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Antimicrobial Agents and Chemotherapy, September 2008, p. 3144-3160, Vol. 52, No. 9
0066-4804/08/$08.00+0 doi:10.1128/AAC.00350-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Chronic Administration of Tenofovir to Rhesus Macaques from Infancy through Adulthood and Pregnancy: Summary of Pharmacokinetics and Biological and Virological Effects
Koen K. A. Van Rompay,1*
Lucie Durand-Gasselin,2
Laurie L. Brignolo,1
Adrian S. Ray,2
Kristina Abel,1
Tomas Cihlar,2
Abigail Spinner,1
Christopher Jerome,3
Joseph Moore,1
Brian P. Kearney,2
Marta L. Marthas,1
Hans Reiser,2 and
Norbert Bischofberger2
California National Primate Research Center, University of California, Davis, California 95616,1 Gilead Sciences, Foster City, California 94404,2 Allevia AG, Bern, Switzerland3
Received 12 March 2008/ Returned for modification 21 April 2008/ Accepted 16 June 2008
The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (
1- to 13-year) 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 area under the concentration-time curve for TFV in plasma of 
10 µg·h/ml, an exposure severalfold 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 chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to 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 the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. 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 as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.
* Corresponding author. Mailing address: California National Primate Research Center, University of California, Davis, CA 95616. Phone: (530) 752-5281. Fax: (530) 754-4411. E-mail: kkvanrompay{at}ucdavis.edu
Published ahead of print on 23 June 2008.
Antimicrobial Agents and Chemotherapy, September 2008, p. 3144-3160, Vol. 52, No. 9
0066-4804/08/$08.00+0 doi:10.1128/AAC.00350-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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