Hepatitis B Virus (HBV) Reactivation in Patients Receiving Tumor Necrosis Factor (TNF)-Targeted Therapy

Abstract

The emergence of tumor necrosis factor-α (TNF-α)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents," and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

“…21,[38][39][40] Several studies reported that elevated HBV viral load subsequently leads to active hepatitis. 24,25 A recent study analyzing patients with inflammatory arthritis also revealed an increased risk of HBV reactivation associated with anti-TNF therapy in patients with chronic HBV infection. 41 However, due to limited wellcontrolled studies, the association between TNF-a blockage and HBV reactivation remains uncertain.…”

“…[21][22][23] However, there are limited reports on its effect on HBV persistence and reactivation in chronic HBV infection during anti-TNF therapy. 24,25 The role of anti-TNF therapy in chronic HBV infection is still not clear, and detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence.…”

Practice Pattern of Hepatitis B Testing in Rheumatoid Arthritis Patients: A Cross‐National Comparison Between the US and Taiwan

“…According to a recent meta-analysis (5) and a case series (6), HBV reactivation rate ranges from 15% to 39% in HBsAg-positive RA patients receiving tumor necrosis factor (TNF) inhibitors, and 3% to 5% in HBsAg-negative patients receiving this class of medication. Reactivation also occurs in those receiving nonbiologic DMARDs (7-9) and a non-TNF biologic agent, abatacept (10,11).…”

HBV treatment in a patient who will be receiving immunosuppressive therapy

“…A recent review of reported cases found that reactivation occurred in 39% (35 of 89) of HBsAg-positive individuals including four fatal cases of acute liver failure and reactivation occurred in 5% (9 of 168) of those who were HBsAg-negative, anti-HBc-positive before starting anti-TNF therapy, including 1 fatal case. 15 Most studies have found the risk to be highest in patients receiving infliximab compared with etanercept or adalimumab. 15,16 Reactivation has also been reported with azathioprine, 6-mercaptopurine, and methotrexate used in nononcologic settings.…”

“…15 Most studies have found the risk to be highest in patients receiving infliximab compared with etanercept or adalimumab. 15,16 Reactivation has also been reported with azathioprine, 6-mercaptopurine, and methotrexate used in nononcologic settings. 17 There have been individual case reports with targeted kinase inhibitors 18 but no published reports of HBV reactivation with inhibitors of vascular growth endothelial factor.…”