Effect of Tenofovir DF on Bone Metabolism in Children
Effect of Tenofovir DF on Bone Metabolism in Children
This study will examine the long-term effects, particularly on bone metabolism, of the drug
 tenofovir DF in children with HIV infection. Tenofovir DF is approved for treating
 HIV-infected adults, but its use in children has not yet been approved. The drug may be
 helpful for children who have been treated with many other drugs and still have detectable
 HIV in their blood despite ongoing therapy. In a previous study, many children given
 tenofovir DF responded well, with increases in T-cell counts and decreases in viral load.
 However, many children also experienced bone thinning. This study will explore the problem of
 bone thinning in children taking tenofovir DF in combination with highly active
 antiretroviral therapy (HAART).

 HIV-infected patients from 4 to 20 years old who are taking tenofovir DF or for whom
 tenofovir DF treatment has been recommended may be eligible for this 3-year study.

 Participants take tenofovir DF every day in addition to their antiretroviral therapy. They
 have frequent follow-up visits for tests and procedures as follows:

 -  Study days 0, 2, and 4: blood tests.

 -  Screening and every study visit starting day 6: Physical exam, medical history, blood
 and urine tests.

 -  Baseline and every 48 weeks: Dental and eye examinations, kidney ultrasound, tuberculin
 skin testing, chest x-ray, electrocardiogram and echocardiogram, computed tomography
 (CT) scan, neuropsychological testing and neurologic assessment.

 -  The bone age hand x-rays are done every 24 weeks, unless the growth plates are fused
 (i.e. the child has stopped growing)

 -  DEXAs are done at 0, 12, 24 weeks and every 24 weeks thereafter. Dual energy x-ray
 absorptionometry (DEXA) scan is used to assess bone density. The patient lies still on a
 table while the spine and hip are scanned using a small amount of radiation. Only the
 spine and hip are scanned in the DEXA scan test.

 -  Baseline and week 24: Optional bone biopsy. Some patients are asked to undergo a bone
 biopsy to better understand the effect of Tenofovir DF on bone. For the procedure, the
 child is given a sedative. The skin over the hipbone is numbed with a small needle, a
 small incision is made and a larger needle is inserted into the bone. Some of the bone
 tissue is withdrawn through the needle and the incision is closed.

 -  Possible lumbar puncture (spinal tap): This optional procedure analyzes cerebrospinal
 fluid (CSF), the fluid that bathes the brain and spinal cord. The patient is given a
 local anesthetic and a needle is inserted into the space between the bones in the lower
 back where the CSF circulates below the spinal cord. A small amount of fluid is
 collected through the needle. There is no specific schedule for this procedure if the
 patient opts for it.

 Patients who are benefiting from tenofovir DF therapy but show signs of bone effects are
 offered treatment with pamidronate (Aredia), a drug used to treat hypercalcemia (too much
 calcium in the blood). Patients who stop taking tenofovir DF because of bone toxicity
 continue to be followed on the regular study schedule. Those who stop the drug for toxicity
 other than bone toxicity or for toxicity not related to tenofovir DF are followed every 4
 weeks until their laboratory test results improve.
Tenofovir disoproxil fumarate (TDF) was approved for the treatment of HIV-infected adults in
 October 2001. In November 2001, we began enrollment to our phase I/II study of tenofovir DF
 in HIV-infected children (02-C-0006). That study has completed enrollment. The virologic and
 immunologic responses seen on that study in a group of heavily treatment-experienced children
 with multidrug resistant HIV were surprisingly good. The drug was well tolerated, but
 significant decreases in bone mineral density were seen in a minority of patients.

 With the current study we will enroll and systematically investigate HIV-infected children
 for whom tenofovir DF is being used as part of salvage combination HIV therapy. The primary
 objective of the study is to characterize the change in bone mineral density (BMD), as
 measured by lumbar spine dual-energy x-ray absorptiometry (DEXA), during and following
 treatment with tenofovir DF-containing antiretroviral therapy in HIV-infected children. The
 study will enroll 3 cohorts of children: 1) HIV-infected children about to start a tenofovir
 DF-containing antiretroviral regimen, 2) HIV-infected children already on tenofovir DF with
 available baseline DEXA results, and 3) HIV-infected children already on tenofovir DF but
 without baseline DEXA results who will come here for investigations of bone metabolism.
 Studies of bone metabolism will include periodic measurements of serum and urine calcium and
 phosphorus, PTH and vitamin D levels, bone resorption markers (urinary collagen cross-linked
 N-telopeptide and free deoxypyridinoline), bone formation markers (serum osteocalcin and bone
 specific alkaline phosphatase), IGF-1 levels, bone age, and DEXA scans. Patients about to
 start tenofovir DF (cohort 1) will be offered the option of having a transiliac crest core
 bone biopsy with tetracycline labeling performed at baseline and at 6 months to assess static
 and dynamic parameters of bone quality and turnover (histomorphometry). Subjects with
 substantial presumed tenofovir DF-related bone toxicity who are deriving benefit from their
 tenofovir DF-containing antiretroviral drug regimen will be offered the option of pamidronate
 therapy. The effects of pamidronate treatment on bone toxicity associated with tenofovir DF
 in these patients will be assessed in an exploratory fashion. It is expected that up to 40
 patients with baseline BMD measurements will be enrolled onto this protocol. An additional 10
 patients who are undergoing tenofovir DF treatment but who did not receive baseline BMD
 measurements will also be permitted to enroll in order to contribute to the data used to
 characterize changes in toxicity.
INCLUSION CRITERIA: Cohort 1 - patients about to start tenofovir DF

 -  HIV-infected children between the ages of 4 years and less than 21 years.

 -  Clinical decision has been made to start the patient on tenofovir DF-containing
 antiretroviral regimen

 -  BSA greater than or equal to 0.85 m2

 -  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.

 -  Not pregnant or breast feeding

 -  25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed)

 -  Less than or equal to grade 1 serum calcium or ionized calcium (supplementation
 allowed)

 -  AST and ALT less than or equal to 7.5 times the upper limit of normal

 -  Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal
 to 70 mL/min/1.73.

 -  Informed consent: patient, parent or legal guardian 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.

 INCLUSION CRITERIA: Cohort 2 - patients already being treated with tenofovir DF who have
 baseline DEXA available

 -  HIV-infected children between the ages of 4 years and less than 21 years.

 -  Current tenofovir DF-containing antiretroviral regimen was started less than 6 months
 ago

 -  Baseline DEXA for L-spine BMD is available and was performed less than six months
 prior to or within the first week of starting tenofovir DF

 -  BSA greater than or equal to 0.85 m2

 -  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.

 -  Not pregnant or breast feeding

 -  25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed)

 -  Less than or equal to grade 1 serum calcium or ionized calcium (supplementation
 allowed)

 -  AST and ALT less than or equal to 7.5 times the upper limit of normal

 -  Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal
 to 70 mL/min/1.73.

 -  Informed consent: patient, parent or legal guardian 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.

 INCLUSION CRITERIA: Cohort 3 - patients already being treated with an antiretroviral
 regimen that includes tenofovir DF who DO NOT have baseline DEXA available

 -  HIV-infected children between the ages of 4 years and less than 21 years.

 -  Current antiretroviral regimen includes tenofovir DF

 -  Baseline (within prior 6 months) DEXA for L-spine BMD is NOT available

 -  BSA greater than or equal to 0.85 m2

 -  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.

 -  Not pregnant or breast feeding

 -  25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed)

 -  less than or equal to grade 1 serum calcium or ionized calcium (supplementation
 allowed)

 -  AST and ALT less than or equal to 7.5 times the upper limit of normal

 -  Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance
 greater than or equal to 70 mL/min/1.73.

 -  Informed consent: patient, parent or legal guardian 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.

 INCLUSION CRITERIA: Eligibility criteria for pamidronate therapy (after enrollment on
 protocol)

 One of the following while on tenofovirDF-containing antiretroviral regimen:

 -  Greater than 6% loss in L-spine BMD in the presence of a BMD Z score less than -2.5 at
 6 months compared to baseline

 -  Minimal trauma fracture

 -  BMD Z-score less than -3

 AND

 One of the following while on tenofovirDF-containing antiretroviral regimen:

 -  Greater than or equal to 0.5 log decrease in VL from baseline

 -  Greater than or equal to 25% increase in absolute CD4 count from baseline

 Improvement in HIV-related signs or symptoms

 OR

 BMD Z-score less than -3 (i.e., pamidronate therapy will also be considered for subjects
 whose BMD Z score is less than -3 at baseline)

 -  Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance
 greater than or equal to 70 mL/min/1.73.

 -  Less than or equal to grade 1 serum phosphate, magnesium, and potassium
 (supplementation allowed)

 -  Not pregnant or breast feeding

 -  No history of hypersensitivity to bisphosphonates

 INCLUSION CRITERIA: Eligibility criteria for bone biopsy (after enrollment on protocol)

 -  No history of bleeding abnormality

 -  No history of hypersensitivity or intolerance to tetracycline or related drugs

 -  Normal CBC and PT/PTT

 -  BMD Z-score greater than -3

 -  Informed consent: patient, parent or legal guardian must sign a separate informed
 consent to document their understanding of the investigational nature and the risks of
 the bone biopsy.