event which can result in liver failure and death, but it is preventable.[1]
HBVr occurs when the immune response of patients with HBV infection is suppressed. It is more common in patients with chronic HBV infection (hepatitis B surface antigen positive [HBsAg+]), but it can also occur in those with past HBV infection regardless of the presence or absence of hepatitis B surface antibody (HBsAg negative, IgG hepatitis B core antibody positive [HBsAg-/anti-HBc+]) because of the persistent presence of HBV DNA in the liver even after serologic recovery.[2][3]
HBVr was first described in patients receiving chemotherapy for malignancies. It has since been reported to be associated with other immunosuppressive therapies including biologics used in a variety of non-malignant diseases, as well as targeted therapies for malignancies. The incidence of HBVr associated with each class of immunosuppressant or immunomodulator is highly varied due to a lack of consensus regarding definitions, and variations in study design and patient selection. Current literature show that B-cell-depleting agents, such as rituximab, are associated with the highest risk of HBVr.[3]
Many comprehensive reviews have been published on the risk of HBVr associated with each class of immunosuppressive therapy, but few have included a meta-analysis of the published studies. Since the publication of the meta-analysis organised by the American Gastroenterological Association in 2015,[4] new classes of immunosuppressants and immunomodulators have been approved for clinical use. Data on the risk of HBVr with these new therapies are sparse. Several professional society guidelines provided recommendations on the prevention of HBVr associated with new classes of immunosuppressants and immunomodulators, but these guidelines focused on select therapies commonly prescribed for diseases within that specialty and most were not accompanied by a systematic review of the published literature.5, 6, 7, 8, 9, 10, 11, 12
We performed a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressants and immunomodulators used for a broad spectrum of diseases; we also analysed the impact of prophylactic HBV antiviral therapy in reducing that risk and provide guidance to physicians across a wide range of specialties. In addition, we reviewed data on 2 commonly prescribed immunosuppressants, corticosteroids and anti-tumour necrosis factor (anti-TNF) agents, to provide updated guidance on risk of HBVr associated with these therapies and indications for prophylactic antiviral therapy.