Pharmacogenomics of drug transporters for antiretroviral long-acting pre-exposure prophylaxis for HIV

9 December 2022

In this CAPRISA-led review, drug transporters and biological factors modulating drug transporter disposition are used to explain discrepancies in PrEP drug efficacies observed in PrEP clinical trials. 

The review titled, ‘Pharmacogenomics of drug transporters for antiretroviral long-acting pre-exposure prophylaxis for HIV’ published in the journal Frontiers in Genetics, also provides insight at a pharmacological level of how these factors further increase the susceptibility of the female genital tract to HIV infections, subsequently contributing to ineffective PrEP interventions in African women.  

Clinical trials testing the effectiveness of Truvada® [a combination of tenofovir disoproxil fumarate/tenofovir and emtricitabine] as oral or topical PrEP in African women yielded mixed results in preventing the sexual transmission of HIV infections. 

Since oral and topical PrEP effectiveness is dependent on adequate drug delivery and availability to cells and tissues targeted by HIV, different host biological factors have been proposed to play an integral role in these women. These include transmembrane drug transporter proteins expressed in various cells. Their expression levels and function has been implicated as key regulators of PrEP pharmacokinetics [which is absorption, distribution, metabolism and excretion] which determines effectiveness. Compartment differences of these drug transporters between the blood and genital tract remain largely undescribed. 

Other biological factors such as genetic polymorphisms, specifically the presence of single nucleotide polymorphisms (SNPs) in drug transporter genes and genital inflammation have been shown to directly affect drug transporter disposition. This review shows that the FGT, renal system and blood are subject to a variety of host biological factors that may undermine PrEP efficacy by affecting drug transporter expression levels and function.    

Nomusa M. Zondo and Derseree Archary (PhD)
Figure: Proposed mechanisms that impact drug transporter expression and function. This diagram depicts the inextricable links between biological factors and varied drug transporter expression levels and function that subsequently affect PrEP pharmacokinetics and effectiveness.