Nutrition: A Co-factor in

HIV Infection/AIDS
Progression
Phara Jourdan
Rosabelle Campos
March 28, 2005
Outline
Trends & Prevalence
Overview of HIV Infection/AIDS
Application of HAART
AIDS Wasting Syndrome
HIV-Associated Lipodystrophy
Nutritional Interventions
Case Study
Summary
Discussion
HIV/AIDS Worldwide
38 million people live with
HIV/AIDS worldwide.
Sub-Saharan Africa is home
to 70% of the people
living with HIV.
2.1 million children are infected
with HIV/AIDS in the world
Top HIV/AIDS-Infected Countries
1. South Africa
2. Nigeria
3. Zimbabwe
4. Tanzania
5. The Congo
6. Ethiopia
7. Kenya
8. Mozambique
Source: Steinbrook R. The AIDS epidemic in 2004. NEJM. 2004;351:115-117.
9. United States
10. Russian Federation
11. China
12. Brazil
13. Thailand

Sub-
Saharan
Africa
AIDS Rates reported in 2002, US
Proportion of AIDS Cases, by Race/Ethnicity

AIDS = Acquired Immune
Deficiency Syndrome

Acquired - because it's a condition one must acquire

or get infected with, not something transmitted
through the genes

Immune - because it affects the body's immune

system, the part of the body which usually works to
fight off germs such as bacteria and viruses

Deficiency - because it makes the immune system

deficient

Syndrome - because someone with AIDS may

experience a wide range of different diseases and
opportunistic infections

Modes of Transmission
Unprotected intercourse
Injection drug use
Other unsafe injections
Blood transfusions
Direct blood contact
Mother to child
Sources: 2004 Report on the global AIDS epidemic. Geneva: Joint United Nations Program on HIV/AIDS, July 2004.
Steinbrook R. The AIDS epidemic in 2004. NEJM. 2004;351:115-117.
The Human Immune Deficiency Virus
Pathophysiology of
HIV/AIDS
A retrovirus unknown until early 1980s:
1. Cannot replicate outside of living host cells
2. Contains only RNA; no DNA
3. Destroys the bodys ability to fight infections and
certain cancers
4. Infects CD4 cells the primary target of HIV
infection
Patients infected with HIV are at risk for illness and
death from:
1. Opportunistic infections
2. Neoplastic complications


CD4 Count in HIV infection
The CD4 cell , also known as "T4" or "helper T cell is responsible for
signaling other parts of the immune system to respond to an infection.

Normal counts range from 500 to 1500 cells per cubic millimeter of blood

Initially in HIV infection there is a sharp drop in the CD4 count and then
the count levels off to around 500-600 cells/mm
3
.

CD4 count is a marker of likely disease progression. CD4 percentage tends
to decline as HIV disease progresses.

CD4 counts can also be used to predict the risks for particular conditions
such as Pneumocystis carinii pneumonia, CMV disease or MAI disease.

Treatment decisions are often based on Viral Load and CD4 count.
Natural History of Untreated HIV
Infection
Opportunistic Infections
Manifestations of HIV Infection
Primary Infection Clinical Latency Advanced Disease
often asymptomatic or overlooked

symptoms 1-6 weeks after
infection

viral like syndrome: sore throat,
fever, lymphadenopathy, rash

differential includes EBV, CMV,
hepatitis, toxoplasmosis

antibody (ELISA, Western Blot)
may not be detected
usually asymptomatic

lymph nodes site of ongoing viral
latency

massive viral production

destruction of CD4 cells

a decrease in lean body mass
without apparent total body weight
change

vitamin B12 deficiency

increased susceptibility to food and
water-borne pathogens.
Symptomatic

Plasma viremia begins to rise

CD4 cell count falls further

A decline in nutrient status or body
composition

Opportunistic infections develop:
fever, weight loss,
lymphadenopathy, thrush, diarrhea,
malignancies, wasting syndrome,
neurologic syndrome including
dementia
AIDS Defined

HIV positive with a CD4 cell count that is or
has been less than 200 cells/mm
3

HIV positive with a CD4 percent below 14%.

HIV positive and with an AIDS defining
illness such as PCP, toxoplasmosis, MAC,
Kaposis Sarcoma, etc. regardless of CD4 cell
count
Antiviral Drug Therapy
Nucleoside/
Nucleotide
Analogues
Nonnucleoside
Reverse
Transcriptase
Inhibitors
Protease
Inhibitors
Fusion
Inhibitors
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zalcitabine
Zidovudine
Delavirdine
Efavirenz
Nevirapine
Amprenavir
Atazanavir
Fosamprenavir
Indinavir
Lopinavir/Ritonavir
Nelfinavir
Ritonavir
Saquinavir
Enfuvirtide
How HIV Drugs Work
Adverse Drug Effects
Mitochondrial
dysfunction
Metabolic
abnormalities
Hematologic
complications
Allergic
reactions
Lactic acidosis

Hepatic toxicity

Pancreatitis

Peripheral neuropathy
Lipodystrophy
Fat accumulation
Lipoatrophy

Hyperlipidemia/
? Premature CAD

Hyperglycemia

Insulin resistance/DM

Bone disorders:
oesteoporosis and
osteopenia
Bone marrow
suppression
Hypersensitivity
reactions

Skin rashes
Medication Side Effects
Anorexia
Sore/dry/painful mouth
Swallowing difficulties
Constipation/Diarrhea
Nausea/Vomiting/Altered Taste
Depression/Tiredness/Lethargy

Pathogenesis of Malnutrition
in HIV Infection
Malnutrition can...
Contribute to impaired immune response
Result in more rapid disease progression &
shortened survival
Contribute to increased frequency and severity
of infections
Result in fatigue, loss of appetite, sense of taste
and smell, and decreased quality of life
Decrease tolerance to therapy and lessen
medication efficacy
Weight Loss: Independent
Predictor of Mortality
Weight loss and wasting have been predominant features of HIV disease
progression since the beginning of the HIV/AIDS epidemic and have long been
established as strong predictors of morbidity and mortality in patients infected
with HIV.

Several studies in the pre-HAART era showed that HIV-related wasting was
strongly associated with more rapid disease progression and increased
mortality in HIV-infected patients.

With the advent of HAART and prophylaxis for opportunistic infections, many
AIDS-defining illnesses that were previously frequent are now rarely seen in
successfully treated patients.

So the prevalence of HIV-related wasting syndrome has greatly diminished ;
however, several studies have concluded that patients treated with HAART
were still at risk for wasting.

Wanke et al. found that ~1/3 of HIV-infected patients in the NFHL study who
were treated with HAART were still at risk for wasting. Thus weight loss,
regardless of treatment status, remains a strong predictor of death.



The Wasting Syndrome
The wasting syndrome is defined as weight loss >10% of
baseline body weight with chronic fever, weakness, or
diarrhea in the absence of other related illnesses
contributing to the weight loss.

unexplained weight loss believed to be due to the HIV
virus

The wasting syndrome is so common in HIV infection
that it is classified according to the Center for Disease
Control (CDC 1987) as a diagnostic indicator of AIDS.

Pathophysiology AIDS Wasting
Oxidative Stress Micronutrient Deficiency
Malabsorption/
Dysphagia
Dietary Intake
Negative Energy
Balance
Intestinal Parasites
Protein Loss
Fat Loss
HIV
Opportunistic
Infection
Immune Function
Pro-inflammatory
Cytokines (TNF alpha)
Anorexia
Metabolic Rate
Endocrine Disorder
Skeletal Protein Breakdown
J AIDS 1988
Potential Mechanisms of
AIDS Wasting
1) Increased energy
expenditure
2) Decreased energy intake
3) Altered metabolism
4) Hormonal Alterations

Energy Expenditure
A review of the literature shows:
Increased REE depending on the stage of immunodeficiency
(denoted by the CD4 count) and the presence of active
infectionsmeasured by indirect calorimetry.
Elevated REE in asymptomatic subjects
A direct relationship between REE and plasma HIV viral
burden
Compared with healthy controls, pts with AIDS and active
infections had a 34% increase in BMR; stable pts with AIDS
were found to have 21% increase.


Melchior JC, et al, Mulligan et al
Calculating Energy Needs
BWH standard is BMR x AF x SF + weight
gain (if applicable)

Injury/Stress Factors:
HIV = 8-15%
AIDS = 20-30%
AIDS with secondary infection = 30%

Protein: 1.2 1.8g/kg (depending on clinical status)
Nutritional Problems
Decreased appetite may result from fever, pain, fatigue,
emotional stress, and altered sensations of taste and smell due to
medication side effects.

Lactose intolerance is an early effect of HIV on the intestinal tract
due to the loss of lactase. The HIV infection changes the structure
of the gut wall, resulting in a decreased lactase level. Intolerance
results in fermentation causing abdominal cramping and a
bloated feeling.

Oral Lesions, caused by Candida albicans, herpes, or Kaposis
sarcoma can make chewing and swallowing difficult and painful.


Nutrional Problems (cont)
Diarrhea and malabsorption can result from direct HIV infection in
the intestine but are more often caused by other pathogens such as
bacteria, Crytosporidium, or herpes simplex that take advantage of
the depressed immune system.

Medications can interfere with eating by causing GI discomfort,
nausea, vomiting, diarrhea, and altered taste

Depression often leads to isolation, apathy, neglect of self-care, and
diminished appetite all which can affect immunocompetence

Socioeconomic factors play an important role in whether the
patient can afford adequate and nutritious food.

Altered Metabolism
Early studies documented weight loss and protein
depletion in untreated patients

The application of HAART has led to a decreased
incidence of malnutrition

Syndrome of altered body fat distribution has
emerged (lipodystrophy) associated with PIs

Hypertriglyceridemia, hypercholesterolemia, and
insulin resistance are commonly seen in patients
treated with HAART therapy.

HIV-Associated Lipodystrophy
Fat
atrophy
Fat
accumulation
Hyperlipidemia Insulin resistance
What Causes Lipodystrophy?
Syndrome most likely has a multi-factorial etiology

Most patients who have lipodystrophy started noticing
symptoms while they were on triple-drug therapy.

Lipodystrophy was first reported among patients taking
combinations of drugs that included a protease inhibitor (PI).

There are also some patients who have experienced one or more
symptoms of lipodystrophy without taking any anti-HIV drugs
at all.

It's still not clear what role these anti-HIV drugs play in the
development of lipodystrophy.

What does Lipodystrophy
look like?
Hormonal Factors
Testosterone deficiency: Testostereone levels have been found
to be markedly reduced in some HIV-infected patients and a
reduction in free serum testosterone levels correlates closely
with loss of BCM.

Growth hormone resistance or deficiency: Many HIV-infected
patients with hypogonadism or malnutrition display functional
GH resistance.
Anabolic/Anti-catabolic agent
Important in maintaining protein balance and muscle mass

Nutritional Supplements in HIV
Infection to counteract
AIDS Wasting
MVI
Glutamine
Carnitine
Appetite Stimulant
Hormone Therapy
Resistance Training
Role of Micronutrients in the
Pathogenesis of HIV infection
Micronutrients play important roles in maintaining
immune function and neutralizing the reactive
oxygen intermediates produced by activated
macrophages and neutrophils in their response to
microorganism
Micronutrient deficiencies are common among HIV
infected persons.
Micronutrient deficiency has been associated with
further immunopression, oxidative stress,
subsequent acceleration of HIV replication and CD4+
T-cell depletion. (semba)
Fawzi et al.
Study: Randomized controlled trial of multivitamin
supplementation among HIV-infected pregnant women in
Tanzania.
Subjects: n=1078, 2 yr study
Method: Compared supplementation consisting of
multivitamins alone, vitamin A alone, or both with placebo
Results: Women who were randomly assigned to receive
multivitamin supplementation were
less likely to have progression to advance stages of HIV disease,
had better preservation of CD4+ T-cell counts and lower viral loads
had lower HIV-related morbidity and mortality rates
Vitamin A appeared to reduce the effect of multivitamins and,
when given alone, had some negative effects
Conclusion: Multivitamin supplementation could reduce the
risk of or delay HIV-associated disease and mortality.
New England Journal Medicine, 2004
Glutamine Application in
HIV/AIDS
Glutamine is the most abundant amino acid in the body and is
considered a conditionally essential amino acid during periods
of catabolism.
During periods of increased metabolic stress, glutamine is
released freely from the skeletal muscle, and intracellular
glutamine concentrations fall by more than 50%
Increased de novo synthesis of glutamine in the skeletal muscle
often results in muscle-wasting syndrome
Glutamine synthesis cannot keep up with the higher
requirements during stress.
Individuals deficient in glutamine manifest changes in gut
morphology including increased membrane permeabilitiy
resulting in bacterial translocation, malabsorption, and diarrhea
Lack of support to immunocytes and fibroblasts cause
immunosuppression and impaired wound healing


Glutamine Application in
HIV/AIDS (cont)
Data suggest that glutamine supplementation offers
the potential to limit skeletal muscle wasting, reduce
diarrhea and malabsorption, enhance immune host
defense, and reduce the incidence of opportunistic
infections associated with HIV infection and AIDS
Shabert J et al. Med Hypotheses. 1996;46:252-256

Glutamine: body BCM in AIDS
patients with Weight Loss
Double-blind, placebo-controlled trial
N=26 patients with >5% weight loss since disease onset

Subjects received GLN-antioxidants (40g/d) in divided doses or
glycine (40g/d) as the placebo for 12 wks.
Result: Over 3 mos, the GLN-antioxidant group gained 2.2kg in
body weight (3.2%), whereas the control group gained 0.3kg (0.4%)
P=0.04 for difference between groups.
The GLN-antioxidant group gained 1.8kg in body cell mass,
whereas the control group gained 0.4kg (P=0.007.)
Intracellular water increased in the GLN-antioxidant group but not
in the control group.
In conclusion, GLN-antioxidant supplementation can increase body
weight, body cell mass, and intracellular water when compared
with placebo supplementation.

Shabert J, Winslow C. et al. Nutrition 1999;15:860-864

L-Carnitine in HIV Infection
Carnitine is a conditionally essential amino acid found
predominantly in red meat. It is also found in milk (human and
cows), pork, lamb, tempeh, and supplements.
It is conditionally essential because the body can make it from
lysine and methionine with assistance from Vitamin C and other
compounds produced in the body.
Carnitine is synthesized in the Kidney and stored in the
muscles.
Carnitines function is to shuttle long-chain fatty acids into the
mitochondria to be utilized as fuel.
HIV/AIDS is a risk factor for carnitine deficiency

Carnitine contd (Morretti, et al.)
Small study (n=11), Italy
Pts refusing ART, normal Carnitine levels, stable weight, declining
CD4 counts, asymptomatic
6 g intravenous Carnitine Qday times 150 days
By second week, all subjects report increased feeling of well-being
CD4 cell counts significantly increased by day 90 and 150, but there
was an evident (non-significant) positive trend at day 15 and 30
compared to baseline.
Overall upward trend in CD8 cell counts as well
Only moderate changes in plasma viral load
No toxicity was reported at this level
Authors conclude that carnitine targets immune system rather than
virus
Authors propose possibility that carnitines antiapoptotic effect
could be due to antioxidant activity

Morretti, et al. Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A
Pilot Study, Blood, Vol 91, No. 10, May 15, 1998: pp 3817-3824
Appetite Stimulant: Dronabinol
Derived from delta-9-tetrahydrocannabinol (major active
component of Marijuana)
Useful in decreasing nausea and increasing appetite
Insignificant gains or even loss of total BW
May induce central nervous system events such as anxiety,
confusion, emotional lability and hallucinations, possibly
addictive.
Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

Appetite Stimulant: Megestrol
Acetate (Megace)
A synthetic derivative of the natural steroid hormone,
progesterone.
Improved appetite in a number of studies
Takes two weeks for effect.
Considerable increases in BW, although mostly in body fat
May be due to testosterone lowering effect, not reversed by
supplementation w/testosterone
May induce or exacerbate DM, cause adrenal insufficiency
when abruptly discontinued after long-term use
Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000
Testosterone & Testosterone
Analogues
About half of men with advanced HIV have androgen deficiency.
May contribute to muscle wasting.
May be due to effects of undernutrition, chronic illness, or medications such as Megesterol
acetates effect on gonadotropin secretion.
25% have primary hypogondadism most often idiopathic but may be due to OI, malignant
infiltration of testes, or testicular effects of HIV infection or medication.
Most studies have shown IM testosterone supplementation to result in wt gain, increased
LBM, overall feeling of well-being.
Studies of testosterone analogues show varied efficacy in improving nutritional status but
may carry risks for hepatic toxic effects:
Nandrolone decanoate 100mg/mL IM q 2wks = increased BW, LBM and quality of life.
Oxymethalone 150 mg/day found to have similar results
Testosterone cypionate 200mg IM q 2wks for 3 mos, no result except for increased quality of
life.
Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

Growth Hormone
AIDS pts may be growth hormone resistant. In studies of GH in AIDS pts,
doses used are significantly higher than those required for replacement.
GH has been shown to increase LBM and protein synthesis and reduce urinary
nitrogen excretion.
GH costs ~$18,000/yr but Medicaid has approved reimbursement, making this
therapy more accessible.
Short-term use of growth hormone (12 wks) has effects on wt gain that persist
after therapy is discontinued.
Using GH for short periods when required, rather than as continuous therapy
will minimize costs while maximizing patient nutritional status.
Indicated for use when all other methods have failed and pt has normal
testosterone levels or on replacement testosterone for at least 4-6 wks.
Contraindicated if pt has malignancy

Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000
Resistance Training
Supervised exercise training is a promising anabolic strategy
for pts with AIDS.
Studies of exercise training have shown increased muscle
function, wt gain, strength, LBM.
Effects of resistance training alone in AIDS wasting pts remains
unknown.
However, use of resistance training with testosterone and
oxandralone has been shown to be effective in AIDS pts with
AIDS wasting.


Journal of the American Medical Association, April 14 199, Volume 281(14), pp 1282-1290.
The New England Journal of Medicine, June 3 1999
Resistance Training (cont)
Strawford, et al studied 24 eugonadal men with HIV associated wt loss.
All subjects received supervised progressive resistance exercise with
physiologic IM testosterone replacement 100 mg/wk to suppress
endogenous testosterone for 8 weeks.
Randomization was between anabolic steroid, oxandralone, 20 mg/day
and placebo.
Measured: LBM, nitrogen balance (10d met ward measure), body wt,
muscle strength, and androgen status
Result: 22 completed the study (11per group). Both showed sig increase in N
retention, LBM, wt, and strength. The mean gains were sig greater in
oxandrolone group than in placebo, greater strength gains for upper/lower
body muscle groups by max wt lifted, and dynomometry. Mean HDL
cholesterol dropped sig in oxandrolone group. Protease inhibitors made no
difference in outcome.
Conclusion: moderate androgen regimen (with oxandrolone) substantially
increased lean tissue, strength gains from PRE, compared to testosterone
replacement alone.

Journal of the American Medical Association, April 14 1999
Summary
HIV/AIDS remains an epidemic worldwide
Malnutrition is a complication in HIV related morbidity and
mortality
Weight loss is an independent predictor of mortality
Despite HAART, patients remain at risk for AIDS wasting
syndrome
Contributors of AIDS wasting syndrome include increased energy
expenditure, decreased energy intake, altered metabolism, and
hormonal factors
Multivitamin supplementation could reduce the risk of or delay
HIV-associated disease and mortality.
Data suggest glutamine supplementation may help limit skeletal
muscle wasting and increase BCM in patients with weight loss

Summary (cont)
Pts have been found to be deficient in Carnitine, may benefit from
supplementation since it may have antiapoptic effect through
antioxidant activity.
Appetite Stimulants may result in wt gain, but mostly in fat and may
also have some negative side effects.
Testosterone deficiency may lead to wasting, supplementation may be
beneficial leading to improved sense of well being, strength, etc,
however Testosterone analogues may be hepatotoxic.
Correction of Growth Hormone resistance may help reverse wasting,
but it is a costly intervention if pt does not have Medicaid. Short term
use has been shown to be beneficial.
Resistance training has been shown to increase wt and LBM, but one
study found that training plus oxandralone was most beneficial.


Discussion



Questions?
References
Semba RD, Tang AM. Micronutrients and the pathogenesis of human
immunodeficiency virus infection. Br J Nutrition 1999;81:181-9.
Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of
multivitamin supplements and HIV disease progression and mortality. N Engl
J Medicine 2004;351:23-32.
Melchior JC, Niyongabo T, Henzel D, et al. Malnutrition and wasting,
immunodepression, and chronic inflammation as independent predictors of
survival in HIV-infected patients. Nutrition 1999; 15:865-9
Suttmann U, Ockenga J, Selberg O, et al. Incidence and prognostic value of
malnutrition and wasting in human immunodeficiency virus-infected
outpatients. J Acquir Immune Defic Syndrome Hum Retrovirol 1995;8:239-46.
Silva M. Skolnik PR, Gorbach Sl, et al. The effect of protease inhibitors on
weight and body composition n HIV-infected patients. AIDS 1998; 12:1645-51.
Wanke CA, Silva M, Knox TA, et al. Weight loss and wasting remain common
complications in individuals infected with human immunodeficiency virus in
the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 31:803-5
Tang, Alice M. et al. Weight loss and survival in HIV-Positive Patients in the
Era of Highly Active Antiretroviral Therapy. JAIDS 2002;31:230-236
Mittendorfer B, Gore D, Herndon D, et al. Accelerated glutamine synthesis in
critically ill patients cannot maintain normal intramuscular free glutamine
concentration. J Parenter Enteral Nutri. 1999;23:243-252.

References
Kotler, Donald P. Nutritional Alterations Associated with HIV infection. JAIDS
2000;25:81-87
Ott M, Lambke B, Fischer H, et al. Early changes of body composition in human
immunodeficiency virus-infected patients: tetrapolar body impedance analysis
indicates significant malnutrition. Am J Clin Nutr 1993;57:15-19
Melchior JC, Salmon D, Rigaud D, et al. Resting energy expenditure is increased in
stable, malnourished HIV-infected patients. AM J Clin Nutr 1991;53:437-41
Rivera S, Briggs W, Qian D, et al. HIV RNA levels correlate with prior weight loss.
Mulligan k, Tai VW, Schambelan M. Energy expenditure in human
immunodeficiency virus infection. N engl J Med 1997; 336:70-1.
HIV Prevalence in the United States, 2000. 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, Wash., Feb. 24-28, 2002. Abstract 11.
Centers for Disease Control and Prevention (CDC). HIV and AIDS - United States,
1981-2001. MMWR 2001;50:430-434.4
Centers for Disease Control and Prevention (CDC). HIV Prevention Strategic Plan
Through 2005. January 2001.5.
Centers for Disease Control and Prevention (CDC). HIV/AIDS Surveillance Report
2002;14:1-40.
Gerrior, Jul. Nutritional Challenges in HIV Infection. Tufts University School of
Medicine Nutrition Infection Unit
References
Morretti, et al. Effect of L-Carnitine on Human Immunodeficiency Virus-1
Infection-Associated Apoptosis: A Pilot Study, Blood, Vol 91, No. 10, May 15,
1998: pp 3817-3824
Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings,
April 2000, Volume 75(4), pp 386-394.
Drug Therapy: Treatments for Wasting in Patients with the Acquired
Immunodefeciency Syndrome, The New England Journal of Medicine, June 3
1999, Volume 340(22), pp 1740-50.
Strawford, et al. Resistance Exercise and Supraphisilogic Androgen Thearpy
in Eugonadal Men with HIV-Related Weight Loss: A Randomized
Controlled Trial, Journal of the American Medical Association, April 14 1999,
Volume 281(14), pp 1282-1290.
Shabert J, Winslow C, Lacey JM. Wilmore DW. Glutamine-antioxidant
supplementation increases body cell mass in AIDS patients with weight
loss: a randomized, double-blind controlled trial. Nutrition 1999;15:860-864.
Shabert JK, Wilmore DW. Glutamine deficiency as a cause of human
immunodeficiency virus wasting. Med Hypotheses 1996;46:252-256.