Tenofovir Disoproxil Fumarate to Treat Pediatric HIV
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.
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.
INCLUSION CRITERIA

 HIV-infected children between the ages of 4 years and less than 18 years.

 BSA greater than or equal to 0.50 (m(2))

 An indication for treatment with antiretrovirals as defined by the 2001 Guidelines for the
 Use of Antiretroviral Agents in Pediatric HIV Infection (one of the following):

 Clinical symptoms associated with HIV infection (i.e., clinical categories A, B, or C);

 Evidence of immune suppression indicated by CD4 T-lymphocyte count or percentage (i.e.,
 immune category 2 or 3);

 High or increasing HIV RNA copy number;

 Rapidly declining CD4 T-lymphocyte number or percentage to values approaching those
 indicative of moderate immune suppression (i.e., immune category 2).

 Children failing at least their second antiretroviral regimen as defined by the 2001
 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
 (http://www.hivatis.org/) (one of the following):

 Less than a 10-fold decrease from baseline viral load in patients on a HAART regimen
 (combination regimen that includes a PI and/or NNRTI) after 8-12 weeks of therapy;

 Less than a 5-fold decrease in viral load from baseline in patients on non-HAART regimen
 (e.g., dual NRTI combinations);

 Viral load not suppressed to undetectable levels after 4-6 months of antiretroviral
 therapy;

 Repeated detection of HIV RNA in patients who initially responded to antiretroviral therapy
 with undetectable levels;

 An increase in viral load of greater than 3-fold;

 Change in immunologic classification;

 For children in immunologic category 3, a decline of five percentiles or more in CD4 cell
 percentage;

 A greater than 30% decline in absolute CD4 cell count;

 Progressive neurodevelopmental deterioration;

 Disease progression;

 Intolerant to or showing evidence of toxicity from other antiretroviral treatments.

 HIV RNA greater than or equal to 10,000 copies/mL within the past 3 months (may be from
 outside institution);

 Ability to swallow tablets.

 Sexually active patients must be willing to use a medically acceptable form of birth
 control, which includes abstinence, while they are being treated on this study.

 Hematologic function: Total WBC greater than 1,500/mm(3), Absolute Neutrophil Count greater
 than 750/mm(3), hemoglobin greater 8.0 gm/dL and platelet count greater than 75,000/mm(3)
 at study entry.

 Hepatic function: Liver transaminases must be less than or equal 3.0 times the upper limit
 of normal; lipase less than 1.5 times the upper limit of normal; Creatinine phosphokinase
 (CPK) less than 2.5 times the upper limit of normal.

 Renal function: patients must have an age-adjusted normal serum creatinine OR a creatinine
 clearance greater than or equal to 70 mL/min/1.73.

 Informed Consent: All patients or one of their parents or legal guardians (if the patient
 is less than 18 years old) must sign the study informed consent to document their
 understanding of the investigational nature and the risks of the study before any
 protocol-related studies are performed.

 EXCLUSION CRITERIA

 Therapeutic regimens including:

 -  Nephrotoxic agents: aminoglycoside antibiotics, IV amphotericin B, cidofovir,
 cisplatin, foscarnet, IV pentamidine, oral and IV vancomycin, oral and IV ganciclovir;

 -  Immunomodulating agents (within 30 days of entry), other than GCSF, erythropoeitin,
 corticosteroids, IVIG, or anti-D;

 -  Treatment with chemotherapeutic agents (including hydroxyurea) or radiation therapy
 within the past 6 weeks; or

 -  Current use, or use within the last 28 days, of any investigational agent.

 Clinically significant, unrelated systemic illness (serious infections or significant
 cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment of the
 Principal Investigator or Chairperson would compromise the patient's ability to tolerate
 this therapy or is likely to interfere with the study procedures or results

 Weight less than 10 kg

 Pregnant or breast feeding females will be excluded from this trial. Women of childbearing
 potential must be willing to agree to avoid becoming pregnant while on study and for 4
 months afterwards.