Research
Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy
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* Corresponding author: Brigitte E Sanders-Beer bsanders@bioqual.com
1 Southern Research Institute, Frederick, MD, USA
2 Harvard Medical School, New England Primate Research Center, Southborough, MA, USA
3 BIOQUAL, Inc., 9600 Medical Center Drive, Rockville, MD 20850, USA
4 Vaccine Research Program, Division of AIDS/NIAID/NIH, 6700B Rockledge Drive, Bethesda, MD 20817, USA
AIDS Research and Therapy 2011, 8:3 doi:10.1186/1742-6405-8-3
Published: 21 January 2011Abstract
Background
In many preclinical AIDS research studies, antiretroviral therapy (ART) is administered to experimentally simian immunodeficiency (SIV)-infected rhesus macaques for reduction of viral load to undetectable levels. Prolonged treatment of macaques with a high dose of PMPA (9-[2-(r)-(phosphonomethoxy) propyl] adenine or tenofovir; 30 mg/kg of body weight subcutaneously once daily) can result in proximal renal tubular dysfunction, a Fanconi-like syndrome characterized by glucosuria, aminoaciduria, hypophosphatemia, and bone pathology. In contrast, chronic administration of a low dose of PMPA (10 mg/kg subcutaneously once daily) starting at birth does not seem to be associated with any adverse health effects within 3 years of treatment. In contrast to PMPA, limited information on systemic toxicity in rhesus monkeys is available for FTC (5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; emtricitabine) and stavudine (d4T).
Results
In this study, the clinical and biochemical correlates of tubular nephrosis in SIV-infected rhesus macaques associated with systemic administration of high-dose ART consisting of the three nucleoside analog inhibitors PMPA, FTC, and d4T were investigated. It was found that acute renal failure was uncommon (7.1% of treated animals) and that morphologic evidence of nephropathy, which persisted for more than 300 days following discontinuation of the drug cocktail, was more frequent (52.4% of treated animals). While parameters from single time points lacked predictive value, biochemical alterations in Blood Urea Nitrogen (BUN) and phosphorus were frequently identified longitudinally in the blood of ART-treated animals that developed evidence of nephropathy, and these longitudinal changes correlated with disease severity.
Conclusions
Recommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies.