The protease inhibitors and HIV-associated bone loss

Current Opinion in HIV and AIDS

Volumn 11, Issue 3, 2016, Pages 333-342

  Moran, Caitlin A ^a,b   Neale Weitzmann, M ^a,c   Ofotokun, Ighovwerha ^a,b  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Grady Healthcare System   (United States)

^c ATLANTA VA MEDICAL CENTER   (United States)

Author keywords

cART induced bone Loss; Fracture; HIV; Osteopenia; Osteoporosis; Protease inhibitors

Indexed keywords

COBICISTAT PLUS ELVITEGRAVIR PLUS EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; DARUNAVIR PLUS RITONAVIR; EFAVIRENZ; HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE INHIBITOR; LOPINAVIR PLUS RITONAVIR; NELFINAVIR; RITONAVIR; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT;

ANTIVIRAL THERAPY; BONE DENSITY; BONE DEVELOPMENT; BONE DISEASE; BONE METABOLISM; BONE TURNOVER; CELL DIFFERENTIATION; DRUG INDUCED DISEASE; DRUG MECHANISM; FEMUR NECK; FRAGILITY FRACTURE; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; META ANALYSIS (TOPIC); NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOCLAST; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPOROSIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; VITAMIN D METABOLISM; BONE DISEASES, METABOLIC; CHEMICALLY INDUCED; COMPLICATION; FRACTURES, BONE; HIV INFECTIONS;

ANTI-HIV AGENTS; BONE DISEASES, METABOLIC; FRACTURES, BONE; HIV INFECTIONS; HIV PROTEASE INHIBITORS; HUMANS;

EID: 84959212678     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0000000000000260     Document Type: Review

References (80)

1. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 2015; 373:795-807.
2. Gunthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 2014; 312:410-425.
3. World Health Organization Guideline on when to start antiretroviral therapy and on preexposure prophylaxis for HIV 2015. http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/. [Accessed 30 October 2015].
4. Harrison KM, Song R, Zhang X. Life expectancy after HIV diagnosis based on national HIV surveillance data from 25 states, United States. J Acquir Immune Def Syndr 2010; 53:124-130.
5. Aberg JA. Aging, inflammation, and HIV infection. Top Antivir Med 2012; 20:101-105.
6. Smit M, Brinkman K, Geerlings S, et al. Future challenges for clinical care of an ageing population infected with HIV: a modelling study. Lancet Infect Dis 2015; 15:810-818.
7. Rey D, Treger M, Sibilia J, et al. Bone mineral density changes after 2 years of ARV treatment, compared to naive HIV-1-infected patients not on HAART. Infect Dis 2015; 47:88-95.
8. Ofotokun I, McIntosh E, Weitzmann MN. HIV: inflammation and bone. Current HIV/AIDS reports 2012; 9:16-25.
9. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis 2010; 51:937-946.
10. Finkelstein JS, Brockwell SE, Mehta V, et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab 2008; 93:861-868.
11. Bolland MJ, Wang TK, Grey A, et al. Stable bone density in HAART-treated individuals with HIV: a meta-analysis. J Clin Endocrinol Metab 2011; 96:2721-2731.
12. Hansen AB, Obel N, Nielsen H, et al. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial. HIV Med 2011; 12:157-165.
13. Yin MT, Kendall MA, Wu X, et al. Fractures after antiretroviral initiation. AIDS (London, England) 2012; 26:2175-2184.
14. Brown TT, McComsey GA, King MS, et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Def Syndr 2009; 51:554-561.
15. Briot K, Kolta S, Flandre P, et al. Prospective one-year bone loss in treatment-naive HIV+ men and women on single or multiple drug HIV therapies. Bone 2011; 48:1133-1139.
16. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS (London, England) 2006; 20:2165-2174.
17. Triant VA, Brown TT, Lee H, et al. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008; 93:3499-3504.
18. Young B, Dao CN, Buchacz K, et al. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population. Clin Infect Dis 2011; 52:1061-1068.
19. Womack JA, Goulet JL, Gibert C, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One 2011; 6:e17217.
20. Sharma A, Shi Q, Hoover DR, et al. Increased fracture incidence in middle-aged HIV-infected and HIV-uninfected women: updated results from the Women's Interagency HIV Study. J Acquir Immune Def Syndr 2015; 70:54-61.
21. Guerri-Fernandez R, Vestergaard P, Carbonell C, et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. J Bone Miner Res 2013; 28:1259-1263.
22. Prieto-Alhambra D, Guerri-Fernandez R, De Vries F, et al. HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study. J Acquir Immune Def Syndr 2014; 66:90-95.
23. Battalora L, Buchacz K, Armon C, et al. Low bone mineral density and risk of incident fracture in HIV-infected adults. Antivir Ther 2015; Epub ahead of print.
24. Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 1988; 81:1804-1809.
25. 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.
26. 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 atazana-vir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011; 203:1791-1801.
27. Huang JS, Hughes MD, Riddler SA, et al. Bone mineral density effects of randomized regimen and nucleoside reverse transcriptase inhibitor (NRTI) selection from ACTG A5142. HIV Clin Trials 2013; 14:224-234.
28. Mulligan K, Glidden DV, Anderson PL, et al. Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2015; 61:572-580.
29. Brown TT, Ross AC, Storer N, et al. Bone turnover, osteoprotegerin/RANKL and inflammation with antiretroviral initiation: tenofovir versus nontenofovir regimens. Antivir Ther 2011; 16:1063-1072.
30. Wohl DA, Bhatti L, Small CB, et al. The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir. HIV Med 2016; 17:106-117.
31. Kinai E, Nishijima T, Mizushima D, et al. Long-term use of protease inhibitors is associated with bone mineral density loss. AIDS Res Hum Retroviruses 2014; 30:553-559.
32. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS (London, England) 2000; 14:F63-F67.
33. Zuccotti G, Vigano A, Gabiano C, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone 2010; 46:1633-1638.
34. Grant PM, Kitch D, McComsey GA, et al. Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. Clin Infect Dis 2013; 57:1483-1488.
35. Kooij KW, Wit FW, 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.
36. Bedimo R, Maalouf NM, Zhang S, et al. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS (London, England) 2012; 26:825-831.
37. Rockstroh JK, DeJesus E, Henry K, et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 62:483-486.
38. Brown TT, Moser C, Currier JS, et al. Changes in bone mineral density after initiation of antiretroviral treatment with tenofovir disoproxil fumarate/emtrici-tabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. J Infect Dis 2015; 212:1241-1249.
39. Bonnet E, Ruidavets JB, Genoux A, et al. Early loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip study. BMC Infect Dis 2013; 13:293.
40. Duvivier C, Kolta S, Assoumou L, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS (London, England) 2009; 23:817-824.
41. Moyle GJ, Hardy H, Farajallah A, et al. Changes in bone mineral density after 96 weeks of treatment with atazanavir/ritonavir or lopinavir/ritonavir plus tenofovir DF/emtricitabine in treatment-naive patients with HIV-1 infection: the CASTLE body composition substudy. J Acquir Immune Defic Syndr 2015; 68:40-45.
42. Initiation of ART is associated with bone loss independent of the specific ART regimen. Tebas P, Umbleja T, Dube MP, et al., editors. The results of ACTG A5005s. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, CA:; 2007.
43. Curran A, Martinez E, Saumoy M, et al. Body composition changes after switching from protease inhibitors to raltegravir: SPIRAL-LIP substudy. AIDS (London, England) 2012; 26:475-481.
44. Melton LJ 3rd, Looker AC, Shepherd JA, et al. Osteoporosis assessment by whole body region vs. site-specific DXA. Osteoporos Int 2005; 16:1558-1564.
45. Guaraldi G, Zona S, Cossarizza A, et al. Switching to darunavir/ritonavir monotherapy vs. triple-therapy on body fat redistribution and bone mass in HIV-infected adults: the Monarch randomized controlled trial. Int J STD AIDS 2014; 25:207-212.
46. Hamzah L, Tiraboschi JM, Iveson H, et al. Effects on Vitamin D, bone and the kidney of switching from fixed-dose tenofovir disoproxil fumarate/emtricita-bine/efavirenz to darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS). Antivir Ther 2015; Epub ahead of print.
47. Haskelberg H, Mallon PW, Hoy J, et al. Bone mineral density over 96 weeks in adults failing first-line therapy randomized to raltegravir/lopinavir/ritonavir compared with standard second-line therapy. J Acquir Immune Defic Syndr 2014; 67:161-168.
48. Bedimo RJ, Drechsler H, Jain M, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One 2014; 9:e106221.
49. 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 (London, England) 2013; 27:2403-2411.
50. Bloch M, Tong WW, Hoy J, et al. Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks. HIV Med 2014; 15:373-380.
51. Kearney BP, Mathias A, Mittan A, et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr 2006; 43:278-283.
52. Baxi SM, Greenblatt RM, Bacchetti P, et al. Common clinical conditions-age, low BMI, ritonavir use, mild renal impairment-affect tenofovir pharmacoki-netics in a large cohort of HIV-infected women. AIDS (London, England) 2014; 28:59-66.
53. Pruvost A, Negredo E, Theodoro F, et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fuma-rate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Che-mother 2009; 53:1937-1943.
54. Cihlar T, Ray AS, Laflamme G, et al. Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors. Antivir Ther 2007; 12:267-272.
55. Gutierrez F, Fulladosa X, Barril G, et al. Renal tubular transporter-mediated interactions of HIV drugs: implications for patient management. AIDS Rev 2014; 16:199-212.
56. German P, Warren D, West S, et al. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr 2010; 55:323-329.
57. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2015. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. [Accessed 27 January 2016].
58. Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis 2015; 60:1242-1251.
59. Hernandez-Vallejo SJ, Beaupere C, Larghero J, et al. HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell 2013; 12:955-965.
60. Wang MWH, Shi W, Faccio R, et al. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J Clin Invest 2004; 114:206-213.
61. Cotter AG, Mallon PW. The effects of untreated and treated HIV infection on bone disease. Curr Opin HIV AIDS 2014; 9:17-26.
62. Gibellini D, Borderi M, de Crignis E, et al. Analysis of the effects of specific protease inhibitors on OPG/RANKL regulation in an osteoblast-like cell line. Microbiologica 2010; 33:109-115.
63. Fakruddin JM, Laurence J. HIV envelope gp120-mediated regulation of osteo-clastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through inter-feron-gamma/RANKL cross-talk. J Biol Chem 2003; 278:48251-48258.
64. Modarresi R, Xiang Z, Yin M, et al. WNT/beta-catenin signaling is involved in regulation of osteoclast differentiation by human immunodeficiency virus protease inhibitor ritonavir: relationship to human immunodeficiency virus-linked bone mineral loss. Am J Pathol 2009; 174:123-135.
65. Malizia AP, Cotter E, Chew N, et al. HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in primary human osteoblasts. AIDS Res Hum Retroviruses 2007; 23:243-250.
66. Yin MT, Modarresi R, Shane E, et al. Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporos Int 2011; 22:1459-1468.
67. Santiago F, Oguma J, Brown AM, et al. Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir. Biochem Biophys Res Commun 2012; 417:223-230.
68. Ofotokun I, Titanji K, Vunnava A, et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS (London, England) 2016; 30:405-414.
69. Franco JM, Rubio A, Martinez-Moya M, et al. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 2002; 99:3702-3706.
70. Ofotokun I, Titanji K, Vikulina T, et al. Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat Commun 2015; 6:8282.
71. Reid IR, Bolland MJ, Grey A. Effects of Vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet (London, England) 2014; 383:146-155.
72. Hidron AI, Hill B, Guest JL, et al. Risk factors for Vitamin D deficiency among veterans with and without HIV infection. PLoS One 2015; 10:e0124168.
73. Cervero M, Agud JL, Garcia-Lacalle C, et al. Prevalence of Vitamin D deficiency and its related risk factor in a Spanish cohort of adult HIV-infected patients: effects of antiretroviral therapy. AIDS Res Hum Retroviruses 2012; 28:963-971.
74. Havens PL, Stephensen CB, Hazra R, et al. Vitamin D3decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial. Clin Infect Dis 2012; 54:1013-1025.
75. 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.
76. Cozzolino M, Vidal M, Arcidiacono MV, et al. HIV-protease inhibitors impair Vitamin D bioactivation to 1, 25-dihydroxyVitamin D. AIDS (London, England) 2003; 17:513-520.
77. Kim JH, Gandhi V, Psevdos G Jr, et al. Evaluation of Vitamin D levels among HIV-infected patients in New York City. AIDS Res Hum Retroviruses 2012; 28:235-241.
78. Cervero M, Agud JL, Torres R, et al. Higher Vitamin D levels in HIV-infected out-patients on treatment with boosted protease inhibitor monotherapy. HIV Med 2013; 14:556-562.
79. Koga I, Seo K, Yoshino Y, et al. Increase of 25-hydroxyVitamin D levels after initiation of combination antiretroviral therapy. J Infect Chemother 2015; 21:737-741.
80. Pepe J, Mezzaroma I, Fantauzzi A, et al. An oral high dose of cholecalciferol restores Vitamin D status in deficient postmenopausal HIV-1-infected women independently of protease inhibitors therapy: a pilot study. Endocrine 2015; Epub ahead of print.