Drug transporter expression and genetic polymorphisms in HIV endemic settings = Indlela yokuthutheka kwemithi emzimbeni nesakhiwo esingxube sofuzo ezimweni zokubhebhetheka kwesandulela ngculazi.

Abstract

Pre-exposure prophylaxis (PrEP) in the form of oral Truvada® remains the standard of care for HIV prevention in South Africa. Despite the availability of PrEP, HIV infections continue in young women significantly more than in men. Clinical trials testing antiretrovirals containing tenofovir as topical or oral PrEP formulations in African women, produced inconsistent patterns of efficacies against HIV. Effectiveness of oral and topical PrEP is dependent on adequate drug delivery and availability to cells and tissues targeted by HIV. Our study, therefore, focused on how different biological factors: drug transporter expression, single nucleotide polymorphisms (SNPs) in drug transporter genes and genital inflammation modulate PrEP disposition in African women. We characterized drug transporter mRNA expression in two compartments, the female genital tract (FGT) and blood, at baseline, 3 and 6 months in 45 women taking oral PrEP-Truvada®. Additionally, the impact of SNPs in 393 women and genital inflammation in 45 women on circulating tenofovir and drug transporter mRNA expression were determined. SNPs in drug transporter genes: ABCB1 3435G>A; ABCC1 198217T>C; ABCC2 1249G>A; ABCC4 3463T>C; ABCC4 4131A>C and ABCC4 4976A>G were evaluated using real-time PCR. mRNA expression of efflux P-gp, MRP-2, MRP-4, MATE-1 and influx OAT-1 and OAT-3 drug transporters was evaluated using quantitative real-time PCR. Genital inflammation was measured in cervicovaginal specimens using a 28-cytokine multiplexed platform. Results showed that ABCC4 4976A>G and ABCC4 3463T>C SNPs alter circulating tenofovir differently. While the ABCC4 4976A>G SNP significantly increased the mRNA expression of the ABCC4 gene (p=0.0132), there was inverse association with circulating tenofovir (p=0.018). In contrast, although the ABCC4 3463T>C SNP did not significantly impact mRNA expression of the ABCC4 gene, it was significantly and directly associated with circulating tenofovir (p<0.05). Correlation analyses showed moderately significant associations between the mRNA expression of the influx drug transporter OAT-1 in the FGT and blood pre- and post- PrEP exposure (rs<1, p<0.05). In contrast efflux drug transporters P-gp, MATE-1, MRP-2 and MRP-4 showed significance after PrEP initiation (3 and 6 months) (rs<1, p<0.05). For pro-inflammatory cytokines, linear mixed models showed negatively correlated trends between IL-1β and MCP-1 and influx drug transporter OAT-1 and OAT-3 (p<0.1), while IL1Rα and TNF-α showed these correlations with efflux drug transporters MRP-2 and MRP-4 (p<0.1). Collectively our results suggested that PrEP disposition can be modified through a convergence of host genetics and different biological factors: drug transporter expression, SNPs in drug transporter genes and inflammation. Findings from such studies may be used to better understand PrEP pharmacokinetics and aid in the implementation of optimal PrEP dosages. This 14 will ultimately inform on effective and safe PrEP for HIV prevention especially in vulnerable and at-risk African women.

Iqoqa.

ENingizimu Afrika ipre-exposure prophylaxis (PrEP) oral-Truvada® kuseyiyona ndlela yokunakekela ekuvimbeleni isandulela ngculazi, i-HIV. Kodwa ukutheleleka nge-HIV kuyaqhubeka kakhulu kwabesifazane abasebancane. Ukuvivinywa kwemithi lapho kuhlolwa i-PrEP egcotshwayo/neyasemlonyeni kulabo besifazane abangama-Afrika kuveza izimo ezingazinzile ekulweni ne-HIV. Ukuphumelela kwale mithi egcotshwayo/neyasemlonyeni kuncike kakhulu ekuhambisekeni komuthi okwanele nasebukhoneni bama-cells aqondwe ngqo yi-HIV; izinto ezihambisana nomzimba ezibalulekile zibonakele ekulawuleni ukusebenza kwe-PrEP ezindaweni ezithelelekile. Lolu cwaningo, lwabheka ukuthi izimo zomzimba: indlela yokuthuthwa komuthi emzimbeni, isakhiwo esisodwa ekuthuthweni komuthi emzimbeni isingle nucleotide polymorphisms (SNPs) kanye nokuvuvukala kwezitho zangasese kunomthelela muni ekusebenzeni kwePrEP kwabesifazane abangama-Afrika. Kwakhethwa isithuthi semithi i-mRNA-expression ngezindlela ezimbili: umgudu wezitho zangasese kwabesifazane, ifemale genital tract (FGT) kanye negazi, ekuqaleni kocwaningo, izinyanga ezi-3 neziyi- 6 kwabesifazane abangama-N=45 abathatha i-PrEP-Truvada® ngomlomo. Kwabe sekubhekwa i-mRNA-expression ye-P-gp, MRP-2, MRP-4, MATE-1 kanye ne-OAT-1 kanye ne-OAT-3 okuyizithuthi zemithi ezahlolwa kusetshenziswa ucwaningozibalo lwereal-time-PCR. Umthelela we-SNPs (N=393) kanye nokuvuvukala kwezitho zangasese (N=45) ekuzungeziseni i-tenofovir kanye nesithuthimithi i-mRNA-expression kwabonakala. Ukubonakala kwe-SNPs kwizithuthimithi zofuzo: ABCB1[3435G>A]; ABCC1[198217T>C]; ABCC2[1249G>A]; ABCC4[3463T>C]; ABCC4[4131A>C] kanye ne-ABCC4[4976A>G] kwahlolwa kusetshenziswa ireal-time-PCR. Ukuvuvukala kwezitho zangasese kwakalwa kumasampula ayethathwe ebuntwini babesifazane kusetshenziswa indlela ye-28-cytokine-multiplexed platform. Imiphumela yakhombisa ukuthi i-ABCC4[4976A>G] kanye ne-ABCC4[3463T>C] SNP ishintsha ukuzungeza kwetenofovir ngendlela ehlukile. I-ABCC4[4976A>G] SNP yakhulisa kakhulu i-mRNA-expression ye-ABCC4 gene (p=0.0132), kodwa yanomthelela ophambene ekuzungezeni kwetenofovir (p=0.018). Uma kuqhathaniswa, yize i-ABCC4[3463T>C] SNP ingabanga namthelela otheni kwi-mRNA-expression yofuzo i-ABCC4, yayamana kakhulu nokukhula ekuzungeziseni itenofovir (p<0.05). Ukuhlaziya kwalokhu kuhlobana kwakhombisa ukuhambisana okubalulekile phakathi kwe-mRNA-expression ye-OAT-1 kwiFGT kanye negazi ngaphambi nangemuva kokusetshenziswa kwe-PrEP. Kanti i-P-gp, MATE-1, MRP-2 kanye ne-MRP-4 kwakhombisa ukubaluleka emuva kokuqalwa kwe-PrEP ezinyangeni ezi-3 kuya kweziyi-6 (rs<1, p<0.05). Ekuvuvukaleni kwezitho zangasese, izindlela eziqondile ezingxube zakhombisa ukungahlobani phakathi kwe-IL-1β kanye ne-MCP-1 ene-OAT-1 kanye ne-OAT-3; IL-1Rα kanye ne-TNF-α ene-MRP-2 kanye ne-MRP-4 (p<0.1). Seyihlangene yonke le miphumela yakhombisa ukuthi ukusebenza kwe-PrEP kuyashintshashintsha ngokubambisana kwezimo ezahlukene emzimbeni: yindlela umuthi othutheka ngayo, ama-SNPs, kanye nokuvuvukala kwezitho zangasese. Imiphumela yalolu cwaningo ingasetshenziselwa ukuba kuqondwe kangcono amandla okusebenza kwe-PrEP kanye nokuqalwa kokukala ubungako bomuthi we-PrEP ngendlela efanele. Ngaleyo ndlela, kungaba nokusebenziseka ngempumelelo nangendlela ephephile kwe-PrEP ukuze kunqandwe isandulela ngculazi kwabesifazane bama-Afrika abasengcupheni.