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Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions

Introduction: All first-line anti-tuberculosis drugs can be associated with all phenotypes of cutaneous adverse drug reactions (CADR). Second-line drugs are associated with much poorer outcomes. Thus, identifying the offending drug in poly-pharmacy is difficult. Re -challenge with the drug is the gold standard in identifying the offender, however poses unacceptably high risk of CADR recurrence. Population and drug-specific genomics help identify those susceptible to adverse reactions to a drug facilitating avoidance of the drug. Objective: To investigate the genomic susceptibility in patients with confirmed rifampicin and or isoniazid-associated hypersensitivity reactions using both genome- wide association studies and candidate gene approaches. Methods: A case control study using 14 patients with previous tuberculosis-associated CADR who were re-challenged with first-line anti-tuberculosis drugs and subsequently developed re-challenge reactions to either isoniazid or rifampicin as cases. These were compared with 30 controls who had tolerated rifampicin and isoniazid during the re- challenge process (12 patients, Group 1a) and consecutive patients who had been on TB treatment for at least 12 weeks without developing any adverse drug reaction (1 8 patients, Group 1b) and 200 black South Africans from the general population. HLA genotypes of the samples were determined by SeCoreĀ® HLA Sequence based typing (Invitrogen, Life technologies, USA), and potential ambiguities were resolved by sequencing-based typing. Results: We found HLA-B*58:02 (OR=3.6; 95% CI: 1.4-8.99) and HLA-DRB1*09:01 (OR=15.3; 95% CI: 2.1-113.1) to be significantly more prevalent in patients who developed rifampicin and isoniazid-associated CADR as compared to black South African general population. However, we found no significant associations between HLA genotype and rifampicin/isoniazid-associated CADR when we compared the cases to our study controls that had tolerated rifampicin and isoniazid. HLA-B *58.02 was not found to be statistically associated with HIV positive status (p=0.42) and DRESS phenotype ( p= 0.6279). The majority of our cases were black Africans. Approximately 80% of our cases and controls were HIV-infected. DRESS/DIHS was the prevalent phenotype of CADR, accounting for approximately 80% of cases and controls. Discussion: To our knowledge, this is the first study to show an association between HLA-B*58:02 and HLA-DRB1*09:01 alleles and severe cutaneous adverse drugs reactions secondary to rifampicin and isoniazid in an African population. We identify 2 candidate HLA alleles that need confirmation of their association in African patients who develop rifampicin or isoniazid-associated CADR in larger studies. The value of identifying candidate alleles could lead to CADR preventative screening prior to initiating anti-tuberculosis therapy in black South Africans. The HLA-B*58:02 noted in our cases and controls tolerant of the drugs might not be associated with CADR but could be a reflection of the HIV status and control in HIV-TB co-infected persons. Conclusion: HLA-B*58:02 and HLA-DRB1*09:01 may be associated with rifampicin and isoniazid-associated CADR. Alternately HLA-B*58:02 may be associated with HIV status rather than CADR. A sufficiently powered study is needed to confirm this association.

Identiferoai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/15679
Date January 2015
CreatorsShebe, Khadija Ahmed
ContributorsLehloenya, Rannakoe J, Todd, Gail
PublisherUniversity of Cape Town, Faculty of Health Sciences, Division of Dermatology
Source SetsSouth African National ETD Portal
LanguageEnglish
Detected LanguageEnglish
TypeMaster Thesis, Masters, MMed
Formatapplication/pdf

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