Browsing by Author "Haas, David W"

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    Pharmacogenetics of Tenofovir (Alafenamide or Disoproxil Fumarate Prodrug) Renal Toxicity in HIV positive Black Southern Africans
    (2022) Mateza, Somila; Sinxadi, Phumla; Haas, David W; Maartens, Gary
    Background: Among individuals treated for HIV-1 infection, renal toxicity is more likely with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide (TAF). Limited previous studies suggest potential genetic associations with TDF-associated renal toxicity. We hypothesized that polymorphisms in genes of potential relevance to tenofovir, TDF and TAF disposition are associated with renal toxicity in people living with HIV in Southern Africa. Material and Methods: Adult participants randomized to initiate TAF or TDF (each given with emtricitabine) in the dolutegravir arms of the ADVANCE trial had the option to co-enrol in a pharmacogenetic sub-study. We assessed changes from week 4 (to minimize impact of early dolutegravir-induced increases in creatinine) to week 48 in estimated glomerular filtration rate (eGFRCKD-EPI), and log-transformed changes from baseline to week 48 in urine retinol binding protein and urine β2-microglobulin, each adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr, respectively). Genotyping was done using Illumina MEGAEX, followed by imputation with TOPMed. Genetic associations with each renal outcome (eGFR, uRBP/Cr and uB2M/Cr) were assessed using multivariable linear regression models adjusting for age, sex, treatment group, and screening body mass index, CD4 count, and log10 HIV-1 RNA. Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal tubular dysfunction, and all polymorphisms (+/- 50 kB) in selected genes of interest: ABCB1, ABCC2, ABCC4, ABCC10, ABCG2, AK2, AK3, CES1, CYP3A4, NME1, SLC22A2, SLC22A6, SLC22A8 and SLC22A11. We also explored associations genome-wide. Results: In ADVANCE, 336 participants randomized to either TAF or TDF consented to genetic testing. All were Black-African, 63% were female, median age was 32 years, CD4 count 292 cells/μL, and log10 HIV-1 RNA 4.4 copies/mL. Among the 14 polymorphisms of primary interest, the lowest Pvalues for change in eGFR, uRBP/Cr and uB2M/Cr were ABCC4 rs899494 (P = 0.021), ABCC10 rs2125739 (P = 0.07), and ABCC4 rs1059751 (P = 0.0087), respectively. Among genes of interest, the lowest P-values for change in eGFR, uRBP/Cr and uB2M/Cr were ABCC4 rs4148481 (P = 1.5x10-4 ), rs691857 (P = 3.2x10-4 ), and PKD2 rs72659631 (P = 8.6x10-4 ), respectively. In genome-wide analyses, the lowest P-values for change in eGFR, uRBP/Cr, and uB2M/Cr were COL27A1 rs1687402 (P = 3.2x10-9 ), CDH4 rs66494466 (P = 3.4 x 10-8 ), and ITGA4 rs3770126 (P = 4.5 x10-7 ), respectively. Conclusions: Among Southern African participants in a randomized trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, two polymorphisms previously associated with TDF renal toxicity, ABCC4 rs899494 and ABCC4 rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, but did not withstand correction for multiple testing (nor did associations in genes of interest). A polymorphism in COL27A1, which encodes collagen type XXVII alpha 1 chain, was genome-wide associated with change in eGFR. These findings enhance our understanding of the impact of human genetics on tenofovir-associated renal toxicity.
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    Pharmacogenomics and pharmacokinetics of antiretroviral drugs and their associations with metabolic complications in HIV-infected Black South Africans
    (2016) Sinxadi, Phumla Z; Maartens, Gary; Haas, David W
    BACKGROUND: Antiretroviral therapy (ART), notably efavirenz and lopinavir, have been associated with metabolic abnormalities known to increase cardiovascular risk. Efavirenz and lopinavir pharmacokinetics demonstrate considerable interindividual variability, which in part, may be explained by host genetic factors. Mitochondrial DNA (mtDNA) variation influences ART related metabolic complications. However, the associations between genetic polymorphisms and pharmacokinetics of antiretroviral drugs, and their associations with metabolic complications, are incompletely understood. We explored associations of mitochondrial DNA (mtDNA) haplogroups and ART related metabolic complications, characterized relationships between genetic polymorphisms and plasma efavirenz concentrations, and investigated associations between plasma efavirenz/lopinavir concentrations and lipid and glucose concentrations in HIVinfected Black South Africans. METHODS: We collected clinical and laboratory data from HIV infected patients on ART from Cape Town. We sequenced the mitochondrial genome and determined African mtDNA haplogroups. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport. We measured steady state efavirenz and lopinavir concentrations and used regression analyses to determine associations with metabolic parameters.