Vitamin D Deficiency in HIV: A Shadow on Long-Term Management?

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1 AIDS Rev. 2014;16:59-74 (Supplementary Data) Vitamin D Deficiency in HIV: A Shadow on Long-Term Management? Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Chloe Orkin 1, David A. Wohl 2, Andrew Williams 1 and Henri Deckx 3 1 Barts Health NHS Trust, London, UK; 2 University of North Carolina at Chapel Hill, North Carolina, USA; 3 Janssen Infectious Diseases BVBA, Beerse, Belgium Supplementary data methodology A systematic PubMed search on HIV and vitamin D was conducted and restricted to the period between July 2002 and October The search terms used were hiv [MeSH] OR hiv OR Human Immunodeficiency Virus OR Human Immunodeficiency Viruses and Vitamin D Deficiency [MeSH] OR Vitamin D Deficiency OR Vitamin D Deficiencies OR deficiency of vitamin D OR deficiencies of vitamin D OR deficient in vitamin D OR Vitamin D insufficiency OR Vitamin D insufficiencies OR insufficiency of vitamin D OR insufficiencies of vitamin D OR insufficient in vitamin D OR hypovitaminosis D OR vitamin D. These combined searches identified 323 papers. Combining this output with additional searches using the terms therapy [Subheading] OR therapy OR treatment OR management identified that 230 of these 323 papers contained the additional terms. Similarly, adding the terms Antiretroviral Therapy, Highly Active [MeSH] OR Highly Active Antiretroviral Therapy (HAART) OR HAART OR (HAART) OR antiretrovirals OR antiretroviral OR ARV OR ARVs OR (ARV) OR (ARVs) to the original output identified 151 (of the 323) papers. Thus, the 323 papers covered topics of particular relevance. Of the 323 papers, 49 were classified as reviews on PubMed and excluded from our analysis. The abstracts of the remaining 274 papers were checked and a further 173 articles were eliminated for the following reasons: not in English (9); case reports (19); commentary/letter (23); editorial (2); newspapers (5); article type misclassified (19); in vitro/animal studies (27); pediatric/ adolescent studies (19); subject not relevant (50). Searches for vitamin D were conducted on publically-available abstracts for three major HIV meetings for i.e. Conference on Retroviruses and Opportunistic Infections (CROI); International AIDS Conference (IAC); International AIDS Society Conference (IAS). These searches captured 20 abstracts/posters/orals of data not published as full papers. Therefore, 121 articles were included in our evaluation. All 121 abstracts together with freely available papers and CROI/IAC/IAS posters/oral presentations were reviewed, with several full papers identified as key being purchased for further information. The reviewed information was classified into five key topics of vitamin D deficiency in HIV-positive adults: prevalence; consequences; factors; effect of ARV; and management. 1

2 AIDS Reviews. 2014;16 Table S1a. Studies reporting prevalence of vitamin D deficiency in HIV-positive versus HIV-negative adults Study location Study type Study population (HIV + ) Control population (HIV ) Prevalence of vitamin D deficiency HIV + HIV Comments USA 92 Cohort 120 women (WIHS) 71% on HAART 42 women (WIHS) 58%* Not stated No trend with season USA 94 Cross-sectional 1,768 women (WIHS) 72% on HAART USA 45 Cross-sectional 672 adults (SUN) 79% on cart US general population (NHANES) Spain 71 Cross-sectional 352 adults 90% on ART USA 46 Cohort 480 women 42% on HAART India 109 Cohort 35 men (on HAART) 35 men (ARV-naive) South Cross-sectional 174 black Africans with TB Africa 85 2% on ART USA 96 Cross-sectional 89 postmenopausal women 80% on HAART USA 98 Cross-sectional 16 pregnant women 44% on ART USA 97 Cross-sectional 754 women (WIHS) 72% on HAART India 88 Case 45 adults (ARV status not stated in abstract) 510 women (WIHS) 60% 72% p < (HIV + vs. HIV ) Age- and latitudematched population from another study (n = 116) 70% 79% Standardized by age, race, sex. No vitamin D supplementation 44% 72% 122 women 60% 61% 83% 89% 35 men 74% (HAART) vs. 37% (ARV-naive) 196 black Africans with TB 95 postmenopausal women 86% (active TB) 52% (latent TB) 28% VDD 16.4% more prevalent in HIV + 84% vs. HIV ; p < % HAART vs. ARV-naive, and vs. HIV ; p = % (active TB) 37% (latent TB) Seasonal variation in vitamin D status in HIV + and HIV groups 49% 47% No differences in vitamin D levels between groups 24 pregnant women 75%* 80%* No differences in vitamin D levels between groups; p = women 61% 75% HIV + women less likely to be vitamin D deficient than HIV women 45 adults 93% 73% Cutoffs for vitamin D deficiency (VDD): *not stated; 20 ng/ml; 30 ng/ml; < 50 nmol/l. ARV: antiretroviral; cart: combined antiretroviral therapy; HAART: highly active antiretroviral therapy; NHANES: National Health and Nutrition Examination Survey; SUN: Study to understand the natural history of HIV and AIDS in the era of effective therapy; TB: tuberculosis; WIHS: Women s Interagency HIV study. 2

3 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S1b. Studies reporting vitamin D concentrations in HIV-positive versus HIV-negative adults Study location Study type Study population (HIV + ) Spain 108 Cross-sectional 30 men 57% on HAART USA 110 Cross-sectional 43 adults 0% on HAART Italy 111 Cross-sectional 172 adults (53% on PI-containing HAART; 35% on NNRTIs or triple NRTIs; 12% ARV-naive) Italy 112 Cross-sectional 237 adults 100% on cart Uganda 113 Cross-sectional 100 adults (50 TB coinfected) cart treatment not stated in abstract USA 114 Cohort African American men cart treatment not stated in abstract USA 115 Cohort 82 premenopausal women (WIHS) 85% on ART China 118 Cross-sectional 40 HIV + adults (ARV-naive at baseline) USA adults 100% on ART Germany 117 Cross-sectional 50 women 0% on ART Control population (HIV ) Vitamin D levels (ng/ml) HIV + HIV Comments 16 age-matched men 11.4 (5.8)* 14.3 (4.9)* p = 0.04; (HIV + vs. HIV ) 35 adults ARV-naive (100%); age-, sex-, and race-matched; p = 0.94 (HIV + vs. HIV ) 64 adults 41.5 ± 11.8 (PIs) vs ± 9.7 (NNRTIs or 3 NRTIs) 47.5 ± 13.3 (naive) Mean vitamin D significantly higher than all HIV + groups 76 adults 23.4 ( ) 24.0 ( ) p = 0.9 (HIV + vs. HIV ) 50 adults 28 ± 11 (not coinfected); 24 ± 11 (coinfected) US general population (NHANES) 58 premenopausal women (WIHS) 40 HIV adults (matched) 26 ± 7 No difference in vitamin D levels (p > 0.05) (HIV + vs. HIV ) Significantly higher vitamin D levels in HIV + vs. HIV (p 0.001) 20.1 ± ± 7.8 No difference in vitamin D levels (p = 0.62) (HIV + vs. HIV ) 15.9 ± ± 9.0 Vitamin D levels at baseline lower in HIV + vs HIV, not statistically significant (p = 0.07) 34 adults HIV group had higher mean vitamin D levels (p = 0.02) than HIV + group 50 women Serum vitamin D levels were significantly lower in HIV + vs. HIV South Cross-sectional 149 women (ARV-naive) 98 women Vitamin D status not significantly different Africa 86 between groups (p > 0.05) No vitamin D or calcium supplements; no ARV treatment *mean (standard error); median; mean (standard desviation); median (interquartile range). ARV: antiretroviral; cart: combined antiretroviral therapy; HAART: highly active antiretroviral therapy; NHANES: National Health and Nutrition Examination Survey; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; WIHS: Women s Interagency HIV study. 3

4 AIDS Reviews. 2014;16 Table S2. Studies reporting consequences of vitamin D insufficiency/deficiency in HIV-infected adults (excluding bone health/parathyroid hormone) (continued) Disease or physiologic state Cardiovascular disease Location Study type Study population Outcome of VDD/I USA 43 Cross-sectional 674 African Americans without coronary artery disease VDD (< 10 ng/ml) independently associated with significant coronary stenosis (aor: 2.3; 95% CI: ) USA 37 Cross-sectional 139 adults in USCF study VDI ( 30 ng/ml) significantly associated with higher mean carotid intima-media thickness levels vs. vit D sufficiency USA (56 with carotid intima-media thickness) USA 132 Cross-sectional 188 African Americans (69 with subclinical coronary artery disease) Low vit D levels associated with high odds (OR: 10.6; 95% CI: ) of increased carotid intima-media thickness VDD independently associated with development of subclinical coronary artery disease USA 133 RCT 45 adults Low flow-mediated brachial artery dilation in patients with VDD ( 20 ng/ml). Increasing serum vit D levels (supplementation) did not improve low flow-mediated brachial artery dilation Hawaii 134 Cohort 100 adults Significant correlation between vit D levels and flow-mediated brachial artery dilation (p = 0.01), but not carotid intima-media thickness (p = 0.76). Low vit D levels slightly higher odds of coronary artery calcium (p = 0.04) USA 52 Cross-sectional 846 African Americans VDD was significantly associated with coronary artery calcification (aor: 1.98; 95% CI: ) India 88 Case 45 adults No significant difference in carotid intima media thickness in HIV + adults with VDD compared with healthy controls Canada 135 Cross-sectional 283 adults (Canadian HIV Vascular Study) Inflammation USA 116 In patients with median vit D levels < 80 nmol/l, lower vit D concentrations were significantly associated with lower carotid intima-media thickness levels (exploratory regression model) 149 adults No association of inflammatory markers with vit D USA 110 Cross-sectional 43 adults Low levels of vit D and high levels of inflammatory markers (C-reactive protein, interleukin 6, tumor necrosis factor receptor -I and II) were observed (not analyzed for correlation) France adults Low vit D associated with higher inflammation markers (C-reactive protein, tumor necrosis factor receptor-1, resistin) Italy 74 Cross-sectional 90 adults High-sensitivity C-reactive protein levels significantly higher (p < 0.005) in patients with VDD vs. those not deficient. No association between vit D and D-dimer levels (continue) 4

5 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S2. Studies reporting consequences of vitamin D insufficiency/deficiency in HIV-infected adults (excluding bone health/parathyroid hormone) (continued) Disease or physiologic state Location Study type Study population Outcome of VDD/I Inflammation France 75 Cross-sectional 263 adults In patients with severe VDD, there was a significant and positive association with high-sensitivity C-reactive protein (p = 0.04) Nepal 89 Cross-sectional 316 adults Vit D levels < 20 ng/ml associated with higher odds (3.2 x) of increased high-sensitivity C-reactive protein levels compared with vit D levels 20 ng/ml Anemia Tanzania 143 Tanzania pregnant women Low vit D levels (< 32 ng/ml) associated with an increased chance of severe anemia (1.4 x) hypochromic microcytosis (2.3 x) 884 pregnant women Low vit D levels (< 32 ng/ml) associated with higher risk of severe anemia (RR: 1.46; 95% CI: ) Diabetes Australia 138 Cross-sectional 107 men Reduced vit D levels significantly associated with higher serum insulin (p = 0.006) Italy 136 Cross-sectional 1,811 adults VDD (< 20 ng/ml) associated with type 2 diabetes (aor: 1.85; 95% CI: ; p = 0.038) Italy 137 RCT 1,574 adults Baseline vit D was independently associated with type 2 diabetes (HR: 0.96; 95% CI: ) Vit D supplements decreased odds of diabetes mellitus USA 97 Cohort 754 women (WIHS) VDI was associated with insulin resistance: (OR: 1.80; 95% CI: ; p = 0.05) USA adults (SUN) Low vit D levels were associated with insulin resistance only in univariate analysis (not multivariate analysis) Spain 140 Cross-sectional 89 adults VDI was associated with insulin resistance and decreased pancreatic beta cell function USA 141 Netherlands adults (94% men) Significant decreases in blood glucose with vit D supplementation 20 adults Insulin sensitivity was negatively associated with serum vit D levels following supplementation Ovarian function USA 145 Cohort 388 women VDD correlated with serum antimüllerian hormone levels in older women ( 40 years), suggestive of an association between VDD and low ovarian reserve (continue) 5

6 AIDS Reviews. 2014;16 Table S2. Studies reporting consequences of vitamin D insufficiency/deficiency in HIV-infected adults (excluding bone health/parathyroid hormone) (continued) Disease or physiologic state Location Study type Study population Outcome of VDD/I Immune function USA 116 Infection 149 adults Positive association between vit D and CD4 + T-cell restoration (in response to ARVs) Germany 117 Cross-sectional 50 women Significant (p < 0.05) positive correlation between vit D levels and CD4 + count India 88 Case 45 adults Positive association between levels of CD4 + cells and vit D levels Denmark 146 RCT 61 males Higher vit D levels associated with higher activated CD4 + T lymphocytes (p = 0.001) USA 93 Cohort 204 women VDI (at least 30 ng/ml) associated with decreased odds of CD4 + recovery ( % CI: ) Netherlands 67 Cross-sectional 252 adults Vit D status did not affect CD4 + cell recovery France 61 Tanzania adults Low vit D associated with lower CD4 + cell counts 1,103 adults VDD (< 20 ng/ml) not associated with change in CD4 + cell count USA 50 Cross-sectional 112 adults No association between vit D and CD4 + cell count Cambodia; India; South Africa 149 Cross-sectional 74 adults Vit D levels did not correlate with TB immune restoration disease Uganda 87 Cross-sectional 162 adults No difference in Vit D levels in patients developing TB immune restoration disease compared with those not developing the disease South Africa 85 Cross-sectional 174 black Africans VDD ( 50 nmol/l) associated with susceptibility to active TB Tanzania 148 Cohort 1,103 adults VDD significantly associated with incident pulmonary tuberculosis (HR: 2.89; 95% CI: ; p = 0.03) and incident oral thrush (HR: 1.96; 95% CI: ; p = 0.05 vs. vit D sufficiency. USA 46 Cohort 480 HIV infected uninfected women Tanzania 147 VDD ( 20 ng/ml) independently associated with bacterial vaginosis in HIV infection (aor: 3.12; 95% CI: ) but not in noninfection 884 pregnant women Low vit D levels (< 32 ng/ml) associated with significantly higher levels of respiratory infections (HR: 1.27; 95% CI: ) and thrush (HR: 2.74; 95% CI: ) USA 95 Cohort 84 women VDD positively associated with oral candidiasis (p = 0.019) (continue) 6

7 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S2. Studies reporting consequences of vitamin D insufficiency/deficiency in HIV-infected adults (excluding bone health/parathyroid hormone) (continued) Disease or physiologic state Disease progression Perinatal outcomes Location Study type Study population Outcome of VDD/I Tanzania 144, pregnant women Low vit D levels (< 32 ng/ml) associated with 43% higher risk of wasting (BMI 18 kg/m 2 ; HR: 1.43; 95% CI: ), and with progression of HIV disease (RR: 1.20; 95% CI: ) France 69 Cross-sectional 2,000 adults VDD (< 12 ng/ml) independently associated with higher risk of AIDS events and mortality Italy 68 Cohort 810 adults VDD moderately associated with risk of severe disease, AIDS, and mortality Tanzania 82 1,103 adults VDD (< 20 ng/ml) significantly associated with increased mortality (HR: 2.00; 95% CI: ; p = 0.009) Tanzania 148 Cohort 1,103 adults VDD significantly associated with wasting (HR: 3.10; 95% CI: ; p = 0.009) Multiple 90 Cohort 455 adults Baseline VDI independently associated with disease progression and death USA 50 Cross-sectional 112 adults Non-linear relationship between vit D levels and HIV viral load Tanzania 101 Tanzania 150 India 103 Case-control 90 cases (HIV + transmitting mothers); 90 controls (HIV + non-transmitting mothers 884 pregnant women Maternal low vit D levels (< 32 ng/ml), children at higher risk (RR: 1.11; 95% CI: ) of cough and increased risk of stunted growth (RR: 1.29; 95% CI: ) and being underweight (RR: 1.33; 95% CI: ) 884 pregnant women No association between maternal vit D levels and adverse pregnancy outcomes and premature birth. Low maternal vit D levels (< 32 ng/ml) associated with higher risk of mother-to-child transmission of HIV (50%; 95% CI: 2-120) at 6 weeks; 2-fold (95% CI: ) higher risk of mother-to-child transmission of HIV via breast feeding. Low maternal vit D levels, children at higher risk (61%; 95% CI: ) of dying VDD not associated with mother-to-child transmission at 12 months (aor 0.66; 95% CI: ) aor: adjusted odds ratio; ARV: antiretroviral; BMI: body mass index; CI: confidence interval; HR: hazard ratio; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk; SUN: Study to understand the natural history of HIV and AIDS in the era of effective therapy; TB: tuberculosis; USCF: University of California-San Francisco study of the consequences of the protease inhibitor era ; WIHS: Women s Interagency HIV study; VDD: vitamin D deficiency; VDI: vitamin D insufficiency; vit D: vitamin D. 7

8 AIDS Reviews. 2014;16 Table S3. Factors associated with and not associated with vitamin D insufficiency/deficiency in HIV-positive adults Traditional factors Miscellaneous factors HIV-specific factors ARV-related factors Factors associated with VDD/I Black/nonwhite ethnicity/dark Lack of exercise 45* Low CD4 + cell count various skin 37-39*,41*,45*,48,51*,58*,59,64*,65*,67*,68*,69,70-72*,77*,90*,92,93,94*,96,125* thresholds 48,54*,70*,79*,94* HAART/combination ARV use 48,54*,55*,70*,79*,99*,109*,118* Female gender 39*,67*,72*,74,78-80*,84* Smoking/tobacco use 54*,75*,107 CD4 + cell count 96 Non-PI based regimen 93 Older age 69,74,78*,80*,93 High ESR 102* Higher CD4 + cell count 62*,82* Use of ZDV 51*,58*,64* Younger age 67*,82* Low albumin levels 39*,67* Lower CD8 cell count 67*,102* NNRTI use 37*,55*,62*,67*,73*,74,91,107,111 High body mass index 37*,38*,45*,51*,64*,90*,93,94*,135 Hypercholesterolemia 99* Each 1 log 10 lower baseline HIV-1 RNA 90* Low body mass index 55*,73*,78*,90* High estimated glomerular filtration rate 54*,65*,84* HIV viral load > 50 copies/ml 41* Lack of/low exposure to sunlight 71*,75*,100 High blood glucose 65* Lack of HIV viral suppression 71* Spring or winter High parathyroid hormone levels 65*,67*,84*,135 AIDS 62*,68* sampling/season 51*,54*,58*,59,62*,68*,69,70*,73*,76*,79*,82*,85*,90*,112* Summer/autumn 92 Hypertension 45* Length of HIV infection 73* Low calcium intake 67*,100 Previous history of severe diseases 68* Low vitamin D intake 38*,44*,64* Active tuberculosis 85* Factors not associated with VDD/I HCV coinfection 62*,73*,75*,84* Current EFV use 36*,42*,45*,54*,55*,58*,70*,71*,79-81* White skin color 53*,59,62* Renal insufficiency 45* Undetectable HIV RNA 94* HAART/cART use 38*,75*,80*,104,112*,125*,127 Age 54*,94*,104 Glomerular filtration rate 94* Longer time since HIV diagnosis 62* Recent PI use 37*,55*,69,74,77*,94*,135 Body mass index 54*,62*,80*,113 Glucose level 37*,80* HIV + status 94* Type of ART 59,72*,96,98* UV/sun exposure 45*,59,84* Lipid level 37* CD4 + count 80*,104 Certain ARV regimens 54* Daily intake of vitamin D 84* Cardiovascular disease 80* HIV factors 38* TDF use 39* Use of multivitamin supplements 37*,96 HCV coinfection 80*,112* Years with HIV infection 104,125* Use of calcium supplements/calcium serum levels 84*,96,113 Previous AIDS 54* Female gender 37*,54* AIDS disease progression 80* *Based on detailed statistical analyses (i.e. univariate, bivariate, multivariate, or multiregression). ART: antiretroviral therapy; ARV: antiretroviral; cart: combined antiretroviral therapy; EFV: efavirenz; ESR: erythrocyte sedimentation rate; HAART: highly active antiretroviral therapy; HCV: hepatitis C virus; NNRTI: nonnucleoside reverse transcriptase inhibitor; PI: protease inhibitor; UV: ultraviolet; ZDV: zidovudine. 8

9 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S4. Studies reporting the effect of nonnucleoside reverse transcriptase inhibitors on vitamin D levels in HIV-positive adults Location Study type Study population ARV treatment experience Effect of ARV on vitamin D Netherlands 67 Cross-sectional on NNRTI-based regimen. Median (Q1-Q3) HAART duration 238 ( ) weeks NNRTI treatment significantly associated with VDD USA 37 Cross-sectional 139 Mean (SD) NNRTI duration 1.3 (1.5) years Use of NNRTIs for 6 months significantly associated with VDI (arr: 2.45; 95% CI: ; p < 0.001) USA 107 Cross-sectional 62 men 19 on NNRTI; 37 on a PI under routine care for at least 2 months Median vit D levels significantly lower with NNRTI- vs. PI-based regimens (p = ). With NNRTIs, higher prevalence of VDD (14/19) vs. PIs (11/37) use (p = ) Switzerland 62 Cohort months on cart NNRTI use resulted in low vit D serum levels Spain adults Accumulated exposure to ARVs of 947 patient-years (44% received TDF + NNRTI; 138 given EFV) VDD associated with NNRTI therapy (18.05 vs ng/ml [non-nnrti]) Italy 74 Cross-sectional 90 adults Median (IQR) time of therapy 126 (25-171) months Lower proportion of patients treated with NNRTIs (71.5%) had low vit D levels vs. those on PIs (96%) (p = 0.025) Italy 111 Cross-sectional 172 adults 60 on NNRTIs (n = 57; NVP 24; EVF 33) or triple NRTIs (n = 3); 20 HAART-naive; Mean (SD) time on NNRTI = 13.5 ± 8.7 months; on NRTI = 50.8 ± 32.4 months Significant decrease (20%) in 1,25(OH)2D levels vs. treatment-naive controls USA 94 Cross-sectional 1,768 women 350 ARV-naive; 304 on NNRTIs; 34 on PI + NNRTI Recent NNRTI (no PI) use possibly associated with higher odds of VDD (aor: 1.15; 95% CI: ; p = 0.493) compared to no ARV use USA 98 Cross-sectional 16 pregnant women France 122 USA 96 Cross-sectional 89 HIV + postmenopausal women Prepregnancy 56% ARV-naive, 44% had cumulative NRTI, PI and NNRTI use of 52 (7-132), 7 (1-132), and 6 (0-60) months. Gestational NRTI, PI, and NNRTI use totaled 5.5, 4.5, and 0 months 70 adults ARV-naive at baseline then treated for 21 months. All received 2 NRTIs. Boosted PI group (n = 35) (FPV [54%], ATV [20%], SQV [11%], IDV [9%], LPV [6%]. NNRTI group (n = 53) (EFV [69%], NVP [26%]) 80% on ART; of these, PI-based ART 51%; 34% on NNRTI-based ART (75% on EFV, 25% on NVP), 11% on NRTI-based ART, 4% on PI + NNRTIs. No details re duration of treatment Treatment group not predictive of vit D level Compared with baseline, vit D levels remained unchanged at 9 months; tended to fall over next 12 months by 20% (not statistically significant) Vit D levels similar with NNRTI-based ART and EFV use compared with no ART use (continue) 9

10 AIDS Reviews. 2014;16 Table S4. Studies reporting the effect of nonnucleoside reverse transcriptase inhibitors on vitamin D levels in HIV-positive adults (continued) Location Study type Study population ARV treatment experience Effect of ARV on vitamin D France 59 Cohort 422 At baseline, 127 with EFV use; 59 with NVP, ETR use; 140 with NNRTI + TDF UK 72 Cross-sectional 312 adults Mean (range) duration of HIV infection 12 (0-26) years. All on HAART at time of analysis (no other details in abstract) No significant differences in vit D levels related to EFV use No association of low vit D levels and use of EFV (p = 0.347), ETR (p = 0.345), or NVP (p = 0.851) USA 51 Cross-sectional 158 adults On stable ARV 6 months at baseline At baseline, no significant difference in median vit D levels with current use of EFV USA 153 Cross-sectional 23 adults ARV-naive at enrollment. Received ARV therapy for 12 months; EFV-based (n = 12); boosted PI-based (6 on ATV; 4 on LPV; 1 switched from ATV to LPV at 6 months) Compared with baseline, vit D levels slightly lower at 6 months, and slightly higher at 12 months France 54 Cross-sectional 2, ARV-naive; 2,660 on ARV > 3 months No effect of ETR or NVP on VDD EFV only drug significantly associated with VDD (aor: 1.89; 95% CI: ) Belgium adults 12 months of HAART. 43 on PIs Significant decrease in vit D levels with EFV (p = 0.017) and NVP (p = 0.002) use Multiple 58 RCT 221 At screening: PI + 2 NRTIs (n = 128); EFV + 2 NRTIs (n = 61); NVP + 2 NRTIs (n = 22); ZDV/3TC/ABC (n = 10) EFV use at baseline significantly lower (p = ) vit D levels vs. 2 NRTIs/PI reference; with NVP at baseline vit D levels not different from reference UK 70 Cross-sectional 1,077 At time of sampling, 69% taking NNRTI-based cart Current EFV use significantly associated with severe VDD (aor: 2.0; 95% CI: ); NVP use not associated with severe VDD (aor: 0.6; 95% CI: ; p = NS) USA 45 Cross-sectional 672 adults At baseline: 75 cart-naive; 64 previous cart experience; 533 current cart use USA 42 Cross-sectional 463 Received routine care for at least 5 months. 82 ARV-naive; 140 NNRTI-based ARV Thailand 81 Cross-sectional patients received ARVs for median (IQR) of 7.4 ( ) years Spain 71 Cross-sectional 352 adults 37 ARV-naive; 315 ARV-experienced. 129 on NNRTIs. Years (IQR) since start of ARV: 6.4 ( ) VDD patients and 7.2 ( ) non-vdd patients Exposure to EFV (n = 177) higher odds of VDD (aor: 1.98; 95% CI: ) EFV-based regimen associated with VDD (aor: 3.1; 95% CI: ) EFV significantly associated with VDD (OR: 3.60; 95% CI: ) EFV exposure independently associated with VDD/I Belgium 79 Cohort 2,044 adults On ARV (no specific details in abstract) Current EFV use independently associated with severe VDD (continue) 10

11 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S4. Studies reporting the effect of nonnucleoside reverse transcriptase inhibitors on vitamin D levels in HIV-positive adults (continued) Location Study type Study population ARV treatment experience Effect of ARV on vitamin D Thailand 80 Cross-sectional using ARVs for (median IQR) 8.9 (5-10.4) years. 125 on EFV USA 36 Retrospective 87 EFV-based (n = 51); non-efv based (n = 36; 89% given PI/r). On ARVs for 6-12 months Multiple 91 RCT 580 Treatment-naive adults; 290 on RPV + TDF/FTC; 290 on EFV + TDF/FTC for 48 weeks EFV use significantly associated with VDD (OR: 1.9; 95% CI: ; p = 0.001) Increased prevalence of VDD with EFV-based vs. non-efvbased ARV (PR: 1.8; 95% CI: ; p = 0.007) Change from baseline in vit D levels at 48 weeks significantly smaller with RPV ( -0.2 ng/ml) vs. EFV ( -2.5 ng/ml; p = ). Risk of progression to severe VDD significantly higher with EFV (aor: 1.9; p < 0.001) vs. RPV Shading indicates that agents examined in the study resulted in a decrease in vitamin D. ABC: abacavir; aor: adjusted odds ratio; arr: adjusted relative risk; ARV: antiretroviral; ATV: atazanavir; cart: combined antiretroviral therapy; CI: confidence interval; : change from baseline; EFV: efavirenz; ETR: etravirine; FPV: fosamprenavir; FTC: emtricitabine; HAART: highly active antiretroviral therapy; IDV: indinavir; IQR: interquartile range; LPV: lopinavir; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; NVP: nevirapine; OR: odds ratio; PI: protease inhibitor; PR: prevalence ratio; Q: quartile; RCT: randomized controlled trial; RPV: rilpivirine; SD: standard deviation; SQV: saquinavir; TDF: tenofovir disoproxil fumarate; 3TC: lamivudine; VDD: vitamin D deficiency; VDI: vitamin D insufficiency; vit D: vitamin D; ZDV: zidovudine. 11

12 AIDS Reviews. 2014;16 Table S5. Studies reporting the effect of protease inhibitors on vitamin D levels in HIV-positive adults Location Study type Study population ARV treatment experience Effect of ARV on vitamin D Belgium adults 12 months of HAART. 44 on PIs PI-based regimen no difference in vit D levels UK 72 Cross-sectional 312 adults Mean (range) duration of HIV infection 12 (0-26) years. All on HAART at time of analysis (no other details in abstract) USA 98 Cross-sectional 16 pregnant women Pre-pregnancy 56% ARV-naive, 44% had cumulative NRTI, PI and NNRTI use of 52 (7-132), 7 (1-132), and 6 (0-60 months). Gestational NRTI, PI, and NNRTI use totaled 5.5, 4.5, and 0 months. No association of low vit D levels and PI use (p = 0.547) Treatment group not predictive of vit D level USA 37 Cross-sectional 139 adults Mean (SD) PI duration 3.1 (2.2) years Duration of PI use not associated with VDI (arr: 1.00; 95% CI: ; p = 0.989) UK 70 Cross- sectional 1,077 adults At time of sampling, 31% taking RTV-boosted PI-based cart Current PI use not associated with severe VDD (aor: 0.9; 95% CI: ; p = NS) France 59 Cohort 422 adults At baseline, 209 with PI use; 130 with PI + TDF use No significant differences in vit D levels related to PI use France 54 Cross-sectional 2,994 adults 334 ARV-naive; 2,660 on ARV > 3 months No effect of DRV, RTV, SQV, APV, ATV, or LPV on VDD Spain 77 Cross-sectional 450 adults Various cart regimens for varying lengths of time (no specific details in abstract) Only significant effect of cart was lower risk of VDI or VDD seen in patients on boosted PI therapy (OR: 0.08; 95% CI: ; p = 0.018) USA 94 Cross-sectional 1,768 women 350 ARV-naive; 518 on PIs; 34 on PI + NNRTI Recent PI use associated with lower odds of VDD (aor: 0.67; 95% CI: ; p = 0.025) compared to no ARV use France 69 Cross- sectional 2,000 adults 83% on cart Patients using PI at lower odds of VDD USA 42 Cross- sectional 463 adults Received routine care for at least 5 months. 82 ARV-naive; 201 PI-based ARV USA 45 Cross-sectional 672 adults At baseline: 75 cart-naive; 64 previous cart experience; 533 current cart use USA 107 Cross- sectional 62 men 19 on an NNRTI; 37 on a PI under routine care for at least 2 months Canada 135 Cross-sectional 283 adults (Canadian HIV Vascular Study) Not specified in abstract PI-based regimen use associated with decreased odds of VDD Exposure to RTV (n = 210) lower odds of VDD (aor: 0.56; 95% CI: ) Median vit D levels significantly higher with PI- vs. NNRTIbased regimens (p = ). Lower prevalence of VDD with PI (11/37) vs. NNRTIs (14/19) use (p = ) One characteristic with greatest representation in the highest vit D quartile was use of PI-based ARV therapy (p = 0.005) (continue) 12

13 Chloe Orkin, et al.: Vitamin D deficiency in HIV (Supplementary Data) Table S5. Studies reporting the effect of protease inhibitors on vitamin D levels in HIV-positive adults (continued) Location Study type Study population ARV treatment experience Effect of ARV on vitamin D Multiple 58 RCT 221 adults At screening: PI + 2 NRTIs (n = 128); EFV + 2 NRTIs (n = 61); NVP + 2 NRTIs (n = 22); ZDV/3TC/ABC (n = 10) USA 96 Cross-sectional 89 HIV + postmenopausal women 80% on ART; of these, PI-based ART 51%; 34% on NNRTIbased ART (75% on EFV, 25% on NVP), 11% on NRTI-based ART, 4% on PI + NNRTIs. No details re duration of treatment France adults ARV-naive at baseline then treated for 21 months. All received 2 NRTIs. Boosted PI group (n = 35) (FPV [54%], ATV [20%], SQV [11%], IDV [9%], LPV [6%]. NNRTI group (n = 53) (EFV [69%], NVP [26%]) USA 153 Cross-sectional 23 adults ARV-naive at enrollment. Received ARV therapy for 12 months; EFV-based (n = 12); boosted PI-based (6 on ATV; 4 on LPV; 1 switched from ATV to LPV at 6 months) Switching from EFV (p = 0.007) and/or ZDV (p = 0.007) to DRV/r significantly increased vit D levels at week 96 Vit D levels similar with PI-based ART compared with no ART use Compared with baseline, vit D levels remained unchanged at 9 months; tended to fall over next 12 months by 20% (not statistically significant) Compared with baseline, vit D levels slightly lower at 6 months, and slightly higher at 12 months Italy 74 Cross-sectional 90 adults Median (IQR) time of therapy 126 (25-171) months Higher proportion of patients treated with PIs (96%) had low vit D levels vs. those on NNRTIs (71.5%) (p = 0.025) Italy 111 Cross-sectional 172 adults 92 on PI-containing HAART; 20 HAART-naive. Mean (SD) time on PI = 37.5 ± 12.8 months Significant decrease (24%) in 1,25(OH)2D levels vs. treatment-naive controls Shading indicates that agents examined in the study resulted in a decrease in vitamin D. ABC: abacavir; APV: amprenavir; aor: adjusted odds ratio; arr: adjusted relative risk; ARV: antiretroviral; ATV: atazanavir; cart: combined antiretroviral therapy; CI: confidence interval; DRV: darunavir; DRV/r: darunavir/ritonavir; EFV: efavirenz; HAART: highly active antiretroviral therapy; LPV: lopinavir; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; NVP: nevirapine; PI: protease inhibitor; RCT: randomized controlled trial; RTV: ritonavir; SD: standard deviation; SQV: saquinavir; TDF: tenofovir disoproxil fumarate; 3TC: lamivudine; VDD: vitamin D deficiency; VDI: vitamin D insufficiency; vit D: vitamin D; ZDV: zidovudine. 13

14 AIDS Reviews. 2014;16 Table S6. Studies reporting the effect of nucleoside/nucleotide reverse transcriptase inhibitors on vitamin D levels in HIV-positive adults Location Study type Study population ARV treatment experience Effect of ARV on vitamin D Italy 111 Cross-sectional 172 adults 60 on NNRTI (n = 57) or triple NRTIs (n = 3); 20 HAART-naive. Mean (SD) time on NNRTI: 13.5 ± 8.7 months; on NRTI: 50.8 ± 32.4 months Multiple 58 RCT 221 adults At screening: PI + 2 NRTIs (n = 128); EFV + 2 NRTIs (n = 61); NVP + 2 NRTIs (n = 22); ZDV/3TC/ABC (n = 10) France 64 Significant decrease (20%) in 1,25(OH)2D levels vs. treatment-naive controls ZDV use at baseline significantly lower (p = ) vit D levels vs. 2 NRTIs/PI reference. ZDV/3TC/ABC at baseline vit D levels not different from reference 483 adults At least 6 months Low vit D independently associated with ZDV use (p = 0.02) USA 37 Cross-sectional 139 adults Mean (SD) NRTI duration 5.8 (3.8) years Duration of NRTI use not associated with VDI (arr: 1.01; 95% CI: ; p = 0.762) France adults ARV-naive at baseline then treated for 21 months. All received 2 NRTIs. Boosted PI group (n = 35) (FPV [54%], ATV [20%], SQV [11%], IDV [9%], LPV [6%]. NNRTI group (n = 53) (EFV [69%], NVP [26%]) Compared with baseline, vit D levels remained unchanged at 9 months; tended to fall over next 12 months by 20% (not statistically significant) France 54 Cross-sectional 2,994 adults 334 ARV-naive; 2,660 on ARV > 3 months No effect of ZDV, 3TC, ABC, TDF, FTC, or ddi on VDD USA 51 Cross-sectional 158 adults On stable ARV 6 months at baseline At baseline, no significant difference in median vit D levels with current use of ZDV UK 72 Cross-sectional 312 adults Mean (range) duration of HIV infection 12 (0-26) years. All on HAART at time of analysis (no other details in abstract) USA 98 Cross-sectional 16 pregnant women Prepregnancy 56% ARV-naive, 44% had cumulative NRTI, PI, and NNRTI use of 52 (7-132), 7 (1-132), and 6 (0-60 months) Gestational NRTI, PI, and NNRTI use totaled 5.5, 4.5, and 0 months USA 45 Cross-sectional 672 adults At baseline: 75 cart-naive; 64 previous cart experience; 533 current cart use No association of low vit D levels and use of ABC (p = 0.388), ddi (p = 0.571), FTC (p = 0.496), 3TC (p = 0.620), TDF (p = 0.679), or ZDV (p = 0.896) Treatment group not predictive of vit D level Exposure to TDF (n = 263) resulted in lower odds of VDD (aor: 0.69; 95% CI: ) USA 39 Cross-sectional 185 adults (not given in abstract) VDD borderline significance with TDF use (p = 0.09) UK 123 Cohort 56 adults Patients received NNRTI-based therapy for > 12 months. 28 patients received TDF and 28 had other NRTIs (ABC = 24; AZT = 3; ddi = 1) In patients with sufficient vit D levels (> 75 mmol/l), 1,25(OH)2D levels higher with TDF vs. other NRTIs. In patients with VDI (< 75 mmol/l), 1,25(OH)2D levels similar with TDF vs. other NRTIs UK 70 Cross-sectional 1,077 adults At time of sampling, 78% on cart (no specific details on TDF use) Current TDF use not associated with severe VDD (aor: 0.8; 95% CI: ; p = NS) France 59 Cohort 422 adults At baseline, n = 288 with TDF use; n = 130 with PI + TDF use; n = 140 with NNRTI + TDF No significant differences in vit D levels related to TDF use Shading indicates that agents examined in the study resulted in a decrease in vitamin D. ABC: abacavir; aor: adjusted odds ratio; arr: adjusted relative risk; ARV: antiretroviral; cart: combined antiretroviral therapy; CI: confidence interval; ddi: didanosine; EFV: efavirenz; FTC: emtricitabine; HAART: highly active antiretroviral therapy; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; NVP: nevirapine; PI: protease inhibitor; RCT: randomized controlled trial; SD: standard deviation; TDF: tenofovir disoproxil fumarate; 3TC: lamivudine; VDD: vitamin D deficiency; VDI: vitamin D insufficiency; vit D: vitamin D; ZDV: zidovudine. 14