Allopurinol-Induced Severe Cutaneous Adverse Reactions in Vietnamese: The Role of HLA Alleles and Other Risk Factors

Abstract

Aim: To reveal the association of three class I HLA alleles, including HLA-A*33:03, HLA-B*58:01 and HLA-C*03:02, and allopurinol-induced severe cutaneous adverse reactions (SCARs) in Vietnamese patients. Methods: A case–control study on 100 allopurinol-induced SCARs patients, 183 tolerant controls and 810 population controls was performed. The HLA-A*33:03 and HLA-C*03:02 alleles were detected with the nested allele-specific PCR method; the HLA-B*58:01 allele was detected with the sequence-specific primer PCR method. Results: There were strong associations between HLA-B*58:01 and HLA-C*03:02 and allopurinol-induced SCARs. Specific associations were found between HLA-B*58:01 and Stevens–Johnson syndrome/toxic epidermal necrolysis and between HLA-C*03:02 and drug reaction with eosinophilia and systemic symptoms, with a gene dosage effect. The multivariate regression analysis indicated two significant independent risk factors: HLA-B*58:01/HLA-C*03:02 and estimated glomerular filtration rate <60 ml/min/1.73 m². The specificity, positive predictive value and negative predictive value of HLA-B*58:01 testing were higher than the HLA-C*03:02 or the multiplex testing, especially in patients with impaired renal function. Conclusion: The results supported pre-treatment HLA-B*58:01 testing in Vietnamese patients with declined renal function to prevent SCARs.

Keywords::

• allopurinol
• class I HLA
• HLA-B*58:01
• HLA-C*03:02
• severe cutaneous adverse reactions

Author contributions

All authors contributed to the design of the study and edited the manuscript; TH Phung supervised the study and drafted the manuscript; TTH Pham performed the research and data analysis; CH Chu, DV Nguyen and HA Nguyen were responsible for recruitment of participants and SCAR evaluation; B TranQuang and TQN Do were responsible for genetic testing.

Financial & competing interests disclosure

This work was supported by grants from the Vietnam Ministry of Health, grant no. 4694/QD-BYT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the Vietnam National Institute of Hygiene and Epidemiology (IRB-VN01057-6/2018). Written informed consent was obtained from all subjects who were recruited.

Additional information

Funding

This work was supported by grants from the Vietnam Ministry of Health, grant no. 4694/QD-BYT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.