Determinants of anti-retroviral therapy drug-related toxicities in HIV positive patients

Antiretroviral therapy (ART) drugs have increasingly been shown to contribute significantly to the morbidity of HIV positive patients exposed to them. This is more so with increasing survival of HIV patients since the introduction of ART. Individual ART drugs have been associated with specific organ related toxicities and clinical toxicity syndromes, such as Tenofovir disoproxil fumarate (TDF) association with risk of kidney injury. The pattern, pathogenesis, as well as key genetic and non-genetic determinants of some these clinical ART drug-related toxicity syndromes remains uncertain. This thesis sets out to investigate the pattern/clinical/laboratory phenotype of ART drug related kidney toxicity, including the role of emerging biomarkers that define and most accurately diagnose these toxicity syndromes. I, and my co-reviewer (Dr Sudeep Pushpakom, University of Liverpool) then systematically reviewed, and carried out a metanalysis of current evidence with regards to the reported genetic association between TDF exposure, and risk of kidney related toxicity. I further explored a population cohort (MHRA) to ascertain the pattern/clinical phenotype of kidney injury following exposure to TDF in these cohorts of patients, and determine any discernible variation as it relates to what has been reported from clinical trial cohorts. Additionally, I examined the association between single nucleotide polymorphisms (SNPs) of genes encoding protein transporters involved in the bio-disposition of TDF in HIV positive patients, with kidney injury following exposure to ART drugs. Specifically, in an attempt to explore the pattern of kidney injury in HIV patients exposed to TDF in observational databases, I reviewed 407 yellow card records of HIV positive patients on TDF who developed kidney injury and had them reported to MHRA. One hundred and six (106) of these satisfied criteria for TDF related kidney injury, of which 53 (50%) had features of kidney tubular dysfunction (KTD), 35 (33%) were found to have features of glomerular dysfunction, and 18 (17%) had Fanconi syndrome. The median TDF exposure was 316 days (IQR 120-740). The incidence of hospitalisation for TDF kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. To define the clinical phenotype (including surrogate markers) of ART drug related kidney injury, I recruited and investigated the diagnostic utility of KIM-1/Cr (corrected for urinary creatinine excretion) in a 114 cross-sectional cohort of HIV positive patients (104 “on” ART, and 10 “off” ART drugs). HIV positive patients both “on” and “off” ART drugs had a higher baseline median (≥4.17ng/mg), upper quartile (≥8.6ng/mg), and urinary KIM-1/Cr levels compared to either non-HIV positive normal volunteers (0.39 ng/mg), or those with acute kidney injury in the general population (0.57 ng/mg). By ROC analysis, KIM-1/Cr (ng/mg) had a higher AUC (0.67) compared to either serum creatinine (0.64) or eGFR (0.31) in diagnosing patients with kidney injury. When median KIM-1/Cr (≥4.17ng/mg) was utilised as a marker of kidney injury, TDF exposure (per year increase) was significantly associated with risk of kidney injury in multivariate analyses (Odds ratio 1.4, CI 1.02-1.82, P = 0.034). In a candidate gene based-based approach, I subsequently investigated the strength of association between the ABCC2 and ABCC10 sub-family genetic polymorphisms, and risk of kidney injury in HIV positive patients exposed to TDF. Patients with KTD had higher current CD4 cell counts, lower eGFR, and were less likely to possess the genotype CC at position 24 of the ABBC2 (MRP2, rs717620) gene. In multivariate analysis, genotype CC at position 24 of the ABBC2 gene (odds ratio =0.05, 95% confidence interval = 0.003-0.7, P = 0.027) was significantly associated with reduced risk of KTD. These findings support the observation that ART dugs are a leading cause of organ specific morbidity including TDF related kidney injury. Furthermore, we have demonstrated higher thresholds of low molecular weight proteinuria (including RBPCR and KIM-1/Cr) following TDF exposure, in HIV positive patients with normal kidney function (normal eGFR). Further work is required in prospective patient populations to validate some of the findings in our study including the potential diagnostic utility of low molecular weight proteinuria (KIM-1 and RBP) in these cohorts of patients. Additionally, there will be need to explore the clinical significance of possession of the ABCC2 24CC (rs717620) and ABCC10 SNP’s in an appropriately defined patient population