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 ϳ10 g ⅐ 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.Because at present it is not possible to cure human immunodeficiency virus (HIV) infection, prolonged treatment with combinations of anti-HIV drugs is required in order to prevent disease progression. The feasibility of giving HIV-infected persons a normal life span through chronic treatment will be determined by a number of factors, including compliance and cost, but especially the long-term safety and efficacy of the drugs.The nucleotide reverse transcriptase (RT) inhibitor tenofovir {TFV; 9-[2-(phosphonomethoxy)propyl]adenine}, in the form of its orally bioavailable prodrug TFV disoproxil fumarate (TDF), has become one of the most commonly used anti-HIV drugs due to its favorable efficacy and safety profile, based on data collected over more than 7 years for HIV-infected adults (12,24,35,37,47,49).The acyclic nucleoside phosphonates cidofovir, adefovir, and TFV are renally excreted by a combination of glomerular filtration and active tubular secretion (14,15,18,38). The effective uptake of acyclic nucleoside phosphonates by organic anion transporters in proximal tubules leads to accumulation in tubular cells and dose-limiting toxicity in animals (5, 63). Renal toxicity is usually manifested as renal insufficiency and proximal renal tubular dysfunction (PRTD). Dur...

BackgroundHIV reservoirs are rapidly established after infection, and the effect of HAART initiated very early during acute infection on HIV reservoirs remains poorly documented, particularly in tissue known to actively replicate the virus. In this context, we used the model of experimental infection of macaques with pathogenic SIV to assess in different tissues: (i) the effect of a short term HAART initiated at different stages during acute infection on viral dissemination and replication, and (ii) the local concentration of antiviral drugs.ResultsHere, we show that early treatment with AZT/3TC/IDV initiated either within 4 hours after intravenous infection of macaques with SIVmac251 (as a post exposure prophylaxis) or before viremia peak (7 days post-infection [pi]), had a strong impact on SIV production and dissemination in all tissues but did not prevent infection. When treatment was initiated after the viremia peak (14 days pi) or during early chronic infection (150 days pi), significant viral replication persists in the peripheral lymph nodes and the spleen of treated macaques despite a strong effect of treatment on viremia and gut associated lymphoid tissues. In these animals, the level of virus persistence in tissues was inversely correlated with local concentrations of 3TC: high concentrations of 3TC were measured in the gut whereas low concentrations were observed in the secondary lymphoid tissues. IDV, like 3TC, showed much higher concentration in the colon than in the spleen. AZT concentration was below the quantification threshold in all tissues studied.ConclusionsOur results suggest that limited antiviral drug diffusion in secondary lymphoid tissues may allow persistent viral replication in these tissues and could represent an obstacle to HIV prevention and eradication.

The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a di-anion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine if oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil's lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t 1/2 ) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t 1/2 of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety not only enhances the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and gives valuable insight for future prodrug development.