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HIV and Fatigue

Learn about the prevalence and causes of fatigue in individuals living with HIV, how it affects daily life, and tools for measuring and managing fatigue. Explore the emerging landscape of HIV complications, including lipoatrophy and body fat abnormalities.

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HIV and Fatigue

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  1. HIV and Fatigue Mariana Gerschenson, Ph.D. Associate Professor of Medicine Chair of the Cell and Molecular Biology Program John A. Burns School of Medicine

  2. Adults and children estimated to be living with HIV, 2007 Eastern Europe & Central Asia 1.5 million [1.1 – 1.9 million] Western & Central Europe 730 000 [580 000 – 1.0 million] North America 1.2 million [760 000 – 2.0 million] East Asia 740 000 [480 000 – 1.1 million] Middle East&North Africa 380 000 [280 000 – 510 000] Caribbean 230 000 [210 000 – 270 000] South & South-East Asia 4.2 million [3.5 – 5.3 million] Sub-Saharan Africa 22.0 million [20.5 – 23.6 million] Latin America 1.7 million [1.5 – 2.1 million] Oceania 74 000 [66 000 – 93 000] Total: 33 million (30 – 36 million)

  3. Background on Fatigue and HIV • HIV+ have prevalence rates of fatigue of up to 98% • Fatigue affects the ability to work, interactions with family & friends, unable to manage finances, and needing an entire day for a simple household task • Fatigue intensity is higher: duration of HIV, in women, older than age 35, Hispanics, disabled subjects, low income, lack of health insurance, and IV drug use Harmon, J.L. et al, J Assoc Nurses AIDS Care. 2008;19(2):90-7.

  4. HIV Fatigue Tools • HIV-Related Fatigue Scale (HRFS)1-Similar to Likert-type 56-item self-report measurements: fatigue intensity and impact of fatigue on daily function, description of fatigue, and triggers of fatigue • Sign and Symptom Checklist HIV (SSC-HIVrev)2 This self-report tool on HIV-related signs and symptoms measures the presence and intensity of 72 symptoms, with 1 = mild, 2 = moderate, and 3 = severe. 1. Barrosso J. and Lynn, M.R., Journal of the Association of Nurses in AIDS Care, 13: 66-75 (2002) 2. Holzemer et al., Journal of the Association of Nurses in AIDS Care12 (5), pp. 60-70 (2001)

  5. HIV Fatigue Etiology • Active infection and co-infections with Hep C or OI. Fatigue is not associated with CD4 levels or viral load • Anemia • Hormonal Imbalances: low testosterone • Psychological factors: depression, anxiety • Poor nutrition: low Vitamin B12 • Sleep and Activity: Efavirenz [Sustiva] can cause nightmares or unusual dreams. • Medication Side Effects

  6. Emerging New Landscape of HIV Complications: • New factors in the HAART era • Potent/Toxic antiretrovirals • Alcohol • Aging • Genetics • Chronic “smoldering” immune • activation • Mitochondrial toxicity HOST HIV • EVOLVING CHRONIC COMPLICATIONS • Altered Phenotypes-Mitochondrial • Fatigue • Wasting/Myopathy • Lipodystrophy • Increased Diabetes/CV Risk • Dementia, Peripheral Neuropathy • Hepatic-Fatty Liver

  7. Lipoatrophy in 2008 • Understanding the mechanism of HIV lipoatrophy continues to be a relevant issue even in the U.S. (where d4T and even ZDV is being utilized less and less) as a recent study utilizing Tenofovir as part of 1st time antiretroviral therapy (A5142) showed that up to 12% of such individuals had limb fat loss of >20% on study* • ZDV or d4T are being used in Asia and Africa *Haubrich RH, et al. Metabolic Outcomes of ACTG 5142: A Prospective, Randomized, Phase III Trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial Treatment of HIV-1 Infection. 14th Conference on Retrovirus and Opportunistic Infections. LA, CA 2007.

  8. Postulated Mechanisms for Body-Fat Abnormatilites by Drug Class • NRTIs • mtDNA polymerase-g inhibition and mtRNA depletion both lead to • Impaired oxidative phosphorylation • Altered ATP levels • Cell apoptosis • Peripheral subcutaneous lipoatrophy with/without visceral fat accumulation → altered WHR • PIs (unboosted “older” therapies: IDV, SQV, RTV, APV) • Inhibition of Glut4 (by IDV) • Insulin resistance • Inhibition of transcription factors, eg. PPAR-g, SREBP-1 (by RTV) • Cellular apoptosis • LPL, ME, and FAS inhibition (by SQV and RTV) • Decreased adipocyte differentiation • NNRTIs • Efavirenz has been shown to suppress lipogenic pathways of adipocytes in vitro Carr A, et al. AIDS. 2000;14:F25-32; McComsey GA, et al. AIDS. 2005;19:15–23; Domingo P, et al. AIDS. 1999;13:2261–67; Mynarcik D, et al. J AIDS. 2005;38:53–56; Walker UA, et al. J AIDS. 2002;29:117–21; Roche R, et al. AIDS. 2002;16;13–20; Vernochet C, et al. AIDS. 2003;17:2177–80. Domingo P,et al. AIDS. 1999 13(16):2261-7.

  9. Age-related increase In Insulin Resistance Direct PI Effect GLUT4 Chronic Inflammatory Changes induced by HIV Cytokine dysregulation Genetic Predisposition Impaired Mitochondrial Activity INSULIN RESISTANCE NRTI-mediated Mitochondrial toxicity in muscle Increased Intramyocellular/ Intrahepatic Fat Insulin-resistance-mediated failure to suppress lipolysis Elevated plasma FFA Hepatic steatosis Lipodystrophy Visceral Adiposity Fat depletion Development of Metabolic Disease in HIV Patients Shikuma, CM, Day L, Gerschenson, M. Current Drug Targets-Infectious Disorders, 2005.

  10. HIV-infected and non-infected, activated monocytes secreting cytokines Monocytes FAT 1 NRTIs Pre-adipocytes and adipocytes 3 2 HIV virus Mitochondrial and cellular dysfunction induced by NRTIs BLOOD 4 Macrophage-induced amplification of inflammation and cellular damage Infiltrating activated macrophages Mitochondria and Macrophages in HIV Lipoatrophy Model

  11. Mitochondrial DNA Polymerase-γHypothesis NRTI • Mitochondrial DNA polymerase-γhypothesis • The mitochondrial DNA polymerase-γ is the principal polymerase required for mitochondrial DNA replication • Susceptible to inhibition by NRTIs • Inhibition can lead to mtDNA depletion Phosphorylation NRTI-TP DNA Pol-g mtDNAAbundance mtDNA mtDNAOxidation AntioxidantDefenses OXPHOS Energetics ROS Cell Dysfunction Velsor LW. Toxicol Appl Pharmacol. 2004;99:10-19.

  12. ART Cytokines HIV HIV Hypothesis: Potential Consequences of Mitochondrial Dysfunction • Metabolic Disease • (LD, IR,  TGs) • DNA polymerase-g • Uncoupling • Transport • Oxidative Stress • Apoptosis • Phosphorylation • Proteolytic Processing • Glycosylation • Lipodystrophy • Neuropathies • Hepatic Steatosis • Myopathy • Pancreatitis • Lactic Acidosis Day L, et al. Mitochondrion. 2004;4:95–109. AACTG Metabolic Guides: http://aactg.s-3.com/metabolic/lactic.pdf. McComsey GA, Morrow JD. J Acquir Immune Defic Syndr. 2003;34:45-9. Dagan T, Sable C, Bray J, Gerschenson M. Mitochondrion. 2002;1:397-412. Gerschenson, M. and Brinkman, K. Mitochondrion. 2004;4(5-6):763-777.

  13. Talk Summary • Fatigue is common in HIV+ patients • Fatigue is associated with HIV complications e.g. lipoatrophy • HIV lipoatrophy has a mitochondrial etiology; mtDNA, mtRNA, OXPHOS, and ATP levels are altered in subcutaneous fat. • Mitochondrial OXPHOS in PBMCs correlates with subcutaneous fat OXPHOS

  14. HIV as a Model for Fatigue • Metabolic syndrome: hypertension, hyperlipidemia, and insulin resistance • Increase in cytokines: TNF-, IL-6, MCP-1, IL-1 • Human tissue or cell specific studies to understand pathogenesis • Minimally invasive systemic biomarker(s) to correlate with prevention, diagnosis, and progression

  15. References for HIV and Fatigue • Harmon, J.L. et al, Demographic and illness-related variables associated with HIV-related fatigue, J Assoc Nurses AIDS Care. 2008;19(2):90-7. • Shikuma, CM, Day L, Gerschenson, M. Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction.Current Drug Targets-Infectious Disorders, 2005. • Gerschenson M, Brinkman K., Mitochondrial dysfunction in AIDS and its treatment. Mitochondrion. 2004 Sep;4(5-6):763-77. Epub 2004 Sep 25. • Highleyman,L. A Comprehensive Look at HIV-Related Fatigue,, 2001, http://www.thebody.com/content/treat/art2640.html.

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