Tenofovir Disoproxil Fumarate to Treat Pediatric HIV

This is a pediatric phase I study to determine a biologically active dose and to obtain information concerning the safety, tolerability, and pharmacokinetics of tenofovir disoproxil fumarate (TDF, (9 - \[(R)-2\[\[bis \[\[isopropoxycarbonyl) oxy\] methoxy\] phosphinyl\] -methoxy\]propyl\] adenine fumarate (1:1)), formerly known as PMPA prodrug, a potent nucleotide analogue HIV-1 reverse transcriptase (RT) inhibitor, that demonstrates antiviral activity against most NRTI-resistant HIV-1. In addition to obtaining needed biological activity, pediatric safety, tolerability, and pharmacokinetic data, the study will utilize tenofovir DF's potent antiretroviral activity and novel resistance mutation pattern, together with serial measurements of plasma HIV viral load, T-cell flow cytometry, and genotypic and phenotypic viral resistance analysis to conduct pilot studies in pediatric HIV pathogenesis, the response to antiretroviral therapy and to develop strategies to optimize the management of pediatric antiretroviral therapy. We will also use initial viral decay dynamics and other patient characteristics to model prediction for the long-term response to antiretroviral therapy. We will enroll children who have become refractory to or have experienced toxicity on prior antiretroviral therapy. Initial viral genotyping and phenotyping will be performed on the failing regimen, and this data will be used to create the most effective combination regimen with tenofovir DF. After an initial 6 days of tenofovir DF monotherapy, patients will receive tenofovir DF in combination with the optimal antiretroviral therapy as determined by their baseline viral resistance mutation pattern and history. The patients will be followed for at least 96 weeks to assess long-term tolerability and toxicity, and to assess the clinical, virological, and immunological response to tenofovir DF.