Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV

Author:

Cindi Zinhle1,Kawuma Aida N.1,Maartens Gary1,Bradford Yuki2,Sokhela Simiso3,Chandiwana Nomathemba3,Venter Willem D. Francois3,Wasmann Roeland E.1,Denti Paolo1,Wiesner Lubbe1,Ritchie Marylyn D.4,Haas David W.56,Sinxadi Phumla1

Affiliation:

1. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

2. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

3. Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

4. Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania

5. Department of Medicine, Vanderbilt University Medical Center

6. Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA

Abstract

Background Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest. Objective We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Methods Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations. Results A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10−8) and intergenic rs142693425 (P = 1.4 × 10−8), respectively. Conclusion Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine,General Pharmacology, Toxicology and Pharmaceutics

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