AfterBefore

PT

H p

g/m

l

200

150

100

50

0

PT

H p

g/m

l

AfterBefore

200

150

100

50

0

Case Report 1)

• Age 53, 17 yrs HIV infection

• TDF/FTC/EFZ

• Baseline 25(OH)D 10.3ng/ml, PTH 159 pg/ml

• 5 months VitaminD3/ Calcium citrate

• Repeat 25(OH)D 24.5ng/ml, PTH 85 pg/ml

Case Report 2)

• Age 55, 20 yrs HIV infection

• TDF/FTC/EFZ

• Baseline 25(OH)D 15.1ng/ml, PTH 139 pg/ml

• 3 months VitaminD3/ Calcium citrate

• Repeat 25(OH)D 35.4 ng/ml, PTH 78 pg/ml

• Abnormalities of bone and calcium are common in HIV patients.1 • Tenofovir (TDF) decreases bone density in children and adults and causes skeletal lesions in fetal primates.2,3

• Vitamin D insufficiency is common in the population4

• Low vitamin D [measured by 25(OH)D] is a known cause of secondary hyperparathyroidism • Secondary hyperparathyroidism indicates abnormal calcium metabolism and causes osteopenia and osteoporosis.• In subjects with normal renal function, high PTH is alsoassociated with LV hypertrophy, incident hypertension, higher risk of metabolic syndrome and poorer performance on cognitive tests5,6 • We aimed to assess vitamin D status and to determine its influence on the relationship between anti-retroviral medications and abnormal calcium/bone metabolism.• We hypothesized that the effect of TDF on bone is mediated via effects on the 25(OH)D-calcium-PTH axis

Should Vitamin D Be Prescribed with Tenofovir/FTC? K. CHILDS, S. FISHMAN, K. BATEMAN, S. FACTOR, C. WYATT, M. MULLEN, A. BRANCH;

Mount Sinai School of Medicine, New York, NY.

BACKGROUND

References1) Brown and Qaqish AIDS 2006 2) Purdy et al J.Pediatr 2008 3) Gallant et al JAMA 2004 4)

Holick MF. N Engl J Med 2007 5)Saleh et al. Eur Heart J 2003 6) Forman et al Hypertension 2008.

AcknowledgementsThe work was supported, in part, by NIH grants DA016156 and DK066939 (to ADB)

Age a 49 (43, 55)

Years HIV 12 (7, 19)

% Caucasian 80%

% on TDF/FTC 66%

Serum creatinine

(0.5-1.3 mg/dl)

0.9 (0.8, 1.1)

Corrected calcium

(8.6-10.2 mg/dl)

9.3 (9.1, 9.5)

CD4 count (500-1500 cells/mm3)

443 (290, 698)

% HIV viral load

undetectable

75%

• Thirty-nine percent of subjects exposed to the combination of TDF/FTC and suboptimal 25(OH)D had elevated PTH

• Patients on TDF/FTC should have 25(OH)D and PTH levels checked

• Low 25(OH)D and TDF/FTC appear to act synergistically to increase PTH level

• We hypothesize that TDF/FTC causes a reduction in whole body calcium, which results in elevated PTH (model)

• Research is needed to investigate whether prophylactic use of vitamin D3 supplements and calcium citrate will prevent increases in PTH and preserve

bone.

• 25(OH)D insufficiency was common• Among subjects on ART who had low vitamin D:

•PTH was above the ULN in 39% of those on tenofovir/emtricitabine (TDF/FTC) versus 7% on TDF-sparing regimens (p= 0.036)• Median plasma PTH was 80 pg/ml on TDF/FTC versus 55 pg/ml on ART without TDF/FTC (p=0.02).

• No subject with optimal 25(OH)D levels had elevated PTH• Multivariable analysis showed that 25(OH)D levels (p=0.03) and TDF/FTC use (p=0.04) were independently associated with plasma PTH, serum creatinine was not.

TDF/FTC IS ASSOCIATED WITH ELEVATED PTH

Contact: kathryn.childs@mssm.edu or andrea.branch@mssm.edu

Anecdotal case reports:FUTURE RESEARCH DIRECTIONS

CONCLUSIONSRESULTS

TDF/FTC was associated with higher plasma PTH in subjectswith suboptimal 25(OH)D

Fig 1) PTH and 25(OH)D levels among subjects taking ART not including TDF/FTC

Fig 2a) PTH and 25(OH)D levels among subjects taking TDF/FTC

Fig 2b) Among subjects taking TDF/FTC, plasma PTH was significantly higher in subjects with suboptimal 25(OH)D than with optimal 25(OH)D

Fig 3a) PTH and 25(OH)D levels among all subjects on ART

Fig 3b) Among subjects with suboptimal 25(OH)D, plasma PTH was significantly higher in subjects taking TDF/FTC than those on other ART.

Low Serum Phosphate

Increased PTH

Decreased Bone Mineral

Density

DecreasedWhole-body

Calcium

Increased Resorbption of Calcium Increased Excretion of Phosphate

Kidney Damage(Fanconi-like Syndrome)

Increased Excretion of Phosphate

Tenofovir/FTC Low Vitamin D

CONCEPTUAL MODEL

DEMOGRAPHICS25(OH)D & PTH

25(OH)D ng/ml

>7060-7050-6040-5030-4020-3010-20<10

Percentage

50

40

30

20

10

0

Deficient

Suboptimal

OptimalExcessive

25(OH)D was suboptimal in 82%

25(OH)D > 30 ng/ml25(OH)D < 30 ng/ml

200

150

100

50

0

p=0.045p=0.045

• An IRB approved cross-sectional study with medical record review and interviews was done on 51 HIV-infected men taking anti-retroviral therapy (ART) with normal serum calcium. • Blood 25(OH)D and PTH levels were assayed. • TDF was always used with FTC.

METHOD

PTH pg/ml

Fig 2b) Subjects on TDF/FTC: Those with 25(OH)D levels <30ng/ml had higher PTH than those with 25(OH)D >30ng/ml

Fig 3b) Subjects with suboptimal 25(OH)D: PTH levels were higher in subjects taking TDF/FTC than other ART

Decreased Serum

Calcium

Supply Calcium

at Cost to Bone

Low Vitamin D

IncreasedParathyroid

Hormone

SecondaryHyperparathyroidism

OsteoporosisBone pain

Muscle weaknessFatigue

Cardiovascular disease

Immunological impairments

ART NOT TDF/FTC

200

150

100

50

0

TDF/FTC

PTH pg/ml

p=0.021p=0.021

TDF/FTC IS ASSOCIATED WITH ELEVATED PTH

25(OH)D ng/ml

PTH pg/ml

200

150

100

50

06050403020100

Fig 3a) PTH level is more dependant on 25(OH)D level in subjects on TDF/FTC than non-TDF/FTC ART

25(OH)D ng/ml6050403020100

PTH pg/ml

200

150

100

50

0

Fig 2a) PTH levels among subjects taking TDF/FTC ART

TDF/FTC ART, low 25(OH)D

TDF/FTC ART, optimal 25(OH)D

25(OH)D ng/ml6050403020100

PTH pg/ml

200

150

100

50

0

Non-TDF/FTC ART

Fig 1) PTH levels among subjects taking non-TDF/FTC ART

Non-TDF/FTC ART

TDF/FTC ART

a For continous variables, value is median (interquartile range)

PTH Upper Limit Normal

Lower Limit Optimal 25(OH)D

Many subjects on TDF/FTC had PTH

above the ULN