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A Phase I Study of Tenofovir Disoproxil Fumarate (PMPA Prodrug), A Novel Nucleotide Analog Reverse Transcriptase Inhibitor in Children With HIV Infection

Phase 1
Not Enrolling
HIV Infection

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Trial Information

A Phase I Study of Tenofovir Disoproxil Fumarate (PMPA Prodrug), A Novel Nucleotide Analog Reverse Transcriptase Inhibitor in Children With HIV Infection

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
( (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

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

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.


Therapeutic regimens including:

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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

October 2001

Completion Date:

September 2005

Related Keywords:

  • HIV Infection
  • Genotypic Resistance
  • Phenotypic Resistance
  • Immune Reconstitution
  • Bone Density
  • HIV
  • Children
  • Pediatric HIV Infection
  • HIV Infections
  • Acquired Immunodeficiency Syndrome



National Cancer Institute (NCI) Bethesda, Maryland  20892