{"id":{"repo_id":"cape-town","oai_identifier":"oai:open.uct.ac.za:11427/15679"},"canonical_url":"https://search.dev.ndltd.org/etd/cape-town/oai:open.uct.ac.za:11427/15679","repository":{"repo_id":"cape-town","name":"University of Cape Town","base_url":"https://open.uct.ac.za/oai/request"},"display":{"title":"Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions","abstract":"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 SeCore® 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.","abstract_html":"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 SeCore® 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.","abstract_has_math":false,"creators":["Shebe, Khadija Ahmed"],"institution":"Division of Dermatology","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Lehloenya, Rannakoe J","Todd, Gail"],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015","date_published":"2015","updated_at":"2026-07-22T22:23:24Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/11427/15679","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Lehloenya, Rannakoe J","Todd, Gail"]},{"key":"dc:creator","label":"Author","values":["Shebe, Khadija Ahmed"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2015-12-08T11:38:40Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2015-12-08T11:38:40Z"]},{"key":"dc:date.issued","label":"Date","values":["2015"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Division of Dermatology"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cape Town"]},{"key":"dc:type","label":"Dc Type","values":["Master Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Masters"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["MMed"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/11427/15679"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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 SeCore® 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."]},{"key":"dc:title","label":"Title","values":["Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions"]}]}],"canonical_facts":{"dc:contributor.advisor":["Lehloenya, Rannakoe J","Todd, Gail"],"dc:creator":["Shebe, Khadija Ahmed"],"dc:date.accessioned":["2015-12-08T11:38:40Z"],"dc:date.available":["2015-12-08T11:38:40Z"],"dc:date.issued":["2015"],"dc:description.abstract":["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 SeCore® 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."],"dc:identifier.uri":["http://hdl.handle.net/11427/15679"],"dc:language.iso":["eng"],"dc:publisher.department":["Division of Dermatology"],"dc:publisher.institution":["University of Cape Town"],"dc:title":["Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions"],"dc:type":["Master Thesis"],"dc:type.qualificationlevel":["Masters"],"dc:type.qualificationname":["MMed"]},"updated_at":"2026-07-22T22:23:24Z"}