ABSTRACT
Aim: We investigated if single-nucleotide polymorphisms (SNPs) in ATP-binding cassette (ABC) drug transporters alter gene expression and tenofovir disposition in South African women taking Truvada® for HIV prevention. Materials & methods: In 393 women, real-time PCR was used to determine the associations between six SNPs in ABC transporter genes, mRNA expression and circulating-tenofovir. Results: Univariable and multivariable analyses showed that CT and TT relative to CC genotypes for the ABCC4(3463C/T) SNP had significantly higher tenofovir levels. In contrast, the AA genotype for the ABCC4(4976A/G) SNP showed significantly less tenofovir, while mRNA expression was increased. Conclusion: SNPs in the ABCC4 gene may differentially affect gene expression and circulating tenofovir. Their impact may inform on low pre-exposure prophylaxis efficacy and discern effective drugs in clinical trials of African women enriched for certain genotypes.
Subject(s)
Anti-HIV Agents , HIV Infections , Pre-Exposure Prophylaxis , Humans , Female , Tenofovir/therapeutic use , Polymorphism, Single Nucleotide/genetics , ATP-Binding Cassette Transporters/genetics , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/prevention & control , South Africa , RNA, Messenger , Anti-HIV Agents/therapeutic useABSTRACT
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.