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Randomized Controlled Trial
. 2023 Jun 1;33(4):79-87.
doi: 10.1097/FPC.0000000000000495. Epub 2023 Mar 6.

Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV

Zinhle Cindi  1 , Aida N Kawuma  1 , Gary Maartens  1 , Yuki Bradford  2 , Simiso Sokhela  3 , Nomathemba Chandiwana  3 , Willem D Francois Venter  3 , Roeland E Wasmann  1 , Paolo Denti  1 , Lubbe Wiesner  1 , Marylyn D Ritchie  4 , David W Haas  5   6 , Phumla Sinxadi  1
Affiliations
Randomized Controlled Trial

Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV

Zinhle Cindi et al. Pharmacogenet Genomics. .

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.

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Figures

Figure 1.
Figure 1.. Disposition of study participants.
Of 1053 participants enrolled in the ADVANCE study, 268 randomized to TAF- and TDF-containing regimens had available pharmacokinetic sampling data and were evaluable for genetic associations.
Figure 2.
Figure 2.. Manhattan plot of associations with unexplained variability in tenofovir clearance in the TAF arm.
The figure shows −log10 P-values for association among 138 TAF recipients who were evaluable for genetic associations. The black arrow indicates polymorphisms that reached genome-wide significance at P < 5.0×10−8.
Figure 3.
Figure 3.. Manhattan plot of associations with unexplained variability in tenofovir clearance in the TDF arm.
The figure shows −log10 P-values for association among 130 TDF recipients who were evaluable for genetic associations. The black arrows indicate polymorphisms that reached genome-wide significance at P < 5.0×10−8.
See this image and copyright information in PMC

References

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