Original Article

Bone Mineral Density and Vitamin D Levels in HIV Treatment-Naïve African American Individuals Randomized to Receive HIV Drug Regimens

Authors: Paul P. Cook, MD, Alexandra Te Stang, MD, Lia R. Walker, PhD, Shaw M. Akula, PhD, Fiona J. Cook, MD

Abstract

Objectives: Treatment of human immunodeficiency virus (HIV)–infected patients with tenofovir disoproxil fumarate is associated with a decrease in bone mineral density (BMD). Treatment with efavirenz is associated with vitamin D deficiency. We compared the effects of efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) with the effects of raltegravir, darunavir, and ritonavir (RAL/DRV/r) on BMD and 25-hydroxyvitamin D (25[OH]D) levels in HIV-infected, antiretroviral treatment-naive African American subjects.

Methods: This was a pilot study at a single HIV clinic. Forty HIV treatment-naive African American subjects were screened, 35 of whom were randomized to receive either EFV/FTC/TDF or RAL/DRV/r. All of the subjects received supplemental vitamin D 3 and calcium. CD4 counts, HIV RNA, parathyroid hormone, osteocalcin, N-telopeptide, and 25(OH)D levels were obtained at baseline and at 8, 24, 36, and 48 weeks. Dual-energy x-ray absorptiometry of the spine and hip was performed at baseline and at week 48.

Results: Of the 35 subjects enrolled, 10 patients receiving each regimen completed the study. Median baseline 25(OH)D levels were decreased and similar in both groups. All of the patients had plasma HIV RNA <50 copies per milliliter by week 24. By week 48, there was a sustained increase in 25(OH)D in the RAL/DRV/r group ( P = 0.0004) but not in the EFV/FTC/TDF group ( P = 0.78). There were reductions in BMD of the mean total hip ( P = 0.002) and the mean femoral neck (P = 0.004) in the EFV/FTC/TDF group but not in the RAL/DRV/r group.

Conclusions: Treatment of African American patients with HIV using EFV/FTC/TDF is associated with a reduction in BMD of the hip and sustained reductions of 25(OH)D not seen in the group that received RAL/DRV/r. This phenomenon may have long-term consequences on bone integrity in this population.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Brown TT, McComsey GA, King MS, et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 2009;51:554-561.
 
2. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010;51:963-972.
 
3. Duvivier C, Kolta S, Assoumou L, et al. ANRS 121 Hippocampe study group. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS 2009;23:817-824.
 
4. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203:1791-1801.
 
5. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292:191-201.
 
6. Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 2014;55:13-31.
 
7. Centers for Disease Control and Prevention. HIV among African Americans. http://www.cdc.gov/hiv/group/racialethnic/africanamericans. Accessed May 1, 2016.
 
8. Ginde AA, Liu MC, Camargo CA, Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med 2009;169:626-632.
 
9. Welz T, Childs K, Ibrahim F, et al. Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 2010;24:1923-1928.
 
10. Martin A, Moore C, Mallon PW, et al. Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. AIDS 2013;27:2403-2411.
 
11. Bernardino JI, Mocroft A, Mallon PW, et al. Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. Lancet HIV 2015;2:e464-e473.
 
12. Overton ET, Chan ES, Brown TT, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial. Ann Intern Med 2015;162:815-824.
 
13. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911-1930.
 
14. Kooij KW, Wit FWNM, Bisschop PH, et al. Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease. J Infect Dis 2015;211:539-548.
 
15. Bolland MJ, Grey AB, Gamble GD, et al. CLINICAL Review #: low body weight mediates the relationship between HIV infection and low bone mineral density: a meta-analysis. J Clin Endocrinol Metab 2007;92:4522-4528.
 
16. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies. J Infect Dis 2012;205( Suppl 3 ):S391-S398.
 
17. Dao CN, Patel P, Overton ET, et al. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011;52:396-405.
 
18. Sherwood JE, Mesner OC, Weintrob AC, et al. Vitamin D deficiency and its association with low bone mineral density, HIV-related factors, hospitalization, and death in a predominantly black HIV-infected cohort. Clin Infect Dis 2012;55:1727-1736.
 
19. Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 2012;33:456-492.
 
20. Ding C, Wilding JP, Bing C. 1,25-Dihydroxyvitamin D3 protects against macrophage-induced activation of NFkB and MAPK signalling and chemokine release in human adipocytes. PLoS One 2013;8:e61707.
 
21. Meeker S, Seamons A, Paik J, et al. Increased dietary vitamin D suppresses MAPK signaling, colitis, and colon cancer. Cancer Res 2014;74:4398-4408.
 
22. Matlawska-Wasowska K, Finn R, Mustel A, et al. The Vibrio parahaemolyticus type III secretion systems manipulate host cell MAPK for critical steps in pathogenesis. BMC Microbiol 2010;10:329.
 
23. Cannon G, Callahan MA, Gronemus JQ, et al. Early activation of MAP kinases by influenza A virus X-31 in murine macrophage cell lines. PLoS One 2014;9:e105385.
 
24. Zhu X, Zhou F, Qin D, et al. Human immunodeficiency virus type 1 induces lytic cycle replication of Kaposi’-sarcoma-associated herpesvirus: role of Ras/c-Raf/MEK1/2, PI3K/AKT, and NF-kB signaling pathways. J Mol Biol 2011;410:1035-1051.
 
25. Zhang X, Ma L, Qi J, et al. MAPK/ERK signaling pathway-induced hyper-O-GlcNAcylation enhances cancer malignancy. Mol Cell Biochem 2015;410:101-110.
 
26. Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune Defic Syndr 2016;72:58-64.
 
27. Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses 2013;29:256-265.