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Antimicrob. Agents Chemother. doi:10.1128/AAC.00350-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Chronic administration of tenofovir to rhesus macaques from infancy throughout adulthood and pregnancy: summary of pharmacokinetics, biological and virological effects

California National Primate Research Center, University of California, Davis, CA 95616; Gilead Sciences, Foster City, CA 94404; Allevia AG, Bern, Switzerland

^* To whom correspondence should be addressed. Email: kkvanrompay{at}ucdavis.edu.

	Abstract

The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of HIV infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged ( 1 to 13 years) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction; PRTD) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold TFV plasma AUC of 10 µg.h/ml, an exposure several fold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistries, bone mineral density and clinical observations. At low maintenance regimens, plasma concentrations of TFV and intracellular concentrations of TFV diphosphate were similar or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by 10 years of age, one macaque, on TFV treatment since birth, has produced 3 offspring that were healthy by all criteria up to 5 years of age. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for up to 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout the development from infancy to adulthood, including pregnancy.