HIV and Fatigue

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.
200819(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 Care 12 (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 gt20 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. 200014F25-32 McComsey GA,
et al. AIDS. 2005191523 Domingo P, et al.
AIDS. 199913226167 Mynarcik D, et al. J AIDS.
2005385356 Walker UA, et al. J AIDS.
20022911721 Roche R, et al. AIDS.
2002161320 Vernochet C, et al. AIDS.
200317217780. Domingo P, et al. AIDS. 1999
13(16)2261-7.
9
Development of Metabolic Disease in HIV Patients
Shikuma, CM, Day L, Gerschenson, M. Current Drug
Targets-Infectious Disorders, 2005.
10
Mitochondria and Macrophages in HIV Lipoatrophy
Model
11
Mitochondrial DNA Polymerase-? Hypothesis

• Mitochondrial DNA polymerase-? hypothesis
• The mitochondrial DNA polymerase-? is the
  principal polymerase required for mitochondrial
  DNA replication
• Susceptible to inhibition by NRTIs
• Inhibition can lead to mtDNA depletion

NRTI
Phosphorylation
NRTI-TP
DNA Pol-g
mtDNAAbundance
mtDNA
mtDNAOxidation
AntioxidantDefenses
OXPHOS
Energetics
ROS
Cell Dysfunction
Velsor LW. Toxicol Appl Pharmacol. 20049910-19.
12
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. 2004495109.
AACTG Metabolic Guides http//aactg.s-3.com/metab
olic/lactic.pdf. McComsey GA, Morrow JD. J Acquir
Immune Defic Syndr. 20033445-9. Dagan T, Sable
C, Bray J, Gerschenson M. Mitochondrion.
20021397-412. Gerschenson, M. and Brinkman, K.
Mitochondrion. 20044(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.
  200819(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 Sep4(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.