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Review
. 2022 Sep 29:13:940661.
doi: 10.3389/fgene.2022.940661. eCollection 2022.

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

Nomusa M Zondo  1   2 , Parveen Sobia  1   2 , Aida Sivro  1   2 , Sinaye Ngcapu  1   2 , Veron Ramsuran  1   2 , Derseree Archary  1   2
Affiliations
Review

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

Nomusa M Zondo et al. Front Genet. .

Abstract

The use of antiretrovirals (ARVs) as oral, topical, or long-acting pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for HIV prevention. Clinical trials testing Truvada® [tenofovir disoproxil fumarate (TDF)/tenofovir (TFV) and emtricitabine (FTC)] as oral or topical PrEP in African women showed mixed results in preventing HIV infections. Since oral and topical PrEP effectiveness is dependent on adequate drug delivery and availability to sites of HIV infection such as the blood and female genital tract (FGT); host biological factors such as drug transporters have been implicated as key regulators of PrEP. Drug transporter expression levels and function have been identified as critical determinants of PrEP efficacy by regulating PrEP pharmacokinetics across various cells and tissues of the blood, renal tissues, FGT mucosal tissues and other immune cells targeted by HIV. In addition, biological factors such as genetic polymorphisms and genital inflammation also influence drug transporter expression levels and functionality. In this review, drug transporters and biological factors modulating drug transporter disposition are used to explain discrepancies observed in PrEP clinical trials. This review also provides insight at a pharmacological level of how these factors further increase the susceptibility of the FGT to HIV infections, subsequently contributing to ineffective PrEP interventions in African women.

Keywords: African women; PrEP (pre-exposure prophylaxis); drug transporters; female genital tract (FGT); inflammation; single nucleotid polymorphism (SNP).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Drug transporters most relevant in the efflux and influx of PrEP drugs. In the ABC (efflux) family there are three-drug transporter subfamilies along with their respective proteins that are the most relevant in the efflux of PrEP drugs, while in the SLC (influx/uptake) family, there are four drug transporter subfamilies along with their respective proteins that are the most relevant in the uptake or influx of PrEP.
FIGURE 2
FIGURE 2
Proposed mechanism of effects on drug transporter expression and function. The schematic shows the intersection of different biological factors and SNPs in drug transporter genes that affect drug transporter expression in the FGT, renal system and blood, subsequently affecting PrEP efficacy. Genital inflammation and SNPs are known to directly affect drug transporter expression and functionality, while the combined use of HCs and ARVs also affects drug transporter expression and function. Additionally, the presence of STIs and BV are shown to contribute to genital inflammation which in turn affects drug transporter expression and function. HC, Hormonal contraceptives; BV, Bacterial vaginosis; STIs, Sexually transmitted infections.
See this image and copyright information in PMC

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