Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.

TitleDiscordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhang X, Tierney C, Albrecht M, Demeter LM, Morse G, DiFrancesco R, Dykes C, Jiang H, Haas DW
JournalTher Drug Monit
Volume35
Issue2
Pagination209-16
Date Published2013 Apr
ISSN1536-3694
KeywordsAcquired Immunodeficiency Syndrome, Adult, Female, Genetic Association Studies, HIV Protease Inhibitors, Humans, Linkage Disequilibrium, Male, Middle Aged, Organic Anion Transporters, Ritonavir
Abstract

OBJECTIVE: Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants.

METHODS: At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms.

RESULTS: Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons.

CONCLUSIONS: With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.

DOI10.1097/FTD.0b013e318280d0ad
Alternate JournalTher Drug Monit
PubMed ID23503447
PubMed Central IDPMC3603284
Grant ListA1069424 / / PHS HHS / United States
A1069447 / / PHS HHS / United States
AI050409 / AI / NIAID NIH HHS / United States
AI050410 / AI / NIAID NIH HHS / United States
AI062435 / AI / NIAID NIH HHS / United States
AI069415 / AI / NIAID NIH HHS / United States
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AI69432 / AI / NIAID NIH HHS / United States
AI69450 / AI / NIAID NIH HHS / United States
AI69467 / AI / NIAID NIH HHS / United States
AI69501 / AI / NIAID NIH HHS / United States
AL069532 / / PHS HHS / United States
AL27665 / / PHS HHS / United States
BRS-ACURE-06-00140-T001 / / PHS HHS / United States
NS32228 / NS / NINDS NIH HHS / United States
R01 AI077505 / AI / NIAID NIH HHS / United States
RR00044 / RR / NCRR NIH HHS / United States
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RR025747 / RR / NCRR NIH HHS / United States
TR000445 / TR / NCATS NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
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UL1 TR000457 / TR / NCATS NIH HHS / United States
UM1 AI068632 / AI / NIAID NIH HHS / United States
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