Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy

Brigitte E Sanders-Beer,Diane Hebblewaite,Abigail Lara,Lourdes Nieves-Duran,Yvette Y Spano,Lowrey Rhodes,Dawn Golighty,Keith G Mansfield

doi:10.1186/1742-6405-8-3

Abstract

BackgroundIn 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).ResultsIn 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.ConclusionsRecommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies.

Highlights

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
Previous work of others has revealed that long-term administration of PMPA at 30 mg/kg resulted in a Fanconi-like syndrome with glucosuria, aminoaciduria, hypophosphatemia, growth restriction and bone pathology [2]
Viral load was very efficiently controlled by ART, dropping below the assay detection limit (

Summary

Introduction

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. PMPA is the biologically active metabolite of the prescription drug Viread® It is commonly used in SIV pathogenesis studies because it can be administered by the parenteral route and is highly effective at reducing viral loads. The serum biochemical correlates of renal morphologic alterations in SIV-infected macaques that received PMPA, d4T and FTC combination therapy are described and guidelines to prevent and identify serious renal sequellae in future experiments are proposed

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