Vitamin D Supplements May Limit Tenofovir Bone Toxicity

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Vitamin D Supplements May Limit Tenofovir Bone Toxicity
18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston

Mark Mascolini

In a randomized trial of 18-to-25-year-olds, vitamin D3 supplementation appeared to offset a negative impact of tenofovir on parathyroid hormone (PTH), which enhances release of calcium from bone [1]. Supplementation lowered PTH levels in people taking tenofovir but had no PTH impact on study participants taking nontenofovir regimens.

Tenofovir promotes renal phosphate wasting, which could contribute to bone abnormalities in people taking this drug. Vitamin D deficiency or insufficiency (a 25(OH) D level below 30 ng/mL) affects more than 80% of HIV-positive youth in the United States. Adolescent Trials Network (ATN) investigators hypothesized that vitamin D supplementation would increase renal tubular reabsorption of phosphate, decrease levels of PTH, and decrease levels of two bone turnover markers, bone alkaline phosphatase (BAP) and C telopeptide (CTX), in young adults taking tenofovir.

Study participants were 18 to 25 years old, had taken the same antiretroviral combination for at least 90 days, and had a viral load below 5000 copies. They could have any vitamin D level. The investigators excluded pregnant or breastfeeding women or people with hypercalcemia or hypercalciuria. The study population consisted of 118 people taking a tenofovir-containing combination and 85 taking a nontenofovir regimen. The ATN team randomized them 1-to-1 to receive directly observed vitamin D3 at a dose of 50,000 IU every 4 weeks for 12 weeks or to placebo.

Age averaged 20.9 (+/- 2.0), 76 enrollees (37%) were women, and 106 (52%) were African American. Entry CD4 counts averaged 587 (+/- 246), and 110 participants (55%) had a 25(OH)D level below 20 ng/mL. The tenofovir group had significantly lower tubular reabsorption of phosphate (92% versus 93%, P = 0.017 adjusted for baseline characteristics) and significantly higher PTH (47.7 versus 31.2 pg/mL, adjusted P < 0.001). PTH was significantly higher in study participants with insufficient vitamin D (45 versus 35 pg/mL, P = 0.024). The tenofovir and nontenofovir groups did not differ significantly in 25(OH)D level (20.8 and 21.7 ng/mL), CTX, or BAP.

PTH concentrations were significantly higher in tenofovir takers than in people on nontenofovir combinations regardless of baseline 25(OH)D level: 52 versus 35 pg/mL (P = 0.001) with 25(OH)D below 20 ng/mL, and 43 versus 27 pg/mL (P< 0.001) with 25(OH)D above 20 ng/mL.

Average 25(OH)D levels rose significantly in study participants receiving supplements, from 21.4 ng/mL when the study began to 35.5 ng/mL at week 12 (P < 0.001). At study entry, 47% of participants randomized to supplementation had a 25(OH)D level above 20 ng/mL, whereas 95% taking supplements had a level that high at week 12 (P < 0.001). Twelve-week 25(OH)D levels did not differ between supplemented people in the tenofovir group and the nontenofovir group, and 25(OH)D concentrations did not change significantly in youth randomized to placebo.

In the 52 people receiving vitamin D supplementation while taking tenofovir, average PTH fell significantly from baseline to week 12 (49 to 42 pg/mL, P = 0.003). In these people PTH dropped regardless of whether pretreatment 25(OH)D was above 20 ng/mL (-6 pg/mL, P = 0.053) or below 20 ng/mL (-8 pg/mL, P = 0.031). PTH did not change at all in tenofovir-treated people randomized to placebo. Tubular reabsorption of phosphate did not change significantly from baseline to week 12 in the supplement group or the placebo group. Among people receiving supplemental vitamin D while taking tenofovir, average BAP fell moderately but significantly (37 to 36 U/L, P = 0.04). Clinical bone or kidney toxicities arose in no study participants, and calcium did not rise above normal levels.

PTH did not change significantly with supplementation or placebo in people not taking tenofovir. Because vitamin D supplementation affected PTH only in people taking tenofovir, the researchers proposed a possible interaction between tenofovir, PTH, and vitamin D. Whether vitamin D supplementation promotes healthier bones via by lowering PTH remains to be determined.

Two other studies reported at this conference assessed the impact of vitamin D supplementation in people with HIV. Twelve weeks of vitamin D supplementation in D-deficient people with HIV did not improve endothelial function in the first placebo-controlled trial of this strategy in HIV-positive adults [2]. Results hinted that efavirenz may limit the impact of vitamin D supplements. A retrospective study found evidence that vitamin D supplementation may lower the risk of type 2 diabetes in adults with HIV [3]. NATAP reviews both of these studies separately at the links noted in the References.

References1. Havens P, Hazra R, Stephensen C, et al.  Vitamin D3 supplementation decreases PTH in HIV-infected youth being treated with TDF-containing combination ART: a randomized, double-blind, placebo-controlled multicenter trial: Adolescent Trials Network Study 063. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 80.
2. Longenecker C, Hileman C, Carman T, et al. Vitamin D supplementation and endothelial function among vitamin D-deficient HIV-infected persons: a randomized placebo-controlled trial. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 829. NATAP review online at https://www.natap.org/2011/CROI/croi_16.htm. Study poster online at https://www.retroconference.org/2011/PDFs/829.pdf.
3. Guaraldi G, Zona S, Orlando G, et al.  Vitamin D3 supplementation decreases the risk of diabetes mellitus among patients with HIV infection. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 827. NATAP review online at https://www.natap.org/2011/CROI/croi_20.htm. Study poster online at https://www.retroconference.org/2011/PDFs/829.pdf.

 

Background:  Tenofovir (TDF) is associated with renal phosphate wasting, elevation in markers of bone turnover, and decrease in bone density. Vitamin D3 (VITD) treatment increases renal tubular phosphate absorption in VITD deficiency. VITD deficiency/insufficiency (serum 25-OH VITD <30 ng/mL) occurs in >80% of HIV+ youth in the U.S. We hypothesized that VITD administration would increase tubular reabsorption of phosphate (TRP) and decrease serum parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C telopeptide (CTX) in HIV+ youth treated with TDF.

Methods:  Randomized controlled trial (RCT) of VITD 50,000 IU vs placebo (PL) every 4 weeks for 12 weeks (3 directly observed oral doses) in HIV+ youth ages 18 to 24, viral load <5,000 copies/mL, and unchanged cART for ≥90 days. Participants were enrolled based on treatment with cART containing TDF (N = 118) or noTDF (N = 85) and randomized within those groups to VITD (N = 102) or PL (N = 101).

Results:  At baseline, VITD and PL groups were similar in age, race/ethnicity, body mass index, VITD, and calcium (Ca) intake (self-report). Prevalence of VITD insufficiency/deficiency was 84% overall. Participants on no TDF had longer duration of HIV infection and cART, higher viral load, and more advanced Centers for Disease Control and Prevention stage of HIV disease. Those on TDF had lower TRP, higher PTH and CTX; but similar BAP. At week 12, 52% in the VITD group had sufficient VITD, an increase from 17% at baseline, compared to16% at baseline and at week 12 in the PL group (p <0.001 vs VITD). TRP did not change in either group. PTH decreased in the TDF group receiving VITD, but not in the no TDF group receiving VITD or the PL groups. Ca intake affected the strength of the VITD-TDF interaction. CTX and BAP did not change significantly with VITD. There were no clinical bone or renal toxicities or elevations of serum Ca above normal in either group.

PTH (pg/mL) at baseline and change at week 12 by TDF and VITD

Data are medians. P values are by Wilcoxon signed rank test, corrected for multiple comparisons by Sidak’s method. Controlled analysis via generalized estimating equations showed similar results.

Conclusions:  Supplementation with VITD3 50,000 IU monthly for 12 weeks in HIV+ youth was safe and reduced VITD insufficiency by 46%. VITD was associated with a significant decrease in PTH in those on TDF-containing cART. There was no change in TRP, CTX, or BAP. The effect of VITD on PTH was seen only in those on TDF, suggesting a possible interaction between TDF, PTH, and VITD.