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Efavirenz, Tenofovir, and FTC Levels Higher in Colonic Tissue Than Blood
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Concentrations of efavirenz, tenofovir, and emtricitabine (FTC) were higher in colon samples than in blood in a study of 10 people taking a suppressive Atripla regimen [1]. Contrary to results of previous studies, intracellular concentrations of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) did not correlate with parent drug concentrations in tissue.
HIV rapidly infiltrates gut-associated lymphoid tissue (GALT) and profoundly depletes CD4 cells there. Because the impact of long-term suppressive antiretroviral therapy had not been studied in chronically infected people, US researchers conducted this GALT biopsy study in 9 men and 1 woman with viral suppression below 50 copies in blood for more than 1 year while taking efavirenz, tenofovir, and FTC as Atripla. All had GALT biopsy via flexible sigmoidoscopy at a time corresponding to antiretroviral trough concentrations.
The 10 volunteers had a median age of 42 years (interquartile range [IQR] 37 to 49) and a median CD4 count of 532 (IQR 329 to 770). Four volunteers were African American. Median plasma concentrations were 91.7 ng/mL (IQR 77.9 to 157.9) for tenofovir, 331 ng/mL (IQR 280.6 to 968.3) for FTC, and 2619 ng/mL (IQR 1816 to 3239) for efavirenz. Median peripheral blood mononuclear cell (PBMC) concentrations stood at 103 fmol/million cells (IQR 71 to 138.5) for TFV-DP and 7274 fmol/million cells (IQR 5631 to 9151) for FTC-TP.
Median colonic tissue levels measured 857 ng/g (IQR 321 to 1693) for tenofovir, 538 ng/g (IQR 277 to 964) for FTC, and 2550 ng/g (IQR 1950 to 3630) for efavirenz. Intracellular colonic tissue levels were 833.9 fmol/mg (IQR 443.6 to 1351) for tenofovir and 239.0 fmol/mg (IQR 202.2 to 419.8) for FTC.
PBMC and tissue intracellular levels tended to correlate for FTC-TP (r = 0.64, P = 0.054) but not for TFV-DP (r = 0.04, P = 0.92). Tissue intracellular levels correlated poorly with tissue extracellular levels for both tenofovir (r = 0.50, P = 0.14) and FTC (r = 0.11, P = 0.75). Plasma and tissue concentrations correlated for efavirenz (r = 0.75, P = 0.017) for not for tenofovir or FTC.
Tissue-to-peripheral blood concentrations were greater than 1 (indicating higher drug levels in tissue than peripheral blood) for all three parent drugs and their metabolites.
Noting that "significant controversy remains regarding the most biologically meaningful way to express all antiretroviral drug levels in tissue," the researchers concluded that all three antiretrovirals studied reach a higher concentration in colonic tissue than blood during long-term suppressive therapy. The high levels attained in colonic tissue, the investigators proposed, could explain why CD4 recovery in GALT is similar to PBMC levels after successful antiretroviral therapy begins [2].
Lack of correlation between intracellular TFV-DP and FTC-TP concentrations and parent drug concentrations in tissue, the researchers proposed, could reflect "local metabolic and efflux pathways that vary widely at different levels in the GI tract." But they stressed that their findings demonstrate that the three antiretrovirals penetrate colonic tissue at levels equal to or exceeding those in peripheral blood.
References
1. Asmuth DM, Kashuba AD, Acosta EP, et al. Efavirenz/tenofovir/emtricitabine levels in colonic tissue. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract MOPE027.
2. Hayes TL, Asmuth DM, Critchfield JW, et al. Impact of highly active antiretroviral therapy initiation on CD4+ T-cell repopulation in duodenal and rectal mucosa. AIDS. 2013;27:867-877.
http://www.ncbi.nlm.nih.gov/pubmed/23262500
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