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

Abstract

Introduction/objectives: To 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).

Method: CZP 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.

Results: Among 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).

Conclusions: CZP 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.

Keywords: Pharmacovigilance; Psoriatic arthritis; Rheumatic diseases; Rheumatoid arthritis; Spondyloarthritis.

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. CZP, certolizumab pegol

Fig. 2

Cumulative exposure to CZP per region or country in clinical trial and post-marketing TB analysis. a Pooled clinical trial CZP exposure 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. CZP, certolizumab pegol; PY, patient-years; TB: tuberculosis. b Post-marketing CZP exposure to 6 March 2015 (TB cut-off date) Asia-Pacific: Australia, Hong Kong, Malaysia, New Caledonia, Republic of Korea; eastern Europe: Romania, Russia; central Europe: Bulgaria, Czech Republic, Hungary, Poland, Slovakia, Slovenia; western Europe: Andorra, 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, Ecuador, French Guiana, Guadeloupe, Peru, Reunion; rest of the world: Bahrain, Cyprus, Egypt, Kuwait, Lebanon, Libya, Martinique, Qatar, Saudi Arabia, Turkey, UAE. CZP, certolizumab pegol; PY, patient-years; TB, tuberculosis

Fig. 3

Confirmed TB cases from CZP clinical trials data by region. ^aWHO Global Tuberculosis Report 2017; Since 2007, stricter screening rules for latent TB have been used across CZP clinical trials including a PPD cut-off of 5 mm and a TB questionnaire to help identify patients as risk. Countries shaded in blue represent those countries included in the clinical trials data set. Asia-Pacific: Australia, Hong Kong, Japan, 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. CZP, certolizumab pegol; IR, incidence rate; PPD, purified protein derivative; PY, patient-years; TB, tuberculosis

Fig. 4

TB incidence rates over time in CZP clinical trial patients. CZP, certolizumab pegol; TB, tuberculosis. Error bars represent 95% confidence intervals

Fig. 5

Confirmed TB cases from CZP post-marketing data by region. ^aWHO Global Tuberculosis Report 2017; Countries shaded in orange represent those countries included in the post-marketing data set. Asia-Pacific: Australia, Hong Kong, Japan, Malaysia, New Caledonia, Republic of Korea; eastern Europe: Romania, Russia; central Europe: Bulgaria, Czech Republic, Hungary, Poland, Slovakia, Slovenia; western Europe: Andorra, 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, Ecuador, French Guiana, Guadeloupe, Peru, Reunion; rest of the world: Bahrain, Cyprus, Egypt, Kuwait, Lebanon, Libya, Martinique, Qatar, Saudi Arabia, Turkey, UAE. CZP, certolizumab pegol; IR, incidence rate; PY, patient-years; TB, tuberculosis