Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis

BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb− (in Japan, could enrol if HBV DNA−) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.