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

Abstract

BackgroundReactivation 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.MethodsData 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.ResultsIn 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.ConclusionHBV 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.

Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

“…However, we observed that JAK inhibitors enhanced cellular infection of SARS-CoV-2 at higher concentrations, suggesting an effect on interferon signaling, a possible clinical liability that should be closely monitored during trials. Supporting this finding and underlining the importance of identifying diverse options to address cytokine storm, JAK inhibitors are known to increase the prevalence or severity of other viral infections including herpes zoster, JC virus, and hepatitis B [73][74][75] . This study also identified alternative mechanisms of action which have been much less deeply considered in the context of COVID-19, such as certain Syk inhibitors, c-Met inhibitors and PI3K inhibitors.…”

Janus kinase inhibitor baricitinib is not an ideal option for management of COVID-19

“…16 Studies have concluded Baricitinib therapy has constituted for the reactivation of Varicella Zoster, Herpes Simplex and Epstein Barr Virus strains. 17 Fei Zhou et al reports that 50% patients who succumbed to COVID 19 experienced secondary infections. 14 Baricitinib as predicted earlier may not be an ideal drug of choice for COVID 19.…”

Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

“…A wide range of opportunistic infections has been reported in patients receiving JAKinibs; these include non-tuberculous mycobacterium infections, Cryptococcus infections, Cytomegalovirus infections, Epstein–Barr virus infections, BK virus infections, Pneumocystis pneumonia, aspergillosis, candidiasis, histoplasmosis, paracoccidioidomycosis and toxoplasmosis [ 75 ]. Reactivation of hepatitis B virus (HBV) was reported during treatment with JAKinibs [ 76 ]. An integrated analysis of tofacitinib with 5671 patients reported 60 opportunistic infections including 34 non-TB infections in Phase II, Phase III, and LTE studies [ 74 ] with crude IR (95% CI) of 0.46 (0.36–0.59) per 100 PYs.…”