Tuberculosis and viral hepatitis in patients treated with certolizumab pegol in Asia-Pacific countries and worldwide: real-world and clinical trial data

Chak Sing Lau,Keith Lim,Kevin Winthrop,Yi-Hsing Chen,Marc De Longueville,Catherine Arendt

doi:10.1007/s10067-020-05248-4

Abstract

Introduction/objectivesTo evaluate the incidence rate (IR) of tuberculosis (TB) and viral hepatitis B and C (HBV/HCV) during certolizumab pegol (CZP) treatment, worldwide and in Asia-Pacific countries, across clinical trials and post-marketing reports (non-interventional studies and real-world practice).MethodCZP safety data were pooled across 49 clinical trials from 1998 to June 2017. Post-marketing reports were from initial commercialization until March 2015 (TB)/February 2017 (HBV/HCV). All suspected TB and HBV/HCV cases underwent centralized retrospective review by external experts. Incidence rates (IRs) were calculated per 100 patient-years (PY) of CZP exposure.ResultsAmong 11,317 clinical trial patients (21,695 PY), 62 TB cases were confirmed (IR 0.29/100 PY) including 2 in Japan (0.10/100 PY) and 3 in other Asia-Pacific countries (0.58/100 PY). From > 238,000 PY estimated post-marketing CZP exposure, there were 31 confirmed TB cases (0.01/100 PY): 5 in Japan (0.05/100 PY), 1 in other Asia-Pacific countries (0.03/100 PY). Reported regional TB IRs were highest in eastern Europe (0.17/100 PY), central Europe (0.09/100 PY), and Mexico (0.16/100 PY). Across clinical trials, there was 1 confirmed HBV reactivation and no HCV cases. From > 420,000 PY estimated post-marketing CZP exposure, 5 HBV/HCV cases were confirmed (0.001/100 PY): 2 HCV reactivations; 1 new HCV; plus 2 HBV reactivations in Japan (0.008/100 PY).ConclusionsCZP TB risk is aligned with nationwide TB rates, being slightly higher in Asia-Pacific countries excluding Japan. Overall, TB and HBV/HCV risk with CZP treatment is currently relatively low, as risk can be minimized with patient/physician education, screening, and vigilant treatment, according to international guidelines.Key Points:• TB rates were highest in eastern/central Europe, Mexico, and Asia-Pacific regions.• With the implementation of stricter TB screening and risk evaluations in 2007, especially in high TB incidence countries, there was a notable reduction TB occurrence.• Safety profile of biologics in real-world settings complements controlled studies.• TB and hepatitis (HBV/HCV) risk with certolizumab pegol (CZP) treatment is low.

Highlights

Patients with immune-mediated inflammatory diseases (IMIDs) have a greater risk of serious infectious events (SIEs) than the general population [1]
This paper reports incidence rates (IR) of TB, HBV, and HCV during certolizumab pegol (CZP) treatment in pooled data from clinical trials of CZP across its approved indications, as well as post-marketing reports, both worldwide and in the Asia-Pacific region
Clinical trials were performed across a total of 45 countries (Fig. 1), including substantial numbers of patients from countries with a higher nationwide TB incidence, such as Ukraine (87/100,000), Russia (66/100,000), Republic of Korea (77/100,000), Singapore (51/100,000), Fig. 1 Geographic distribution of patients included in CZP clinical trials Asia-Pacific: Australia, Hong Kong, New Zealand, Republic of Korea, Singapore; eastern Europe: Belarus, Croatia, Georgia, Romania, Russia, Serbia, Ukraine; central Europe: Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, Slovenia; western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, The Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, UK; North America: Canada, US; Latin America: Argentina, Brazil, Chile, Colombia; Rest of the World: Israel, South Africa

Summary

Introduction

Patients with immune-mediated inflammatory diseases (IMIDs) have a greater risk of serious infectious events (SIEs) than the general population [1]. The use of biologics and anti-tumor necrosis factor drugs (anti-TNF) is associated with an increased risk of infections including tuberculosis (TB) [2,3,4,5], and possibly viral hepatitis B (HBV) and viral hepatitis C (HCV) [6,7,8]. This is a relevant clinical consideration in the Asia-Pacific region, where nationwide incidence rates (IR) of TB and HBV/HCV are relatively high [9,10,11]. Japan remains a moderate TB burden country with an incidence estimate of 15 cases per 100,000 population in 2017 [14], most of which are diagnosed in patients aged over 75 years [15]

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