Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa. Mpofu, R., Kawuma, A. N, Wasmann, R. E, Akpomiemie, G., Chandiwana, N., Sokhela, S. M., Moorhouse, M., Venter, W. D. F., Denti, P., Wiesner, L., Post, F. A, Haas, D. W, Maartens, G., & Sinxadi, P. British Journal of Clinical Pharmacology, John Wiley & Sons, Ltd, feb, 2024. ![Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex AIMS Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, 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 (SD 9.9) $μ$mol.L-1 . Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [$β$] = 2.78 $μ$mol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use ($β$ = 2.30 [0.53, 4.06]), male sex ($β$ = 5.20 [2.92, 7.48]), baseline serum creatinine ($β$ = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model ($β$ = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.
@article{Mpofu2024,
abstract = {AIMS Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, 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 (SD 9.9) $\mu$mol.L-1 . Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [$\beta$] = 2.78 $\mu$mol.L-1 [95{\%} confidence interval (CI) 0.54, 5.01]), TDF use ($\beta$ = 2.30 [0.53, 4.06]), male sex ($\beta$ = 5.20 [2.92, 7.48]), baseline serum creatinine ($\beta$ = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model ($\beta$ = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.},
author = {Mpofu, Rephaim and Kawuma, Aida N and Wasmann, Roeland E and Akpomiemie, Godspower and Chandiwana, Nomathemba and Sokhela, Simiso Mandisa and Moorhouse, Michelle and Venter, Willem Daniel Francois and Denti, Paolo and Wiesner, Lubbe and Post, Frank A and Haas, David W and Maartens, Gary and Sinxadi, Phumla},
doi = {10.1111/BCP.16009},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Mpofu et al - 2024 - Determinants of early change in serum creatinine after initiation of.pdf:pdf},
issn = {1365-2125},
journal = {British Journal of Clinical Pharmacology},
keywords = {HIV/AIDS,OA,cytochrome P450 enzymes,drug transporters,fund{\_}ack,original,pharmacodynamic,pharmacogenomics,pharmacokinetic},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
pages = {10.1111/bcp.16009},
pmid = {38332460},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/bcp.16009 https://onlinelibrary.wiley.com/doi/abs/10.1111/bcp.16009 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.16009},
year = {2024}
}
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METHODS We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, 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 (SD 9.9) $μ$mol.L-1 . Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [$β$] = 2.78 $μ$mol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use ($β$ = 2.30 [0.53, 4.06]), male sex ($β$ = 5.20 [2.92, 7.48]), baseline serum creatinine ($β$ = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model ($β$ = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. 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