title: PHARMACOGENETIC AND PROTEIN BIOMARKERS ASSOCIATED WITH TENOFOVIR- INDUCED RENAL TOXICITY IN HIV-POSITIVE PATIENTS IN ZAMBIA
Creators: name: Hamachila, Audrey
Publisher: name: University of Liverpool Repository
Year: 2022

description: Tenofovir Disoproxil Fumarate-induced renal toxicity (TDF-RT) in HIV positive patients has been associated with genetic variants in genes encoding drug transporters. I set out to investigate the association of TDF-RT with previously reported single nucleotide polymorphisms (SNPs) in drug transporter genes (SLC22A11, ABCC2, ABCC4 and ABCC10), genes involved in Fanconi syndrome (FS) (OCRL1), and transmembrane (TMEM) and peroxisomal (PEX14 and ITSN) genes. I also performed validation of genetic markers identified from a GWAS in a cohort of UK HIV patients with TDF-FS. Finally, I explored the potential for novel kidney injury biomarkers for monitoring RT outcomes in treatment naïve patients initiated on TDF therapy. We recruited HIV positive patients who were receiving antiretroviral therapy containing TDF from the University Teaching Hospital (UTH) in Lusaka, Zambia, between 2007 and 2017. RT was defined by a creatinine clearance of &lt;60ml/min. 24 selected SNPs were genotyped by iplex MassARRAY® System and validated by TaqMan Real-Time PCR. 887 participants of whom 17.8% had RT were recruited. In the multivariate logistic regression, females (Odds ratio (OR),13.22; baseline age (OR,1.12,; BMI (OR, 0.50 and SCr (OR, 1.2) were independently associated with TDF-RT. 22 SNPs were analysed for an association with TDF-RT. None of the SNPs analysed was associated with TDF-RT. PEX14, rs284301 G&gt;A was significantly associated with RT (p&lt;0.012) but did not remain significant after adjusting for multiple testing. We identified novel haplotypes in the ABCC2 and PEX14 variants although they were not associated with TDF-RT. We also confirmed an association between TDF-FS and GWAS identified SNPs atTMEM120A, PEX14, and ITSN genes in a case-control study. The role of TMEM120A in adipocyte differentiation, ITSN as a key regulator in several signalling pathways and PEX14 in tubular β-oxidation of fatty acids and detoxification of ROS may represent alternative pathways and targets for the most serious TDF-RT phenotype, FS, this area needs further investigation. 52 treatment naïve HIV positive patients (aged ≥ 18 years) who were commenced on TDF ART were prospectively recruited to the biomarker study. Urine samples were collected at baseline, and at 2 and 4 weeks after TDF treatment to analyse KIM-1 and RBP4 corrected for urine creatinine. Participants were followed and monitored for TDF-RT events for up to 6 months. 12 (23.1%) presented with RT after a median of 3.5 months (IQR, 0.75–5.5 months) of TDF exposure. Both KIM-1/Cr (p=0.021) and RBP4/Cr (p=0.01) were significantly different after 4 weeks. KIM-1/Cr was significantly associated with RT outcomes (difference of means, 1.271ng/mg, 95% CI (0.26-2.52), p=0.046). The AUC for KIM-1/Cr (0.713) showed relatively good sensitivity in predicting RT compared to RBP4/Cr (0.462) and CrCl (0.64). Our findings indicate that baseline factors are important predictors of TDF-RT, but SNPs were not associated with TDF-RT in our cohort. However, a GWAS together with larger sample size is needed to investigate the contribution of unknown gene variants in the African population. We have identified some novel SNPs in patients with FS, but this will need further mechanistic and replication studies. We have also demonstrated that cumulative TDF exposure leads to tubular abnormalities and KIM-1 could be utilized to monitor and predict TDF-RT outcomes in HIV patients, but this will need further validation. The thesis highlights that it is possible to undertake mechanistic and genetic investigations in African patients with HIV, where the greatest burden of disease lies, to ensure that any findings and future interventions are relevant and appropriate.