HIV-Associated NAFLD: Disease Burden and Management
- 20 Downloads
Purpose of Review
Highly potent anti-retroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) has led to dramatic improvements in quality of life and lifespan in persons living with HIV (PLWH). PLWH, however, are suffering from other comorbid conditions, including non-alcoholic fatty liver disease (NAFLD). This review summarizes the epidemiology and pathophysiology of NAFLD in PLWH and explores unique diagnostic and treatment considerations in this population.
Though it is well established that there is a high prevalence of NAFLD in PLWH, the mechanisms underlying NAFLD in this population are just beginning to be explored. Traditional NAFLD risk factors, including insulin resistance, visceral adiposity, and genetics, have been consistently linked with NAFLD in PLWH. In addition, HIV-related factors including mitochondrial dysfunction, microbiome alterations, and direct effects of the virus and of ART may play a role.
Given the burden of NAFLD in PLWH, further studies are necessary to investigate mechanisms specific to HIV with which to target therapies.
KeywordsHuman immunodeficiency virus Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Anti-retrovirals Persons living with HIV
Human immunodeficiency virus
Non-alcoholic fatty liver disease
Persons living with HIV
Compliance with Ethical Standards
Conflict of Interest:
Alyson Kaplan declares no potential conflicts of interest.
Jennifer C. Price reports grants from Gilead Sciences and Merck and ownership interest (spouse) in Abbvie, Bristol-Myers Squibb, Johnson and Johnson, and Merck, and is an advisory board member of Surrozon.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.UNAIDS. Fact Sheet - World AIDS Day 2018.; 2018.Google Scholar
- 3.Serrano-Villar S, Gutiérrez F, Miralles C, et al. Human immunodeficiency virus as a chronic disease: Evaluation and management of nonacquired immune deficiency syndrome-defining conditions. Open Forum Infect Dis. 2016;3(2). https://doi.org/10.1093/ofid/ofw097.PubMedPubMedCentralCrossRefGoogle Scholar
- 7.Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–555. https://doi.org/10.1053/j.gastro.2014.11.039.PubMedPubMedCentralCrossRefGoogle Scholar
- 11.Moreno-Torres A, Domingo P, Pujol J, Blanco-Vaca F, Arroyo JA, Sambeat MA. Liver triglyceride content in HIV-1-infected patients on combination antiretroviral therapy studied with 1H-MR spectroscopy. Antivir Ther. 2007;12(2):195–203.Google Scholar
- 16.Macías J, González J, Tural C, et al. Prevalence and factors associated with liver steatosis as measured by transient elastography with controlled attenuation parameter in HIVinfected patients. AIDS. 2014;28(9):1279–1287. https://doi.org/10.1097/QAD.0000000000000248.PubMedCrossRefPubMedCentralGoogle Scholar
- 18.Lombardi R, Lever R, Smith C, et al. Liver test abnormalities in patients with HIV monoinfection: Assessment with simple noninvasive fibrosis markers. Ann Gastroenterol. 2017;30(3):349–356. https://doi.org/10.20524/aog.2017.0141.
- 19.Vuille-Lessard É, Lebouché B, Lennox L, et al. Nonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients. AIDS. 2016;30(17):2635–2643. https://doi.org/10.1097/QAD.0000000000001241.PubMedCrossRefPubMedCentralGoogle Scholar
- 21.Kardashian A, Ma Y, Scherzer R, et al. Sex differences in the association of HIV infection with hepatic steatosis. AIDS. 2017;31(3):365–373. https://doi.org/10.1097/QAD.0000000000001334.
- 22.Perazzo H, Cardoso SW, Yanavich C, et al. Predictive factors associated with liver fibrosis and steatosis by transient elastography in patients with HIV mono-infection under long-term combined antiretroviral therapy. J Int AIDS Soc. 2018;21(11):e25201. https://doi.org/10.1002/jia2.25201.PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Lemoine M, Assoumou L, De Wit S, et al. Diagnostic accuracy of noninvasive markers of steatosis, NASH, and liver fibrosis in HIV-Monoinfected individuals at risk of nonalcoholic fatty liver disease (NAFLD): Results from the ECHAM study. J Acquir Immune Defic Syndr. 2019;80(4):e86–e94. https://doi.org/10.1097/QAI.0000000000001936.PubMedCrossRefGoogle Scholar
- 24.•• Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection. AIDS. 2017;31(11):1621–1632. https://doi.org/10.1097/QAD.0000000000001504. Important meta-analysis examining the prevalence of and risk factors for NAFLD and NASH using both non-invasive techniques and liver biopsy.PubMedCrossRefGoogle Scholar
- 25.Lemoine M, Barbu V, Girard PM, et al. Altered hepatic expression of SREBP-1 and PPARγ is associated with liver injury in insulin-resistant lipodystrophic HIV-infected patients. AIDS. 2006;20(3):387–395. https://doi.org/10.1097/01.aids.0000206503.01536.11.PubMedCrossRefGoogle Scholar
- 26.Mohammed SS, Aghdassi E, Salit IE, et al. HIV-positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIVnegative patients. J Acquir Immune Defic Syndr. 2007;45(4):432–438. https://doi.org/10.1097/QAI.0b013e318074efe3.PubMedCrossRefGoogle Scholar
- 29.• Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic steatohepatitis and hepatic fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral therapy. Clin Infect Dis. 2015;60(10):1569–1578. https://doi.org/10.1093/cid/civ101; This study of 62 HIV-monoinfected individuals who underwent liver biopsy abnormal liver enzymes demonstrated that the majority had clinically significant liver pathology with NASH being the most common histologic abnormality.
- 30.• Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: A casecontrol study. Aliment Pharmacol Ther. 2015;41(4):368–378. https://doi.org/10.1111/apt.13052; This retrospective case-control study of 33 HIV+ patients with NAFLD and 33 HIV- patients with NAFLD found that the HIV+ group had increased liver disease severity and higher NASH prevalence on biopsy as compared to the HIV- group. CrossRefGoogle Scholar
- 31.Iogna Prat L, Roccarina D, Lever R, et al. Etiology and severity of liver disease in HIV-positive patients with suspected NAFLD: Lessons from a cohort with available liver biopsies. J Acquir Immune Defic Syndr. 2019;80(4):474–480. https://doi.org/10.1097/QAI.0000000000001942.PubMedCrossRefPubMedCentralGoogle Scholar
- 46.Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74(5):1045–1052. https://doi.org/10.1210/jcem.74.5.1373735.Google Scholar
- 57.Liang JS, Distler O, Cooper DA, et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitorinduced hyperlipidemia. Nat Med. 2001;7(12):1327–1331. https://doi.org/10.1038/nm1201-1327.PubMedCrossRefPubMedCentralGoogle Scholar
- 59.Bonjoch A, Pou C, Pérez-Álvarez N, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: A pilot, prospective, randomized clinical trial. J Antimicrob Chemother. 2013;68(6):1382–1387. https://doi.org/10.1093/jac/dks539.PubMedCrossRefPubMedCentralGoogle Scholar
- 64.Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33. https://doi.org/10.1186/1471-230X-6-33.
- 69.Imajo K, Kessoku T, Honda Y, et al. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology. 2016;150(3):626–637. https://doi.org/10.1053/j.gastro.2015.11.048.PubMedCrossRefGoogle Scholar
- 71.Morse CG, McLaughlin M, Proschan M, et al. Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy. AIDS. 2015;29(17):2297–2302 https://doi.org/10.1097/QAD.0000000000000841.PubMedPubMedCentralCrossRefGoogle Scholar
- 72.•• 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. https://doi.org/10.1002/hep.29367; Important evidence-based consensus guidelines issued by the American Association for the Study of Liver Diseases on the management of NAFLD.PubMedCrossRefPubMedCentralGoogle Scholar
- 74.European AIDS Clinical Society. European AIDS Clinical Society Guifelines 9.0. Uganda Refug Response - Mon Snapshot Oct 2017. 2017.Google Scholar
- 76.European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004; •• Important evidence-based consensus guidelines issued by the European Association for the Study of Liver Disease on the management of NAFLD.
- 80.Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol. 2011;106(3):460–468. https://doi.org/10.1038/ajg.2010.488.PubMedCrossRefPubMedCentralGoogle Scholar
- 92.Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: A systematic review and meta-analysis. BMJ Open. 2017;7(1):e013927. https://doi.org/10.1136/bmjopen-2016-013927.PubMedPubMedCentralCrossRefGoogle Scholar
- 94.• Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–1767. https://doi.org/10.1002/hep.29477; This randomized control trial conducted in 289 subjects with NASH found that there was a decrease in fibrosis stage in those on cenicriviroc, a CCR5/CCR2 antagonist, compared to placebo. PubMedPubMedCentralCrossRefGoogle Scholar
- 96.Klibanov OM, Williams SH, Iler CA. Cenicriviroc, an orally active CCR5 antagonist for the potential treatment of HIV infection. Curr Opin Investig Drugs. 2010;11(8):940–950.Google Scholar
- 97.Thompson M, Saag M, Dejesus E, et al. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS. 2016;30(6):869–878. https://doi.org/10.1097/QAD.0000000000000988.PubMedPubMedCentralCrossRefGoogle Scholar
- 100.• Ajmera VH, Cachay E, Ramers C, et al. Novel MRI assessment of treatment response in HIV-associated NAFLD : a randomized trial of an SCD 1 inhibitor (ARRIVE Trial). Hepatology. 2019. https://doi.org/10.1002/hep.30674; This double-blind, randomized, placebo-controlled trial of 50 patients with HIV-associated NAFLD found no significant reduction in hepatic fat or change body fat and muscle composition with 12 weeks of aramchol. PubMedCrossRefGoogle Scholar
- 101.Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: A randomized clinical trial. JAMA - J Am Med Assoc. 2014;312(4):380–390. https://doi.org/10.1001/jama.2014.8334.PubMedPubMedCentralCrossRefGoogle Scholar
- 102.Calza L, Colangeli V, Borderi M, et al. Improvement in liver steatosis after the switch from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with non-alcoholic fatty liver disease. Infect Dis (Auckl). 2019;51(8):593–601. https://doi.org/10.1080/23744235.2019.1629008.PubMedCrossRefGoogle Scholar
- 104.Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39(6):540–543.Google Scholar
- 106.Tenorio AR, Chan ES, Bosch RJ, et al. Rifaximin has a marginal impact on microbial translocation, T-cell activation and inflammation in HIV-positive immune non-responders to antiretroviral therapy - ACTG A5286. J Infect Dis. 2015;211(5):780–790. https://doi.org/10.1093/infdis/jiu515.PubMedPubMedCentralCrossRefGoogle Scholar