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

Inclusion Criteria

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.