HIV AIDS Infection by MikeJenny


									Nutrition: A Co-factor in
 HIV Infection/AIDS
Phara Jourdan
Rosabelle Campos
March 28, 2005
   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                      9.       United States
                         2.     Nigeria                          10.       Russian Federation
                         3.     Zimbabwe                         11.       China
 Sub-                    4.     Tanzania                         12.       Brazil
 Africa                  5.     The Congo
                                                                 13.       Thailand
                         6.     Ethiopia
                         7.     Kenya
                         8.     Mozambique

Source: Steinbrook R. The AIDS epidemic in 2004. NEJM. 2004;351:115-117.
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
    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
A retrovirus unknown until early 1980s:
 1.  Cannot replicate outside of living host cells
 2.  Contains only RNA; no DNA
 3.  Destroys the body’s ability to fight infections and
       certain cancers
  4. Infects CD4 cells – the primary target of HIV
 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/mm3.

   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
Opportunistic Infections
          Manifestations of HIV Infection
Primary Infection                   Clinical Latency                       Advanced Disease

often asymptomatic or overlooked    usually asymptomatic                   Symptomatic

symptoms 1-6 weeks after            lymph nodes site of ongoing viral      Plasma viremia begins to rise
infection                           latency
                                                                           CD4 cell count falls further
viral like syndrome: sore throat,   massive viral production
fever, lymphadenopathy, rash                                               A decline in nutrient status or body
                                    destruction of CD4 cells               composition
differential includes EBV, CMV,
hepatitis, toxoplasmosis            a decrease in lean body mass           Opportunistic infections develop:
                                    without apparent total body weight      fever, weight loss,
antibody (ELISA, Western Blot)      change                                 lymphadenopathy, thrush, diarrhea,
may not be detected                                                        malignancies, wasting syndrome,
                                    vitamin B12 deficiency                 neurologic syndrome including
                                    increased susceptibility to food and
                                    water-borne pathogens.
    AIDS Defined
   HIV positive with a CD4 cell count that is or
    has been less than 200 cells/mm3
   HIV positive with a CD4 percent below 14%.

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

Lactic acidosis         Lipodystrophy           Bone marrow       Hypersensitivity
                           Fat accumulation    suppression       reactions
Hepatic toxicity           Lipoatrophy
                                                                  Skin rashes
Pancreatitis            Hyperlipidemia/
                        ? Premature CAD
Peripheral neuropathy

                        Insulin resistance/DM

                        Bone disorders:
                        oesteoporosis and
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

   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    Intestinal Parasites

          Immune Function                                    Dysphagia


             Pro-inflammatory                              Dietary Intake
           Cytokines (TNF alpha)
                                                          Negative Energy
             Metabolic Rate
           Endocrine Disorder                             Fat Loss

         Skeletal Protein Breakdown                      Protein Loss
                                                                        J AIDS 1988
Potential Mechanisms of
AIDS Wasting
 1)   Increased energy
 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
    infections—measured by indirect calorimetry.
   Elevated REE in asymptomatic subjects
   A direct relationship between REE and plasma HIV viral
   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 Kaposi’s
    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

     Hyperlipidemia   Insulin resistance

         Fat                 Fat
     accumulation          atrophy
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
                      •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
   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
   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
   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
    cow’s), 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
   Carnitine’s 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 cont’d                                (Morretti, et al.)

           Small study (n=11), Italy
           Pt’s 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
           Authors propose possibility that carnitine’s 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

      Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000
  Appetite Stimulant: Megestrol
  Acetate (Megace)
     A synthetic derivative of the natural steroid hormone,
     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
       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
        acetate’s 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

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
   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
   HIV/AIDS remains an epidemic worldwide
   Malnutrition is a complication in HIV related morbidity and
   Weight loss is an independent predictor of mortality
   Despite HAART, patients remain at risk for AIDS wasting
   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.

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    Morretti, et al. Effect of L-Carnitine on Human Immunodeficiency Virus-1
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    Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings,
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    Drug Therapy: Treatments for Wasting in Patients with the Acquired
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    Strawford, et al. Resistance Exercise and Supraphisilogic Androgen Thearpy
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    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.

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