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ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment

The Pharmacogenomics Journal volume 21, pages 586–593 (2021)Cite this article

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Abstract

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00–1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00–2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

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Fig. 1: Distribution of TFV plasma concentrations in patients having.

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Funding

This study was carried out as part of our routine work, and was not specifically funded.

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Authors and Affiliations

  1. Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli Sacco, Milan, Italy

    Stefania Cheli, Sara Baldelli, Marta Fusi, Dario Cattaneo & Cristina Montrasio

  2. Clinical Epidemiology and Biometry Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Annalisa De Silvestri

  3. Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy

    Davide Minisci, Cristina Gervasoni & Paola Meraviglia

  4. Gestione Ambulatoriale Politerapie (GAP) Outpatient Clinic, ASST Fatebenefratelli Sacco, Milan, Italy

    Cristina Gervasoni & Dario Cattaneo

  5. Unit of Clinical Pharmacology ASST Fatebenefratelli Sacco, Department of Biomedical and Clinical Sciences L. Sacco, Università di Milano, Milan, Italy

    Emilio Clementi

  6. IRCCS E. Medea Scientific Institute, Bosisio Parini, Italy

    Emilio Clementi

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  1. Stefania Cheli
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Correspondence to Cristina Montrasio.

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Ethical approval

Data used for this study were collected for clinical purposes and were previously anonymised, according to the requirements set by the Italian Data Protection Code (leg. decree 196/2003) and by the general authorizations issued by the Data Protection Authority. Approval by Ethics Committee was unnecessary because, under Italian law, such an approval is required only in the hypothesis of prospective clinical trials on medical products for clinical use (art. 6 and art. 9, leg. decree 211/2003). Each patient included in this study provided a written informed consent for genetic testing and publication of clinical data for research purposes.

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Cheli, S., Baldelli, S., De Silvestri, A. et al. ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment. Pharmacogenomics J 21, 586–593 (2021). https://doi.org/10.1038/s41397-021-00235-7

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