Vitamin D Absorption in HIV Infected Young Adults Being Treated With Tenofovir Containing cART

This is a 48 week randomized double-blind, placebo-controlled prospective cohort study of
adolescents and young adults with HIV infection in the ATN who are currently being treated
with cART that includes TDF as one component of the regimen that includes at least three Food
and Drug Administration (FDA)-approved ARVs for at least 180 days. Subjects must have at
least one documented viral load that is below 200 copies/mL that is collected following
initiation of TDF containing cART and greater than 90 days prior to randomization; no viral
load above 200 copies/mL if measured within the 90 days prior to randomization; and an HIV
viral load obtained at screening that is below 200 copies/mL.

Treatment assignments will be balanced by subject sex at birth, age (<20 years vs. >=20
years), and race (African American vs. other). Enrolled subjects will be randomized to
receive vitamin D3 50000 IU or matching placebo, given orally every four weeks by DOT. In
addition to the randomized study agent, all subjects will receive a MVI to be taken orally
once daily. This "standard" MVI will contain ingredients not to exceed 600 IU of vitamin D3
and 200 mg Ca.

Dual energy x-ray absorptiometry (DXA) measurement of bone mineral content (BMC)/bone mineral
density (BMD) of whole body, spine, and hip, will be performed at baseline and study weeks 24
and 48. Blood and urine sampling to assess the Ca-phosphorous (PO4) axis, parathyroid hormone
(PTH)-FGF23-vitamin D signaling, bone turnover, and renal glomerular and tubular function
will occur at baseline and study weeks 12, 24, and 48. Blood samples to measure Gluc
homeostasis will be drawn at baseline and week 48, and will be run by batch analysis.

Safety, measured by serum calcium (SCa) and serum creatinine (SCr), will be monitored by
subject's record review at study sites since these labs will generally be measured as a part
of routine clinical care. The Adolescent Medicine Trials Network for HIV/AIDS Interventions
109 (ATN 109) study will use the SCa and SCr values obtained within 10 weeks at the time of
the visit beginning at the baseline visit. If these evaluations were not performed within the
prior 10 weeks they will be drawn at the time of each visit. Viral load and cluster of
differentiation 4 (CD4) cell count results will be recorded for this study, ATN 109, at
screening, baseline and study weeks 12, 24, 48, and Post-Week 48 provided the evaluations
were done within the protocol specified timeframe. If the evaluations were not performed
within the protocol specified timeframes they will be drawn at the time of the visit.

Inclusion Criteria:

To be considered eligible for enrollment, an individual must meet the criteria listed below
at the time of randomization:

NOTE: If the DXA scan is scheduled prior to randomization, all eligibility criteria must be
met prior to performing the DXA scan.

- Age 16 years and 0 days to 24 years and 364 days;

- Behaviorally infected with HIV (e.g., sexual contact, injection drug use; not infected
by perinatal transmission, blood transfusion, or at age younger than 9 years);

- HIV-1 infection as documented in subject's medical record by at least one of the
following criteria:

- reactive HIV screening test result with an antibody based FDA-licensed assay
followed by a positive supplemental assay (e.g., HIV-1 Western Blot, HIV-1
Indirect Immunofluorescence, Antibody Differentiation Assay (Multispot)); or

- positive HIV-1 DNA polymerase chain reaction (PCR) assay; or

- plasma HIV-1 quantitative RNA assay >1,000 copies/mL; or

- positive plasma HIV-1 RNA qualitative assay

- Subjects must have at least one documented HIV viral load that is below 200 copies/mL
collected following initiation of TDF containing cART and greater than 90 days prior
to randomization; no HIV viral load above 200 copies/mL if measured within the 90 days
prior to randomization; and an HIV viral load obtained at screening that is below 200
copies/mL.

- Currently being treated for at least 180 days by the time of randomization with a TDF
containing cART with at least 2 other FDA approved ARVs (NOTE: This may include a
TDF-containing fixed drug combination medication);

- Negative serum hepatitis B surface antigen (HBsAg) at screening or by history within 4
weeks prior to screening (see section 7.1.3);

- Willingness and ability to remain on the same cART regimen for the duration of study
participation;

- Willingness and ability to participate in the study, follow all study procedures for
the duration of study participation, and provide written informed consent or assent
with parental permission, if applicable; and

- For females of child-bearing potential, agreement to use a minimum of one
proven-effective method of birth control and willingness to postpone pregnancy for the
duration of study participation (see section 5.3.2 for permitted hormonal
contraceptives)

Exclusion Criteria:

To be considered eligible for enrollment, an individual must not meet any of the criteria
listed below at the time of randomization:

NOTE: If the DXA scan is scheduled prior to randomization, all eligibility criteria must be
met prior to performing the DXA scan.

- Prior hypersensitivity to vitamin D;

- History of sarcoidosis, arteriosclerosis, renal stones, glomerulonephritis,
interstitial kidney disease, nephrotic syndrome, hypercalcemia, osteoporosis and/or
other bone diseases, clinical diagnosis of hypoparathyroidism or hyperparathyroidism;

- Lactation or pregnancy currently or within the past 24 weeks;

- Chemotherapy or radiation therapy for malignancy within the past 12 months;

- Known presence of GI disease that, in the opinion of the clinician, would interfere
with study agent administration or absorption (e.g. Crohn's, Colitis);

- For subjects ≥ 18 years, confirmed creatinine clearance < 70 ml/min (estimated
glomerular filtration rate (GFR) from SCr using Cockcroft and Gault (CG) equation) and
for subjects <18 years, confirmed creatinine clearance < 70ml/min/1.73m2 (estimated
GFR from SCr using Schwartz formula (see section 3.5). (Estimated GFR may be
calculated using the formulae programmed on the ATN website);

- SCa > Upper Limit Normal (ULN) for local laboratory values (see section 7.1.3);

- Active Grade 3 or higher clinical or laboratory toxicity except atazanavir (ATV)
associated indirect hyperbilirubinemia (see section 9.5.2.2);

- Weight is > 350 pounds (lbs) or 159 kilograms (kgs);

- Positive hepatitis C antibody by history or at screening (see section 7.1.3); and

- Use of any medications as specified in sections 5.3.1, 5.3.3 and 5.4.

- Females Only: Use of certain hormonal contraceptives as specified in the protocol.