Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy

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dc.contributor.advisorSinxadi, Phumla
dc.contributor.advisorMaartens Gary
dc.contributor.authorMpofu, Rephaim
dc.date.accessioned2024-05-27T08:47:28Z
dc.date.available2024-05-27T08:47:28Z
dc.date.issued2023
dc.date.updated2024-05-22T08:38:04Z
dc.description.abstractIntroduction: Dolutegravir increases serum creatinine by inhibiting renal secretion of creatinine, potentially resulting in inappropriate regimen switches. We investigated determinants of early changes in serum creatinine in a Southern African cohort starting dolutegravir-based antiretroviral therapy. Methods: We conducted a secondary analysis of data from participants in a randomised controlled trial of dolutegravir with tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) plus emtricitabine (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic, and genetic factors associated with the change in serum creatinine from baseline to week 4 using linear regression adjusting for age, sex, baseline serum creatinine, HIV-1 RNA viral load, CD4 T-cell count, total body weight, and co-trimoxazole use. Results: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 µmol.L-1. Dolutegravir area under the 24-hour concentration-time curve (change in creatinine regression coefficient [β] = 2.78 [95% confidence interval 0.54, 5.01]) and male sex (β = 5.20 [2.92, 7.48]) were associated with an increased change in serum creatinine at week 4, while higher baseline serum creatinine (β = -0.22 [-0.31, -0.12]), use of TAF (β = -2.30 [-4.06, -0.53]) and Uridine glucuronosyltransferase 1A1 (UGT1A1) polymorphism rs929596 (β = -2.33 [-4.49, -0.17]; not significant after adjustment for multiple comparisons) were associated with a decreased change in serum creatinine. Conclusion: We identified clinical and pharmacokinetic determinants of change in serum creatinine in participants starting a dolutegravir-based regimen. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.
dc.identifier.apacitationMpofu, R. (2023). <i>Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy</i>. (). ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/39723en_ZA
dc.identifier.chicagocitationMpofu, Rephaim. <i>"Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy."</i> ., ,Faculty of Health Sciences ,Department of Medicine, 2023. http://hdl.handle.net/11427/39723en_ZA
dc.identifier.citationMpofu, R. 2023. Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy. . ,Faculty of Health Sciences ,Department of Medicine. http://hdl.handle.net/11427/39723en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Mpofu, Rephaim AB - Introduction: Dolutegravir increases serum creatinine by inhibiting renal secretion of creatinine, potentially resulting in inappropriate regimen switches. We investigated determinants of early changes in serum creatinine in a Southern African cohort starting dolutegravir-based antiretroviral therapy. Methods: We conducted a secondary analysis of data from participants in a randomised controlled trial of dolutegravir with tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) plus emtricitabine (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic, and genetic factors associated with the change in serum creatinine from baseline to week 4 using linear regression adjusting for age, sex, baseline serum creatinine, HIV-1 RNA viral load, CD4 T-cell count, total body weight, and co-trimoxazole use. Results: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 µmol.L-1. Dolutegravir area under the 24-hour concentration-time curve (change in creatinine regression coefficient [β] = 2.78 [95% confidence interval 0.54, 5.01]) and male sex (β = 5.20 [2.92, 7.48]) were associated with an increased change in serum creatinine at week 4, while higher baseline serum creatinine (β = -0.22 [-0.31, -0.12]), use of TAF (β = -2.30 [-4.06, -0.53]) and Uridine glucuronosyltransferase 1A1 (UGT1A1) polymorphism rs929596 (β = -2.33 [-4.49, -0.17]; not significant after adjustment for multiple comparisons) were associated with a decreased change in serum creatinine. Conclusion: We identified clinical and pharmacokinetic determinants of change in serum creatinine in participants starting a dolutegravir-based regimen. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed. DA - 2023 DB - OpenUCT DP - University of Cape Town KW - Clinical Pharmacology LK - https://open.uct.ac.za PY - 2023 T1 - Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy TI - Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy UR - http://hdl.handle.net/11427/39723 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/39723
dc.identifier.vancouvercitationMpofu R. Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy. []. ,Faculty of Health Sciences ,Department of Medicine, 2023 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/39723en_ZA
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.subjectClinical Pharmacology
dc.titleClinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy
dc.typeThesis / Dissertation
dc.type.qualificationlevelMasters
dc.type.qualificationlevelMMed
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