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Current HIV Research


ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Research Article

Association between Nonalcoholic Fatty Liver Disease and Bone Mineral Density in HIV-Infected Patients Receiving Long-term TDF-Based Antiretroviral Therapy

Author(s): Zhijie Xu, Pengyuan He, Jianzhong Xian, Wuzhu Lu, Jingxian Shu, Wentao Luo, Chongjie Gan, Ruoman Ke, Jinyu Xia, Zongping Han and Mingxing Huang*

Volume 19, Issue 1, 2021

Published on: 17 September, 2020

Page: [40 - 46] Pages: 7

DOI: 10.2174/1570162X18999200917120449

Price: $65


Background: Tenofovir (TDF) has a detrimental effect on bone mineral density (BMD), while nonalcoholic fatty liver disease (NAFLD) is associated with a lower BMD.

Objective: To help understand the mutual effects of NAFLD and TDF on BMD, this study was designed to explore the potential association between NAFLD and BMD in HIV-infected patients receiving long-term TDF-based antiretroviral therapy (ART).

Methods: A total of 89 HIV-infected patients who received TDF-based ART for more than three years were enrolled in this cross-sectional study. We measured BMD using an ultrasonic bone density apparatus, and liver ultrasonography was performed to determine the severity of the fatty liver. The association of NAFLD with BMD was examined using multiple logistic regression analyses.

Results: Patients with NAFLD showed a worse BMD status than those without NAFLD. The incidence rates of osteopenia (42.86% versus 25.93%) and osteoporosis (17.14% versus 3.70%) were significantly higher in HIV-infected patients with NAFLD than in those without NAFLD. After multivariate adjustment, the odds ratio (OR) for patients with NAFLD exhibiting a worse BMD status compared with those without NAFLD was 4.49 (95% confidence interval [CI] 1.42, 14.15).

Conclusion: Based on our results, NAFLD was significantly associated with a worse BMD status, including osteopenia and osteoporosis, in HIV patients after receiving long-term TDF-based ART. Furthermore, we may want to avoid using TDF for ART in HIV-infected patients with NAFLD.

Keywords: Bone mineral density, nonalcoholic fatty liver disease, tenofovir, HIV, bone toxicity, bone metabolism.

Graphical Abstract
Lewden C, Bouteloup V, De Wit S, et al. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 2012; 41(2): 433-45.
[] [PMID: 22493325]
Foster C, Lyall EG. Children with HIV: improved mortality and morbidity with combination antiretroviral therapy. Curr Opin Infect Dis 2005; 18(3): 253-9.
[] [PMID: 15864104]
Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 2006; 368(9534): 489-504.
[] [PMID: 16890836]
Ndondoki C, Dabis F, Namale L, et al. [Survival, clinical and biological outcomes of HIV-infected children treated by antiretroviral therapy in Africa: systematic review, 2004-2009]. Presse Med 2011; 40(7-8): e338-57.
[] [PMID: 21295437]
Santini-Oliveira M, Grinsztejn B. Adverse drug reactions associated with antiretroviral therapy during pregnancy. Expert Opin Drug Saf 2014; 13(12): 1623-52.
[] [PMID: 25390463]
Roca B. Adverse drug reactions to antiretroviral medication. Front Biosci 2009; 14: 1785-92.
[] [PMID: 19273162]
Hoosen K, Mosam A, Dlova NC, Grayson W. An update on adverse cutaneous drug reactions in HIV/AIDS. Dermatopathology (Basel) 2019; 6(2): 111-25.
[] [PMID: 31700852]
Berenguer J, Polo R, Lozano F, et al. Expert Panel of GeSIDA and the National Aids Plan. Executive summary of the GeSIDA/National AIDS Plan consensus document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2014). Enferm Infecc Microbiol Clin 2014; 32(7): 447-58.
[] [PMID: 24986715]
Berenguer J, Polo R, Aldeguer JL, et al. Expert Panel of GESIDA and the National AIDS Plan. Executive summary of the GESIDA/National AIDS Plan Consensus Document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2015). Enferm Infecc Microbiol Clin 2015; 33(8): 544-56.
[] [PMID: 26021186]
Soriano V. Update of the DHHS antiretroviral treatment guidelines. AIDS Rev 2014; 16(2): 117-8.
[PMID: 24984766]
Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS 2008; 22(16): 2155-63.
[] [PMID: 18832879]
Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011; 6(8): e23688.
[] [PMID: 21897852]
Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005; 40(8): 1194-8.
[] [PMID: 15791522]
Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Mansky KC. Tenofovir-associated bone density loss. Ther Clin Risk Manag 2010; 6: 41-7.
[PMID: 20169035]
Ryom L, Mocroft A, Kirk O, et al. D:A:D Study Group. Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. J Infect Dis 2013; 207(9): 1359-69.
[] [PMID: 23382571]
Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS 2012; 26(7): 867-75.
[] [PMID: 22313955]
Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis 2010; 51(5): 496-505.
[] [PMID: 20673002]
Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther (Lond) 2014; 19(8): 765-71.
[] [PMID: 24584104]
Casado JL, Bañón S, Santiuste C, et al. Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir. AIDS 2016; 30(2): 231-9.
[] [PMID: 26684820]
Gatanaga H, Tachikawa N, Kikuchi Y, et al. Urinary beta2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses 2006; 22(8): 744-8.
[] [PMID: 16910829]
Day SL, Leake Date HA, Bannister A, Hankins M, Fisher M. Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice. J Acquir Immune Defic Syndr 2005; 38(3): 301-4.
[PMID: 15735448]
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(12): 1791-801.
[] [PMID: 21606537]
Grant PM, Kitch D, McComsey GA, et al. Long-term Bone Mineral Density Changes in Antiretroviral-Treated HIV-Infected Individuals. J Infect Dis 2016; 214(4): 607-11.
[] [PMID: 27330053]
Negredo E, Diez-Pérez A, Bonjoch A, et al. Switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: changes in bone turnover markers and circulating sclerostin levels. J Antimicrob Chemother 2015; 70(7): 2104-7.
[] [PMID: 25769303]
Woodward CL, Hall AM, Williams IG, et al. Tenofovir-associated renal and bone toxicity. HIV Med 2009; 10(8): 482-7.
[] [PMID: 19459988]
Satapathy SK, Sanyal AJ. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin Liver Dis 2015; 35(3): 221-35.
[] [PMID: 26378640]
Lonardo A, Ballestri S, Marchesini G, Angulo P, Loria P. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis 2015; 47(3): 181-90.
[] [PMID: 25739820]
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34(3): 274-85.
[] [PMID: 21623852]
Mantovani A, Gatti D, Zoppini G, et al. Association between nonalcoholic fatty liver disease and reduced bone mineral density in children: A meta-analysis. Hepatology 2019; 70(3): 812-23.
[] [PMID: 30706504]
Eshraghian A. Bone metabolism in non-alcoholic fatty liver disease: vitamin D status and bone mineral density. Minerva Endocrinol 2017; 42(2): 164-72.
[PMID: 27973461]
Upala S, Jaruvongvanich V, Wijarnpreecha K, Sanguankeo A. Nonalcoholic fatty liver disease and osteoporosis: a systematic review and meta-analysis. J Bone Miner Metab 2017; 35(6): 685-93.
[] [PMID: 27928661]
Musso G, Paschetta E, Gambino R, Cassader M, Molinaro F. Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver. Trends Mol Med 2013; 19(9): 522-35.
[] [PMID: 23816817]
Syn WK, Choi SS, Liaskou E, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 2011; 53(1): 106-15.
[] [PMID: 20967826]
Yilmaz Y, Kurt R, Eren F, Imeryuz N. Serum osteocalcin levels in patients with nonalcoholic fatty liver disease: association with ballooning degeneration. Scand J Clin Lab Invest 2011; 71(8): 631-6.
[] [PMID: 21859358]
Indridason OS, Franzson L, Sigurdsson G. Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover. Osteoporos Int 2005; 16(4): 417-23.
[] [PMID: 15776220]
Targher G, Bertolini L, Scala L, et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2007; 17(7): 517-24.
[] [PMID: 16928437]
Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine 2014; 47(1): 70-80.
[] [PMID: 24968737]
Eliades M, Spyrou E, Agrawal N, et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 38(3): 246-54.
[] [PMID: 23786213]
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67(1): 328-57.
[] [PMID: 28714183]
Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54(1): 344-53.
[] [PMID: 21520200]
Liangpunsakul S, Chalasani N. What should we recommend to our patients with NAFLD regarding alcohol use? Am J Gastroenterol 2012; 107(7): 976-8.
[] [PMID: 22764020]
Sanyal AJ. American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123(5): 1705-25.
[] [PMID: 12404245]
Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol 2003; 15(5): 539-43.
[PMID: 12702913]
Krieg MA, Cornuz J, Ruffieux C, et al. Comparison of three bone ultrasounds for the discrimination of subjects with and without osteoporotic fractures among 7562 elderly women. J Bone Miner Res 2003; 18(7): 1261-6.
[] [PMID: 12854836]
Fujiwara S, Sone T, Yamazaki K, et al. Heel bone ultrasound predicts non-spine fracture in Japanese men and women. Osteoporos Int 2005; 16(12): 2107-12.
[] [PMID: 16195817]
Hashmi FR, Elfandi KO. Heel ultrasound scan in detecting osteoporosis in low trauma fracture patients. Orthop Rev (Pavia) 2016; 8(2): 6357.
[] [PMID: 27433300]
Herd RJ, Ramalingham T, Ryan PJ, Fogelman I, Blake GM. Measurements of broadband ultrasonic attenuation in the calcaneus in premenopausal and postmenopausal women. Osteoporos Int 1992; 2(5): 247-51.
[] [PMID: 1392264]
Tatarinov A, Egorov V, Sarvazyan N, Sarvazyan A. Multi-frequency axial transmission bone ultrasonometer. Ultrasonics 2014; 54(5): 1162-9.
[] [PMID: 24206675]
Hans D, Dargent-Molina P, Schott AM, et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet 1996; 348(9026): 511-4.
[] [PMID: 8757153]
Glüer CC, Cummings SR, Bauer DC, et al. Osteoporosis: association of recent fractures with quantitative US findings. Radiology 1996; 199(3): 725-32.
[] [PMID: 8637996]
Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994; 843: 1-129.
[PMID: 7941614]
Okonkwo RI, Weidmann AE, Effa EE. Renal and Bone Adverse Effects of a Tenofovir-Based Regimen in the Treatment of HIV-Infected Children: A Systematic Review. Drug Saf 2016; 39(3): 209-18.
[] [PMID: 26692394]
Bedimo R, Rosenblatt L, Myers J. Systematic review of renal and bone safety of the antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection. HIV Clin Trials 2016; 17(6): 246-66.
[] [PMID: 27809711]
Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr 2008; 152(4): 582-4.
[] [PMID: 18346519]
Gallant JE, Staszewski S, Pozniak AL, et al. 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292(2): 191-201.
[] [PMID: 15249568]
Tebas P, Kumar P, Hicks C, et al. Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks. AIDS 2015; 29(18): 2459-64.
[] [PMID: 26355674]
Casado JL, Santiuste C, Vazquez M, et al. Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients. AIDS 2016; 30(9): 1423-31.
[] [PMID: 26919733]
Li M, Xu Y, Xu M, et al. Association between nonalcoholic fatty liver disease (NAFLD) and osteoporotic fracture in middle-aged and elderly Chinese. J Clin Endocrinol Metab 2012; 97(6): 2033-8.
[] [PMID: 22466338]
Moon SS, Lee YS, Kim SW. Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women. Endocrine 2012; 42(2): 423-9.
[] [PMID: 22407492]
Pirgon O, Bilgin H, Tolu I, Odabas D. Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2011; 75(2): 189-95.
[] [PMID: 21521307]
Purnak T, Beyazit Y, Ozaslan E, Efe C, Hayretci M. The evaluation of bone mineral density in patients with nonalcoholic fatty liver disease. Wien Klin Wochenschr 2012; 124(15-16): 526-31.
[] [PMID: 22850810]
Pardee PE, Dunn W, Schwimmer JB. Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children. Aliment Pharmacol Ther 2012; 35(2): 248-54.
[] [PMID: 22111971]
Chang EJ, Yi DY, Yang HR, Vitamin D. Vitamin D Status and Bone Mineral Density in Obese Children with Nonalcoholic Fatty Liver Disease. J Korean Med Sci 2015; 30(12): 1821-7.
[] [PMID: 26713058]
Golabi P, Sayiner M, Fazel Y, Koenig A, Henry L, Younossi ZM. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis. Expert Rev Gastroenterol Hepatol 2016; 10(1): 63-71.
[] [PMID: 26469309]
Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20(2): 475-85.
[] [PMID: 24574716]
Gunn NT, Shiffman ML. The Use of Liver Biopsy in Nonalcoholic Fatty Liver Disease: When to Biopsy and in Whom. Clin Liver Dis 2018; 22(1): 109-19.
[] [PMID: 29128050]
Hamaguchi M, Kojima T, Itoh Y, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007; 102(12): 2708-15.
[] [PMID: 17894848]
Mishra P, Younossi ZM. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am J Gastroenterol 2007; 102(12): 2716-7.
[] [PMID: 18042105]
Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J Gastroenterol 2019; 25(11): 1307-26.
[] [PMID: 30918425]
Beilfuss A, Sowa JP, Sydor S, et al. Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently. Gut 2015; 64(5): 791-9.
[] [PMID: 25134788]
Papapostoli I, Lammert F, Stokes CS. Effect of short-term vitamin D correction on hepatic steatosis as quantified by controlled attenuation parameter (CAP). J Gastrointestin Liver Dis 2016; 25(2): 175-81.
[] [PMID: 27308648]
Foroughi M, Maghsoudi Z, Ghiasvand R, Iraj B, Askari G. Effect of Vitamin D Supplementation on C-reactive Protein in Patients with Nonalcoholic Fatty Liver. Int J Prev Med 2014; 5(8): 969-75.
[PMID: 25489444]
Barchetta I, Del Ben M, Angelico F, et al. No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. BMC Med 2016; 14(1): 92.
[] [PMID: 27353492]
Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA. Proinflammatory cytokine (TNFalpha/IL-1α) induction of human osteoclast formation. J Pathol 2002; 198(2): 220-7.
[] [PMID: 12237882]
Bauer DC, Glüer CC, Cauley JA, et al. Study of Osteoporotic Fractures Research Group. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. A prospective study. Arch Intern Med 1997; 157(6): 629-34.
[] [PMID: 9080917]

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