Clinical utility of pre-treatment four-digit-resolution HLA genotyping to guide anti-tumor necrosis factor choice and concomitant immunomodulator use

Background and Aims Immunogenicity and the development of an undetectable drug level is a modifiable cause of anti-tumor necrosis factor (anti-TNF) treatment failure. We modeled the clinical utility of pre-treatment HLA-DQA1∗05:01 and HLA-DQA1∗05:05 allele subtype testing to guide immunomodulator use in patients with Crohn's disease treated with an anti-TNF. Methods The Personalised Anti-TNF Therapy in Crohn's Disease study is a UK-wide, prospective observational study of infliximab and adalimumab in anti-TNF-naïve patients with active Crohn's disease. Rates of drug-clearing antibody development, defined by the presence of anti-TNF antibodies and undetectable drug levels, were estimated using the Kaplan-Meier method. Genetic association tests were performed using Cox proportional hazards regression. Results About 40% of participants carried an actionable HLA-DQA1∗05 allele subtype. HLA-DQA1∗05:01 (hazard ratio [HR] 1.87 [95% CI: 1.37-2.53], P <. 0001) and HLA-DQA1∗05:05 (HR 2.45 [95% CI: 1.32-4.54], P =. 004) were the most significant allele subtypes associated with the development of drug-clearing antibodies in infliximab- and adalimumab-treated patients, respectively. Immunomodulator use increased the time to drug-clearing antibodies in all patients treated with infliximab. In adalimumab-treated patients, only individuals who carried the HLA-DQA1∗05:05 allele subtype benefited from combination immunomodulator use with a number needed to treat of 4.6 (95% CI: 2.4-20.5) to prevent one episode of a drug-clearing antibody. Discussion Pre-treatment four-digit HLA testing informs on anti-TNF treatment choice and immunomodulator use. In HLA-DQA1∗05:01 carriers, adalimumab monotherapy should be used and infliximab avoided. In HLA-DQA1∗05:05 carriers, infliximab or adalimumab can be used with a concomitant immunomodulator. In patients who do not carry either HLA-DQA1∗05:01 or HLA-DQA1∗05:05, adalimumab monotherapy or infliximab with a concomitant immunomodulator are recommended.