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

• BMC of whole body and BMD of spine, total hip, and femoral neck - compare at different timepoints [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  For BMC of whole body and BMD of spine, total hip, and femoral neck, compare change from baseline to week 24, change from baseline to week 48, and change from baseline to week 96 by randomized study group, with analyses using measured BMC/BMD and Z-scores;
• Compare the time course of change in SCa, UCa / UCr, SPO4, TRP, 25-OHD, 1,25-OHD, free 1,25-OHD index, PTH, FGF23, BAP, OC, and CTX at various timepoints [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To compare the time course of change from baseline to weeks 12, 24 48, and 96, and the overall change from baseline to week 48 and baseline to week 96, in SCa, UCa / UCr, SPO4, TRP, 25-OHD, 1,25-OHD, free 1,25-OHD index, PTH, FGF23, BAP, OC, and CTX;
• Assess renal glomerular safety by measuring change in SCr and estimated GFR at various timepoints [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To assess renal glomerular safety by measuring change in SCr and estimated GFR from baseline to weeks 12, 24 48, and 96 by randomized study group;
• Assess renal tubular function by measuring change in TRP, UGluc, URBP/UCr ratio, UB2MG, UProt/ UCr ratio [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To assess renal tubular function by measuring change in TRP, UGluc, URBP/UCr ratio, UB2MG, UProt/ UCr ratio by randomized study group;
• Measure change from baseline to week 48 and change from baseline to week 96 in Gluc homeostasis [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To measure change from baseline to week 48 and change from baseline to week 96 in Gluc homeostasis (fasting insulin and Gluc and calculated HOMA-IR and their relationship to changes in 25-OHD, 1,25-OHD, and free 1,25-OHD index for the randomized study groups and for different attained vitamin D serum concentrations;
• Compare 25-OHD serum concentrations by randomized study group at various timepoints [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To compare 25-OHD serum concentrations by randomized study group at all-time points and change from baseline to week 48 and 96;
• Compare the mean 25-OHD serum concentration and to measure the effect of concurrent treatment with EFV or ritonavir on serum 25-OHD concentrations and changes during the study [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To compare the mean 25-OHD serum concentration by randomized study group and to measure the effect of concurrent treatment with EFV or ritonavir on serum 25-OHD concentrations and changes during the study;
• Measure the relationship of 25-OHD, 1,25-OHD, and free 1, 25-OHD serum concentrations BMD/BMC, markers of Ca-PO4-FGF23 activity, markers of bone turnover, renal glomerular and tubular toxicity, and Gluc homeostasis at various timepoints [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  To measure the relationship of 25-OHD, 1,25-OHD, and free 1, 25-OHD serum concentrations to baseline and change from baseline to week 24, baseline to week 48, and baseline to 96 in BMD/BMC, markers of Ca-PO4-FGF23 activity, markers of bone turnover, renal glomerular and tubular toxicity, and Gluc homeostasis

This is a 96 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.

This is a 96 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 screening; no viral load above 200 copies/mL if measured within the 90 days prior to screening; and a 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.

DXA measurement of whole-body BMC, and BMD at spine and hip, will be performed at baseline and study weeks 24, 48, and 96. Blood and urine sampling to assess the Ca-PO4 axis, PTH-FGF23-vitamin D signaling, bone turnover, and renal glomerular and tubular function will occur at baseline and study weeks 12, 24, 48, and 96. Blood samples to measure Gluc homeostasis will be drawn at baseline and weeks 48 and 96, and will be run by batch analysis.

Safety, measured by SCa and 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 ATN109 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 the visit. Viral load and CD4 cell count results will be recorded for the ATN109 study at screening, baseline and study weeks 12, 24, 48, and 96 provided the evaluations were done within the protocol specified timeframe. If the evaluations are not performed within the protocol specified timeframes they will be drawn at the time of the visit (see section 7.0 for additional details).

• Dietary Supplement: Vitamin D3 50,000 IU
  Group A: Vitamin D3 50,000 IU orally every four weeks by DOT
• Dietary Supplement: MVI Tablet
  A standard MVI will be supplied to all study subjects and will contain ingredients not to exceed 600 IU of vitamin D3 and 200 mg Ca. Subjects will take one MVI tablet orally once daily.
• Dietary Supplement: Vitamin D3 placebo
  Group B: Vitamin D3 placebo orally every four weeks by DOT

• Experimental: Group A: Vitamin D3 50,000 IU
  Interventions:

  • Dietary Supplement: Vitamin D3 50,000 IU
  • Dietary Supplement: MVI Tablet
• Placebo Comparator: Group B: Vitamin D3 placebo
  Interventions:

  • Dietary Supplement: MVI Tablet
  • Dietary Supplement: Vitamin D3 placebo

Inclusion Criteria:

• 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); or
  • positive HIV-1 DNA 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 viral load that is below 200 copies/mL collected following initiation of TDF containing cART and greater than 90 days prior to screening; no viral load above 200 copies/mL if measured within the 90 days prior to screening; and a viral load obtained at screening that is below 200 copies/mL.
• Currently being treated for at least 180 days 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 96-week duration of the study;
• Willingness and ability to participate in the study, follow all study procedures for the 96-week duration, 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

Exclusion Criteria:

• 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 GFR from SCr using 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 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.

• National Institute on Drug Abuse (NIDA)
• National Institute of Mental Health (NIMH)