Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder
Table 2
Association between HAART use and low 25(OH)D levels.
Authors (year), journal
Nation
Patients
Results
Comments
Poowuttikul, Thomas et al. (2014), Journal of the International Association of Providers of AIDS Care
US
160 HIV-infected youth (45 no ART; 67 cART with tenofovir or EFV; 48 other cART).
25(OH)D in tenofovir/EFV group: 20.3 ± 18.1 ng/mL. 25(OH)D in other cART group 21.2 ± 16.8 ng/mL. 25(OH)D in no ART group 14.6 ± 7.3 ng/mL.
Severe vitamin D deficiency (25(OH)D ≤10 ng/mL) was related to lower CD4 counts and CD4% but not to HIV plasma RNA. EFV or tenofovir therapy did not have different effects on vitamin D levels compared to other antiretroviral medications.
1985 HIV-positive among EuroSIDA study group (180 naive, 155 ART, and 1650 cART).
36.6% naive had 25(OH)D <12 ng/mL. 39.3% ART had 25(OH)D <12 ng/mL. 35.5% cART had 25(OH)D <12 ng/mL. 38.8% naive had 25(OH)D <20 ng/mL. 32.2% ART had 25(OH)D <20 ng/mL. 30.4% cART had 25(OH)D <20 ng/mL.
25(OH)D deficiency was frequent in HIV-infected persons (83% on combined antiretroviral therapy) and was independently associated with a higher risk of mortality and AIDS events. Patients receiving a PI-based antiretroviral regimen were at low risk of hypovitaminosis D, whereas no significant association was found with EFV or tenofovir use.
Allavena, Delpierre et al. (2012), Journal of Antimicrobial Chemotherapy
France
2994 HIV-positive patients (334 cART naive versus 2660 exposed).
79.3% had 25(OH)D <30 ng/mL among ART naive. 67.6% had 25(OH)D <30 ng/mL among cART exposed.
In multivariate analysis cART, treatment was associated with vitamin D deficiency (aOR 2.61), together with current smoking, estimated glomerular filtration rate ≥90 mL/min/1.73 m2, vitamin D measurement not performed in summer, and CD4 <350 cells/mm3.
1500 (73.4%) patients under HAART. 1362 (74.7%) patients under HAART had 25(OH)D <30 ng/mL.
25(OH)D levels varied according the different combinations of cART (). Median 25(OH)D levels in patients treated with 2 NRTI + 1 NNRTI and patients 2 NRTI + 1 PI were 12.5 ng/mL versus 14.3 ng/mL, respectively, ().
Welz, Childs et al. (2010), AIDS
UK
755/1077 HIV-positive, patients under cART.
52.1% patients under cART had 25(OH)D <10 ng/mL.
EFV treatment was significantly associated with severe 25(OH)D reduction (OR: 2.0). Tenofovir (OR: 3.5) and EFV use OR: 1.6), but not severe 25(OH)D deficiency (OR: 1.1), was associated with increased bone turnover.
Cervero, Agud et al. (2012), AIDS Research and Human Retroviruses
Spain
352HIV-positive patients (37 cART naive versus 315 cART exposed).
95.2% had 25(OH)D <30 ng/mL among cART naive. 68.4% had 25(OH)D <30 ng/mL among cART exposed.
EFV exposure was associated with 25(OH)D deficiency (). Patients receiving PIs () or NNRTI () had higher odds of increased PTH levels; this was significant only in 25(OH)D deficient patients ().
Van Den Bout-Van Den Beukel et al. (2008) [52], AIDS Research and Human Retroviruses
Netherlands
252 HIV-positive patients.
25(OH)D levels in white NNRTI-treated patients: 54.5 (27.9–73.8) nmol/L; 25(OH)D levels in white PI-treated patients 77.3 (46.6–100.0) nmol/L. 25(OH)D levels in black NNRTI-treated patients: 22.0 (14.7–38.4) nmol/L. 25(OH)D levels in black PI-treated patients 29.0 (20.4–5) nmol/L.
Female sex, younger age, dark skin, and NNRTI treatment were significant risk factors in univariate analysis, although in multivariate analyses skin pigmentation remained the only independent risk factor.
Fox, Peters et al. (2011), AIDS Research and Human Retroviruses
12 countries in Europe
256 European patients taking EFV + 2NNRTI or PI + 2NNRTI.
25(OH)D on PI + 2NNRTI 41.6 (38.6, 44.5) nmol/L. 25(OH)D on EFV + 2NNRTI 35.0 (31.0, 39.1) nmol/L.
Lower baseline vitamin D levels were associated with EFV () and zidovudine () use. The increase in 25(OH)D values in about 27% of patients who discontinued EFV () was relevant.
51 HIV patients under EFV-containing treatment. 36 HIV patients under non-EFV-containing treatment.
Median 25(OH)D level before cART 52.7 nmol/L 25(OH)D reduction in EFV-treated versus non-EFV-treated patients: −12.7 ± 3.7 nmol/L.
A significant decline in 25(OH)D serum levels after the initiation of an EFV-based regimen, compared to a non-EFV-based regimen () in HAART patients was found. In addition, subjects receiving EFV had a 1.8-fold increased probability of developing vitamin D deficiency, compared to those starting PIs.
Conesa-Botella, Florence et al. (2010), AIDS Research and Therapy
Belgium
89 HIV-positive patients before and after 12-month HAART.
43.7% had 25(OH)D <20 ng/mL before HAART and 47.1% before 12-month HAART. 70.1% had 25(OH)D <20 ng/mL before HAART and 81.6% before 12-month HAART.
A 3-fold increased risk of 25(OH)D levels below 20 ng/mL was described in subjects receiving NNRTIs () after 12 months of HAART.
Schwartz, Moore et al. (2014), Journal of the International Association of Providers of AIDS Care
72% HIV-negative subjects had 25(OH)D <20 ng/mL. 18% HIV-negative subjects had 25(OH)D <30 ng/mL. 70% HIV-positive patients ART naive had 25(OH)D <20 ng/mL. 20% HIV-positive patients ART naive had 25(OH)D <30 ng/mL. 57% HIV-positive patients under cART had 25(OH)D <20 ng/mL. 24% HIV-positive patients under cART had 25(OH)D <30 ng/mL.
EFV use in cART significantly reduced the 25(OH)D levels (15 versus 19 ng/mL; ). Hypertriglyceridemia was present in HIV-infected under ART (13% versus 7% of HIV-infected cART and 5% of HIV-uninfected; ), with a positive relationship between 25(OH)D levels and triglycerides (). No relationships could be found between 25(OH) and cholesterol. Vitamin D deficiency was not correlated to HIV status but influenced by HIV treatment.
Fux, Baumann et al. (2011), AIDS
Switzerland
262 HIV-positive patients starting HAART (EFV versus PIs).
40.6% under EFV had 25(OH)D <30 nmol/L after 1-year therapy and 25.0% under PIs had 25(OH)D <30 nmol/L after 1 year therapy.
EFV treatment was associated with lower 25(OH)D levels compared to PIs. CYP polymorphisms and black ethnicity may define patients in whom EFV treatment will cause clinically relevant 25(OH)D deficiency.
Pasquet, Viget et al. (2011), AIDS
France
352 HIV-positive patients under cART.
41.0% patients under cART had 25(OH)D <30 nmol/L.
Authors found an association between hypovitaminosis D and exposure to NNRTIs () but not to EFV and NVP, probably because of a lack of statistical power of their analysis. However, considering the crude and adjusted coefficients for EFV and NVP in their regression models, the authors suggested a NNRTI class effect, rather than a specific EFV or NVP impact, on vitamin D levels.
Ryan, Dayaram et al. (2013), Current HIV Research
US
1368 naive HIV-positive patients (686 cART with RPV; 682 cART with EFV).
In EFV arm median 25(OH)D reduction after therapy was greater in older (–3.2 ng/mL) versus younger (–1.6 ng/mL). In RPV arm median 25(OH)D remained relatively unchanged for both older (0.8 ng/mL) and younger (–0.8 ng/mL).
Progression from insufficient (50–74 nmol/L) or deficient (25–49 nmol/L) at baseline to severely deficient (<25 nmol/L) 25(OH)D at week 48 after cART was 0% in older and 2% in younger under RPV, whereas it was 13% in older and 8% in younger under EFV.
690 naive HIV-positive patients (345 cART with RPV; 345 cART with EFV).
In EFV arm median 25(OH)D reduction after 48-week therapy was (–2.5 ng/mL). In RPV arm median 25(OH)D reduction after 48-week therapy was (–0.2 ng/mL).
Patients with severe 25(OH)D deficiency were 5% in both groups at baseline but were significantly higher in EFV group at 48 weeks (9% versus 5%, ). In addition, the patients with 25(OH)D insufficiency/deficiency at baseline, the ones who received EFV, developed more frequently severe 25(OH)D deficiency (8% versus 2%, ).
Viani, Peralta et al. (2006), The Journal of Infectious Diseases
US and Puerto Rico
303 HIV-positive patients under cART (102 received vitamin D supplementation, the others placebo).
At baseline, 54% had 25(OH)D <20 ng/mL. 45% of treatment group had 25(OH)D <20 ng/mL. 93% of treatment group had sufficient 25(OH)D levels after 12 weeks of therapy.
Oral vitamin D supplementation (50,000 IU monthly) increased 25(OH)D serum concentration from a baseline of 21.9 (13.3) to 35.9 (19.1) ng/mL after 12 weeks () with no change for placebo. Although use of the antiretroviral efavirenz was associated with lower baseline 25-OHD concentration, efavirenz did not diminish the response to vitamin D supplementation. No toxicity was revealed.
