Summary

• Use of anti-tumor necrosis factor (TNF) agents, including REMICADE has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus.¹
• Patients should be tested for HBV infection before initiating anti-TNF therapy, including REMICADE.¹
• For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended.¹
• Patients who are carriers of HBV and require treatment with anti-TNF agents should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.¹
• The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.¹
• Several retrospective and open label studies have described the use of REMICADE in patients who have active hepatitis B, inactive hepatitis B or in patients who have clinical markers for HBV exposure.^2–7

PRODUCT LABELING

Please refer to the following sections of the full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS.

CLINICAL DATA

Clinical Trials

The safety and efficacy of using REMICADE in patients with active or chronic hepatitis has not been investigated in controlled clinical trials.  Patients were excluded from participating in clinical trials of REMICADE if they had a serious infection such as hepatitis in the previous 3 months prior to entry into the study and/or if they had signs or symptoms of severe, progressive, or uncontrolled hepatic disease.^8–19

Retrospective Studies

Cassano et al

Cassano et al (2011)⁶ reported, in a letter to the editor, a retrospective analysis involving patients with moderate to severe plaque psoriasis and occult HBV infection who were treated with anti-TNF agents including REMICADE.

Study Design/Methods

• Data collection occurred over a period of 55 months. Patients with concomitant Hepatitis C were excluded.
• All patients in the analysis had chronic plaque psoriasis, with or without the presence of psoriatic arthritis, treated with anti-TNF agent monotherapy.
• Patients were treated with either adalimumab, etanercept or REMICADE. Eligibility for anti-TNF therapy was confirmed with prescreening examinations which included hepatitis B and C markers.
• Baseline measurements of HBV-DNA were conducted in patients who were occult HBV carriers.
• Patients were evaluated for serum aminotransferases, HBsAg and HBV-DNA on a monthly basis for the first three months followed by an evaluation every three months or before retreatment in patients who received intermittent therapy.

Results

• The analysis included 62 patients who were carriers of occult HBV (42 males and 20 females).
• All 62 patients had negative HBeAg and HBsAg with no detectable HBV-DNA in the serum. All 62 patients were positive for anti-HBc antibodies and 50 patients were also anti-HBs positive. There were no relevant serum transaminase level abnormalities detected at baseline.
• Of the 62 patients; 8 were treated with REMICADE, 10 with adalimumab and 44 were treated with etanercept. Sixteen patients had a previous history of treatment with different anti-TNF agent.
• There were no signs of HBV activation during the course of the observational treatment period. In all cases there was a persistent negativity in both HBsAg and HBV-DNA during the treatment period.

Kim et al

Kim et al (2010)² conducted a retrospective chart review to investigate the potential of reactivating possible existing HBV infection in 266 patients who had taken an anti-TNF agent for the treatment of rheumatic diseases from January 2002 to May 2008.

Study Design/Methods

• Patients were included if they were being treated for a rheumatic condition with an anti-TNF agent (REMICADE, adalimumab or etanercept) and also had documented serologic tests for HBV surface antigen (HBsAg), HBV surface antibody (HBsAb) and IgG HBV core antibody (HBcAb; a marker that indicates previous exposure to HBV). Patients were then divided into either HBcAb-positive (n=88), or HBcAb-negative (n=170) groups based on their serologic status.

Results

• For the purposes of this study significantly elevated aminotransferase levels were used as an indicator of HBV infection reactivation.  Results of serological analysis revealed that elevated aminotransferase levels were more common in the HBcAb-positive group compared to the HBcAb-negative group (15.9% vs 5.9%).
• Additionally, a multiple logistic regression analysis was performed controlling for HBcAb status, concomitant medications (isoniazid, NSAIDs, and MTX), and type of anti-TNF agent.  This analysis showed that only HBcAb status was a significant risk factor for elevated liver enzymes in these patients being treated with an anti-TNF agent (P=0.008).

Li et al

Li et al (2009)³ retrospectively reviewed the medical records of 11 rheumatoid arthritis (RA) patients with concurrent HBV or hepatitis C virus (HCV) to evaluate the effect of 3 different anti-TNF agents (REMICADE, etanercept, and adalimumab) on hepatic function and viral load.

Study Design/Methods

• Prior to treatment with an anti-TNF agent, all patients had failed a variety of disease-modifying antirheumatic drugs (methotrexate [MTX], gold, hydroxychloroquine, and sulfasalazine).
• Patients who failed at least a 3-month trial on an anti-TNF agent were switched to a second agent. They received anti-TNF agents in conjunction with their previous regimen of MTX, hydroxychloroquine, or sulfasalazine. Serum ALT, AST, and HBV/HCV viral load were used as markers of hepatic injury and disease progression, respectively.

Results

• Of the 11 patients identified, there were 3 RA patients with HBV and 8 RA patients with HCV. Viral hepatitis was diagnosed in 5 patients prior to a diagnosis of RA, viral hepatitis was diagnosed in 5 patients after a diagnosis of RA, and the duration of hepatitis was unknown in one patient.
• In addition, 5 patients were treated with adalimumab, 4 patients were treated with etanercept, and 2 patients were treated with REMICADE as their first anti-TNF agent. Due to treatment failure, 4 patients were switched to a second anti-TNF agent (one patient failed etanercept and was switched to REMICADE, 2 patients failed REMICADE and were switched to etanercept, and one patient failed adalimumab and was switched to etanercept).
• Of the 3 RA patients with HBV, one patient had a transient increase in ALT from the normal range but returned to normal within 24 hours of starting treatment.
• Of the 8 RA patients with HCV, one patient had a permanent increase in AST and ALT with levels above the normal range at 60 months, and 2 patients who had a baseline increase in AST and/or ALT from the normal range both had a mild decrease in transaminases at the subsequent interval follow-up.
• Of the 11 RA patients, 6 had a baseline hepatitis viral load before initiating treatment. With the exception of one patient who had a fourfold increase in viral load from baseline after switching from etanercept to REMICADE, there was no significant increase in viral load after initiating therapy.

Garcia-Vidal et al

Garcia-Vidal et al (2009)⁴ examined a retrospective study cohort to identify risk factors associated with the development of opportunistic infections in patients treated with REMICADE, and to describe the epidemiology of infections in this population.

Results

• Of the 94 REMICADE-treated patients identified, 9 opportunistic infections were diagnosed during the study period (4 TB, one visceral leishmaniasis, 2 pyogenic muscular abscess [one Salmonella spp. and one Streptococcus pneumonia], and 2 viral infections [reactivation of HBV and zoster ophthalmicus]).
• The incidence of opportunistic infection was 9.5% (9/94), and the risk for opportunistic infection was significantly higher in the first year of treatment (OR 8; 95% CI, 2-50).
• The case of HBV reactivation occurred in a 34-year-old man who was treated with REMICADE for Crohn's disease (CD).  Previous immunosuppressive agents included MTX and azathioprine (AZA).  The diagnosis of HBV reactivation occurred 7 months after the first dose of REMICADE; total REMICADE dose 45 mg/kg.

Chung et al

Chung et al (2009)⁵ conducted a retrospective study to evaluate the outcome of HBV carriers who had been treated with anti-TNF therapy.

Results

• Of the 103 patients treated with an anti-TNF agent, 8 (3 with RA and 5 with ankylosing spondylitis [AS]) were inactive HBsAg carriers with documented HBsAg seropositivity and HBeAg seronegativity.
• All of the patients had normal ALT/AST levels and undetectable HBV DNA by polymerase chain reaction (PCR) upon initiation of anti-TNF therapy. In addition, all patients were treated with nonsteroidal antiinflammatory drugs, and some received MTX (10.0 to 17.5 mg/week) with low-dose glucocorticoids. Upon glucocorticoid or MTX use, no patient presented with abnormality on liver function tests.
• Reactivation of HBV occurred in one REMICADE-treated patient with AS (12.5%, [n=1, 95% CI, 0-0.354]). The patient was a 34-year-old man who had normal liver enzyme levels and negative HBV PCR results prior to REMICADE infusion.
• At week 6, at the time of the third REMICADE infusion (5 mg/kg), his blood test revealed normal AST and ALT levels. At week 14, when the patient returned for the fourth REMICADE infusion, he complained of general weakness, and right upper quadrant abdominal pain. AST and ALT levels were 457 IU/l and 1054 IU/l, respectively, and HBV PCR revealed an increased HBV load of 3,130,000 IU/ml (reference value <60 IU/ml).
• After HBV reactivation was diagnosed, REMICADE was discontinued, and entecavir 0.5 mg/day was initiated. After 3 months, AST and ALT levels returned to normal. HBV PCR results were negative on follow-up.

Open-Label Trial

Esteve et al (2004)⁷ evaluated the occurrence of hepatitis C and B in a total of 80 Crohn’s Disease (CD) patients who had been treated with REMICADE at 3 Spanish hospitals.

• Of the 80 patients 45 were men, 35 were women and the mean age was 38.2 years
• Hepatitis C and B markers and liver function tests were prospectively determined prior to the first REMICADE infusion.
• Chronic hepatitis B infections were identified in 3 patients. Two of the patients experienced a reactivation of chronic HBV after REMICADE treatment (one of whom died while awaiting liver transplantation), and the third patient had no clinical or biochemical worsening of liver disease during or after REMICADE treatment.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 06 October 2023.

Summarized in the response are relevant data from retrospective and open-label clinical trials which evaluated the use of REMICADE in patients who had active hepatitis B, inactive hepatitis B or in patients who are carriers for HBV.