Tenofovir Disoproxil Fumarate to Treat Pediatric HIV
This study will test the safety, side effects and antiviral activity of different doses of tenofovir DF in children and adolescents with human immunodeficiency virus (HIV) infection. Tenofovir DF belongs to a group of drugs called nucleotide analog reverse transcriptase inhibitors. These drugs prevent the virus from replicating (making more copies of itself).
HIV becomes resistant to many drugs used to fight the virus and these drugs become ineffective. In laboratory tests, tenofovir DF has remained effective against HIV longer than other anti-HIV medicines, and when resistance does develop, the virus may still be sensitive to other drugs.
HIV-infected children between the ages of 4 and 18 years who weigh at least 10 kg (22 pounds) may be eligible for this study. They must be able to receive antiretroviral therapy and have completed at least two previous antiretroviral courses of treatment without benefit.
Upon entering the study, participants will have physical, eye and neuropsychiatric examinations, blood tests, including tests to determine what anti-HIV drugs the patient is resistant to, an echocardiogram (echo), electrocardiogram (EKG), chest X-ray, head CT scan, skin tests, and special tests to examine the bones. These physical exams and tests will be repeated throughout the study to determine changes in health.
Participants will continue their current anti-HIV therapy for 2 weeks and then stop all medicines for a 1-week 'washout' period. After the washout period, patients will begin taking tenofovir DF. For the first 2 days on the drug, a small blood sample (1/2 teaspoon) will be collected 11 times over a 48-hour period through. A heparin lock (a tube kept in place in a vein) may be put in place to avoid multiple needle sticks. Blood samples will be collected for another 4 days to measure how well tenofovir DF alone works against HIV before other drugs are added to the treatment regimen. After these first 6 days, at least two other anti-HIV drugs will be added. They will be selected based on the results of the earlier blood tests for resistance and on the child's medication history.
After 3 days of combination therapy, patients will continue therapy on an outpatient basis. They will be seen in the clinic every 4 weeks at the start of the study and then every 12 weeks for physical exams, lab tests and other procedures as needed. The study will last approximately 48 weeks. Patients who benefit from therapy may be able to continue to receive tenofovir DF from the drug company sponsor or as part of another study, or the protocol for this study may be amended to lengthen the treatment period.
|Study Design:||Endpoint Classification: Safety Study
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Tenofovir Disoproxil Fumarate (PMPA Prodrug), A Novel Nucleotide Analog Reverse Transcriptase Inhibitor in Children With HIV Infection|
|Study Start Date:||October 2001|
|Estimated Study Completion Date:||September 2005|
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.
|United States, Maryland|
|National Cancer Institute (NCI)|
|Bethesda, Maryland, United States, 20892|