Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa
© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
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) μmol.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 μmol.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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
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| Enthalten in: |
British journal of clinical pharmacology - 90(2024), 5 vom: 08. Apr., Seite 1247-1257 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mpofu, Rephaim [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.04.2024 Date Revised 29.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.16009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM368219496 |
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| 245 | 1 | 0 | |a Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa |
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| 500 | |a Date Completed 29.04.2024 | ||
| 500 | |a Date Revised 29.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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) μmol.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 μmol.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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a HIV/AIDS | |
| 650 | 4 | |a cytochrome P450 enzymes | |
| 650 | 4 | |a drug transporters | |
| 650 | 4 | |a pharmacogenomics | |
| 650 | 4 | |a pharmacokinetic‐pharmacodynamic | |
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| 650 | 7 | |a Heterocyclic Compounds, 3-Ring |2 NLM | |
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| 700 | 1 | |a Chandiwana, Nomathemba |e verfasserin |4 aut | |
| 700 | 1 | |a Sokhela, Simiso Mandisa |e verfasserin |4 aut | |
| 700 | 1 | |a Moorhouse, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Venter, Willem Daniel Francois |e verfasserin |4 aut | |
| 700 | 1 | |a Denti, Paolo |e verfasserin |4 aut | |
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| 700 | 1 | |a Maartens, Gary |e verfasserin |4 aut | |
| 700 | 1 | |a Sinxadi, Phumla |e verfasserin |4 aut | |
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