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. |
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| Viard et al. (2011) [21], AIDS | 31 European countries, Israel, and Argentina | 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. |
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| 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. |
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| Theodorou et al. (2014) [29], Clinical Nutrition | Belgium | 2044 HIV-infected subjects. | 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 (P < 0.0001). 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, (P = 0.0001). |
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| 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. |
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| 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 (P = 0.018). Patients receiving PIs (P = 0.014) or NNRTI (P = 0.025) had higher odds of increased PTH levels; this was significant only in 25(OH)D deficient patients (P = 0.004). |
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| 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. |
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| 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 (P = 0.0062) and zidovudine (P = 0.015) use. The increase in 25(OH)D values in about 27% of patients who discontinued EFV (P = 0.007) was relevant. |
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| Brown and McComsey (2010) [32], Antivirus Therapy | US | 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 (P < 0.001) 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. |
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| 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 (P = 0.02) after 12 months of HAART. |
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| Schwartz, Moore et al. (2014), Journal of the International Association of Providers of AIDS Care | US | 507 HIV-negative subjects. 358 HIV-positive patients cART naive. 893 HIV-positive patients under cART. |
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; P < 0.001). Hypertriglyceridemia was present in HIV-infected under ART (13% versus 7% of HIV-infected cART and 5% of HIV-uninfected; P < 0.001), with a positive relationship between 25(OH)D levels and triglycerides (P < 0.01). No relationships could be found between 25(OH) and cholesterol. Vitamin D deficiency was not correlated to HIV status but influenced by HIV treatment. |
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| 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. |
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| 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 (P = 0.05) 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. |
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| 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. |
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| Wohl et al. (2014) [30], Antivirus Therapy | US | 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%, P = 0.032). 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%, P = 0.0079). |
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| 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 (P < 0.001) 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. |
1,25(OH)(2)D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; ART: antiretroviral therapy; cART: combined antiretroviral therapy; EFV: efavirenz; HAART: highly active antiretroviral therapy; NNRTI: nonnucleoside reverse-transcriptase inhibitor; NRTI: nucleoside reverse-transcriptase inhibitor; PI: protease inhibitor; RPV: rilpivirine; US: United States.