Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.

TitleGenomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.
Publication TypeJournal Article
Year of Publication2015
AuthorsWanga V, Venuto C, Morse GD, Acosta EP, Daar ES, Haas DW, Li C, Shepherd BE
JournalPharmacogenet Genomics
Volume25
Issue9
Pagination450-61
Date Published2015 Sep
ISSN1744-6880
KeywordsAcquired Immunodeficiency Syndrome, Adult, Anti-HIV Agents, Benzoxazines, Creatinine, Dideoxynucleosides, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Ritonavir, Tenofovir
Abstract

BACKGROUND: Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.

METHODS: Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.

RESULTS: Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).

CONCLUSION: Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

DOI10.1097/FPC.0000000000000156
Alternate JournalPharmacogenet. Genomics
PubMed ID26148204
PubMed Central IDPMC4522226
Grant ListAI-025859 / AI / NIAID NIH HHS / United States
AI-027658 / AI / NIAID NIH HHS / United States
AI-027661 / AI / NIAID NIH HHS / United States
AI-027675 / AI / NIAID NIH HHS / United States
AI-032782 / AI / NIAID NIH HHS / United States
AI-034853 / AI / NIAID NIH HHS / United States
AI-038855 / AI / NIAID NIH HHS / United States
AI-038858 / AI / NIAID NIH HHS / United States
AI-045008 / AI / NIAID NIH HHS / United States
AI-046370 / AI / NIAID NIH HHS / United States
AI-046376 / AI / NIAID NIH HHS / United States
AI-050409 / AI / NIAID NIH HHS / United States
AI-054907 / AI / NIAID NIH HHS / United States
AI-054999 / AI / NIAID NIH HHS / United States
AI-058740 / AI / NIAID NIH HHS / United States
AI-068634 / AI / NIAID NIH HHS / United States
AI-068636 / AI / NIAID NIH HHS / United States
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U01 AI025859 / AI / NIAID NIH HHS / United States
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U01 AI046370 / AI / NIAID NIH HHS / United States
U01 AI046376 / AI / NIAID NIH HHS / United States
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UL1 RR024156 / RR / NCRR NIH HHS / United States
UL1 RR024160 / RR / NCRR NIH HHS / United States
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UL1 RR024996 / RR / NCRR NIH HHS / United States
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UM1 AI069423 / AI / NIAID NIH HHS / United States
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UM1 AI069434 / AI / NIAID NIH HHS / United States
UM1 AI069439 / AI / NIAID NIH HHS / United States
UM1 AI069447 / AI / NIAID NIH HHS / United States
UM1 AI069450 / AI / NIAID NIH HHS / United States
UM1 AI069452 / AI / NIAID NIH HHS / United States
UM1 AI069465 / AI / NIAID NIH HHS / United States
UM1 AI069467 / AI / NIAID NIH HHS / United States
UM1 AI069470 / AI / NIAID NIH HHS / United States
UM1 AI069471 / AI / NIAID NIH HHS / United States
UM1 AI069472 / AI / NIAID NIH HHS / United States
UM1 AI069474 / AI / NIAID NIH HHS / United States
UM1 AI069477 / AI / NIAID NIH HHS / United States
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UM1 AI069494 / AI / NIAID NIH HHS / United States
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UM1 AI069496 / AI / NIAID NIH HHS / United States
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