Metabolic Syndromes Associated With HIV

Mitigating the Side Effects of Drug Therapy

William W. Stringer, MD; Fred R. Sattler, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO.12 - DECEMBER 2001

In Brief: HIV infection and highly active antiretroviral therapy (HAART) are associated with a variety of metabolic disorders such as AIDS wasting syndrome, cachexia, sarcopenia, metabolic dysregulation, lipodystrophy, abnormalities of serum lipids, and lactic acidosis. Adjunctive therapies (eg, diet, antilipid therapy), risk-factor modification (eg, smoking cessation, blood pressure control), aerobic exercise, and anabolic treatments can be used to mitigate the effects of HIV infection and the adverse effects of HAART, thereby improving long-term health in individuals infected with HIV.

In the past, a positive blood test for human immunodeficiency virus (HIV) meant certain death within a short period. Recent medical discoveries and continuing research have led to treatments that allow many patients to survive longer and feel well enough to continue normal activities for a greater length of time. HIV infection is increasingly becoming a more chronic disease that may eventually result in a near-normal life span.

Current Medical Therapy for HIV

Before 1996, essentially the only medicines available to treat HIV infection were zidovudine (AZT), didanosine, and zalcitabine, and life expectancy was short. However, in recent years several new classes and types of HIV medications have been combined to form the basis for highly active antiretroviral therapy (HAART) (1-3). This has resulted in dramatic decreases in the mortality and morbidity from HIV in the United States and Western Europe (4); therefore, increasing consideration must be given to the long-term health of individuals infected with HIV, especially because HIV infection and treatment may increase the risk of other common diseases such as heart disease, diabetes, or hypercholesterolemia.

The major classes of HIV medications used today are nucleoside analog reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (table 1) (5,6). As new classes and medications become available, it is important to consult sources that are routinely updated and accurate. The US Department of Health and Human Services/Henry J. Kaiser Family Foundation document (1) is an excellent source for information, as are the Internet resources at the Medscape Web site and the Journal of the American Medical Association HIV/AIDS information center Web site (table 2).

TABLE 1. Drugs Licensed in the United States for the Treatment of HIV Infection
Drug	Common Formulation	Typical Dosage*	Adverse Effects
Nucleoside Reverse Transcriptase Inhibitors
Zidovudine (AZT) (Retrovir)**	300-mg tablets	300 mg PO bid	Anemia
Didanosine (ddI) (Videx)	200-mg tablets	400 mg PO qhs	GI upset, pancreatitis
Zalcitabine (ddC) (Hivid)	0.75-mg tablets	0.75 mg PO tid	Neuropathy
Stavudine (d4T) (Zerit)	40-mg capsules	40 mg PO bid	Neuropathy, mitochondrial abnormalities
Lamivudine (3TC) (Epivir)**	150-mg tablets	150 mg PO bid	Rare
Abacavir sulfate (ABC) (Ziagen)	300-mg tablets	300 mg PO bid	Rash, fevers
Nonnucleoside Reverse Transcriptase Inhibitors
Nevirapine (Viramune)	200-mg tablets	200 mg PO bid***	Rash
Delavirdine mesylate (Rescriptor)	100-mg tablets	400 mg PO tid	Rash
Efavirenz (Sustiva)	200-mg capsules	600 mg PO qhs	Altered mental state
Protease Inhibitors
Ritonavir (Norvir)	100-mg capsules	600 mg PO bid	GI upset, paresthesias
Indinavir sulfate (Crixivan)	400-mg capsules	800 mg PO q8h	Nephrolithiasis
Saquinavir (Fortovase)	200-mg capsules	1,200 mg PO q8h	Nausea
Nelfinavir mesylate (Viracept)	250-mg tablets	1,250 mg PO bid	Diarrhea
Amprenavir (Agenerase)	150-mg capsules	1,200 mg PO bid	Nausea
*For adults with normal renal and hepatic function. **Also available as Combivir, a fixed-dose combination of 300 mg zidovudine and 150 mg lamivudine per tablet; dose is one tablet orally twice daily. **Initial oral dose is 200 mg daily for 2 weeks. GI=gastrointestinal Reprinted with permission from Wolfe PR: Practical approaches to HIV therapy: recommendations for the year 2000. Postgrad Med 2000:107(4):132.

TABLE 2. Web Sites Offering Regular Updates on HIV Treatment

Medscape: http://hiv.medscape.com/updates/quickguide

JAMA HIV/AIDS information: http://www.ama-assn.org/special/hiv/

HIV/AIDS Treatment Information Service: http://www.hivatis.org

Adult AIDS Clinical Trials Group: http://aactg.s-3.com

American Diabetes Association (ADA): http://www.diabetes.org

National Cholesterol Education Program (NCEP): http://www.nhlbi.nih.gov/chd

In addition to the metabolic syndromes associated with HIV, common side effects and complications of the medications include nausea, abdominal pain, diarrhea, fatigue, headache, myopathy, peripheral neuropathy, rash, and hypersensitivity reactions. Changes in blood tests observed with these medications may include liver abnormalities, anemia, hyperamylasemia, and neutropenia. Because the side effects and the drug interactions are myriad, patients require close monitoring for detection of adverse drug events. In addition, HIV medications are known to affect the absorption, metabolism, and excretion of other HIV drugs and common tuberculosis drugs. Such intricacies make HIV therapy quite complex, and treatment is usually best performed by a specialist in HIV therapy. The cost of drug therapy can be up to $2,000 per month, and the routine laboratory monitoring for complications imposes an additional expense. Finally, resistance can develop to all HIV medications, due to virion mutations caused primarily by subtherapeutic drug levels and lack of adherence.

Metabolic Syndromes Associated With HIV

Several distinct syndromes are observed with HIV infection (7) and HAART.

AIDS wasting syndrome (AWS), the loss of body mass from decreased calorie intake, reduced appetite, and starvation, is case defining for AIDS in up to 18% of subjects who test positive for HIV (HIV+). AWS is diagnosed when there is an involuntary loss of greater than 10% of body weight (8). Loss of weight from inadequate calorie intake usually occurs during serious secondary infections when appetite is impaired (9). Diarrhea and malabsorption are additional contributing factors common to AWS. The effect of weight on survival is very important, because patients who have lost more than 10% of their preinfection body weight have a median survival of only 48 days, compared with 520 days for patients with less significant weight losses (10).

Cachexia, the loss of lean body mass despite adequate or even increased intake of calories, is likely associated with hypermetabolism and may be associated with inflammation caused by increased levels of cytokines, interleukins, and interferons (11-13). This type of loss of lean body mass, especially muscle, is associated with active retroviral replication and opportunistic infections and should therefore be treated with appropriate antiretroviral therapy.

Sarcopenia, also called muscle wasting, can be seen with AWS and cachexia and results in decreased lean body mass. It can also result from muscle myopathy caused by the effect of NRTIs, especially AZT (14), on mitochondrial function, or from myositis (an immunodysregulatory effect associated with muscle pain, tenderness, sarcopenia, and elevated muscle enzymes); or it may be related to an HIV-induced myopathy. These may occur with well-controlled HIV infection [high CD4 lymphocyte counts and low HIV polymerase chain reaction (PCR) titers]. These two laboratory markers are used to evaluate the effects of HAART. Specifically, high CD4 counts and low viral titers imply successful HAART; low CD4 counts and high viral titers suggest the opposite.

Metabolic dysregulation, such as lipodystrophy (LD) (lipohypertrophy or lipoatrophy), glucose intolerance, frank diabetes mellitus, and hyperlipidemia are more common in patients who are on HAART. The changes in fat storage, fat distribution, and lipid metabolism are likely related to changes in adipose cell function. LD has a prevalence of 2% to 84% in patients treated with HAART (15), although some patients who were not previously exposed to protease inhibitors (PI-naïve patients) have had similar changes. There is no current gold standard for the diagnosis of LD.

Lipohypertrophy is the deposition of fat that may be observed in 1% to 56% of patients infected with HIV (15). The initial reports of this syndrome in several men involved adipose tissue just behind the neck ("buffalo hump") or visceral abdominal fat ("crix belly" or "protease paunch") that formed without evidence of adrenal cortical overactivity (16). However, deposition of adipose tissue in the breasts, upper torso, or neck is observed in both men and women. Lipohypertrophy with central obesity may be an acceleration of the normal aging process in men that usually results in increased waist-to-hip ratio; however, these changes have been observed in young patients and some infants receiving HAART.

Conversely, lipoatrophy may occur with loss of adipose tissue in the face, arms, or legs. Prevalence is estimated at 1% to 24% (15). Moreover, lipohypertrophy and lipoatrophy may occur in the same patient, and that raises the question of whether we are observing one, or more than one, syndrome (17).

Although changes in fat deposition are troublesome and usually progressive, the most important changes may be at the biochemical level. Carr et al (18) studied 113 HIV+ patients receiving PI therapy. In addition to the morphologic changes described above, biochemical changes in lipid, glucose, uric acid, and insulin levels were observed. Increases were common in serum lipids, total cholesterol, low-density lipoprotein cholesterol (LDL), and triglycerides; reductions in high-density lipoprotein cholesterol (HDL) were also common.

The elevation in blood sugar observed with PI therapy was similar to the changes observed in patients who had type 2 diabetes mellitus (high blood sugars, high insulin levels, and insulin receptor resistance). Associated risk factors frequently seen in type 2 diabetes, including hypertension and hyperuricemia, may also be observed in individuals who have HIV. HIV control was excellent in this study (18), as evidenced by increases in CD4 lymphocyte counts and undetectable levels of HIV RNA with PCR amplification, suggesting that the changes in lipids were not related to poor control of HIV.

HIV infection and PI treatment are associated with elevations in triglycerides and cholesterol, similar to the changes observed with type 2 diabetes in individuals who are not HIV infected (19). Using the 1998 American Diabetes Association (ADA) guidelines, the same study by Carr et al (18) found overt diabetes mellitus in 7% of the PI-treated subjects and impaired glucose tolerance in an additional 16%. Subjects not treated with PIs did not have overt diabetes or glucose intolerance. Most subjects with HAART-induced diabetes were asymptomatic and required an oral glucose tolerance test for diagnosis. Also, the degree of insulin resistance was significantly associated with the degree of lipodystrophy (none, mild, moderate, or severe lipodistrophy was associated with increasing insulin resistance levels of 1.73, 2.25, 2.60, or 3.86 mIU, respectively). Carr et al (18) proposed the HIV case definition for PI-related lipid changes (table 3).

TABLE 3. Indicators for Lipid Changes Related to Protease Inhibitor Therapy

Physical Features*
Clinical evidence (physical exam or patient's report) of:
     Fat wasting of the face, arms, legs, or buttocks (possibly with prominent leg and arm veins)
     Fat accumulation in the abdomen or over the dorsocervical spine

Metabolic Features*
Fasting hyperlipidemia (cholesterol > 5.5 mg/dL or triglyceride > 2.0 mg/dL)
Fasting C-peptide > 2.5 mg/dL
Impaired fasting blood glucose 110 to 126 mg/dL or diabetes > 200 mg/dL on 2-hr blood glucose by oral glucose tolerance test

Exclusion Criteria
3 months before assessment, patient should not have had:
     AIDS-defining event or other severe clinical illness
     Anabolic steroids, glucocorticosteroids, or immune modulators

*The development of one or more of these features since the start of protease inhibitor therapy indicates a lipid change.

Lactic acidosis with hepatic steatosis is a metabolic syndrome associated with HIV infection and HAART. Although fatal cases with markedly elevated lactic acidosis levels and fulminant hepatic steatosis are rare, more modest elevations of lactic acid are not uncommon in patients treated with HAART. It appears that certain HIV medications, especially NRTIs, can affect the ability of the muscle and liver cells to generate adenosine triphosphate (ATP). HIV medications appear to affect the ability of the cytosolic processes (eg, glucose metabolism, tricarboxylic acid cycle) or mitochondria (oxidative phosphorylation) to produce energy, resulting in lactic acidosis. This is not associated with a lack of oxygen but appears to be a disturbance in the metabolic machinery.

Mitochondrial myopathy has been described with long-term zidovudine therapy (20-23); however, other newer NRTI medications, including didanosine, stavudine, and zalcitabine, have also been associated with this syndrome (24-26). Some evidence suggests that the mitochondrial DNA polymerase-gamma function is impaired, resulting in altered mitochondrial DNA and protein synthesis (27).

Recognition of the clinical syndrome of lactic acidosis and hepatic steatosis is difficult because the symptoms (eg, nausea, vomiting, fatigue, muscle or abdominal pain), are usually mild and nonspecific and have a subacute presentation lasting weeks to months. The elevations of hepatic enzymes (eg, aspartate transaminase, alanine transaminase) are not uniformly present. Indeed, even muscle markers of inflammation or dysfunction (eg, creatine kinase or aldolase) may not be seen with myopathy. The electrolytes or arterial blood gases may indicate severe metabolic acidosis or lactic acidosis; a serum lactate level can be obtained to document the diagnosis. Liver biopsy or computed tomography images should document hepatic fat deposition. Withdrawal of all medications with cautious reinstitution of HIV medications (avoiding the suspected NRTI) when the metabolic abnormalities have resolved is usually effective.

Adjuvant Therapies for Metabolic Syndromes

Newer drug therapy has improved life expectancy in individuals infected with HIV to a point where consideration should be given to preventing and mitigating of common metabolic diseases such as coronary artery disease, diabetes, and hypercholesterolemia. Optimal patient management, therefore, may involve a combination of diet therapy, aerobic exercise, antilipid medication, risk-factor modification (eg, smoking cessation, hypertension therapy), and anabolic therapy similar to the long-term health recommendations in people who are not infected with HIV. Some possible therapies related to metabolic syndromes are detailed in table 4 (28-32).

TABLE 4. Proposed Therapies for HIV Metabolic Syndromes
Syndrome	Proposed Therapies
Wasting	Add calories to diet for weight gain
	Address depression, drug side effects, and other factors that may interfere with dietary intake
	Aggressively treat opportunistic infections, especially candidiasis and diarrhea syndromes
	Aggressively use HAART
	Treat hypogonadism, if present
	Consider recombinant human growth hormone, testosterone, anabolic steroids (such as oxandrolone) (28), or possibly insulin-like growth factor-1 (29-32)
Cachexia	Aggressively treat opportunistic infections
	Aggressively use HAART
Sarcopenia	Add calories to diet for weight gain
	Begin or continue aerobic exercise training
	Avoid use of AZT
	Aggressively use HAART
Metabolic dysregulation/lipodystrophy	Adjust calories in diet for weight control
Begin or continue aerobic exercise training
	Begin or continue risk-factor modification (eg, smoking cessation, hypertension control)
	Use cholesterol-lowering agents such as statins or fibrates
Markedly elevated lactic acid levels with hepatic steatosis	Withdraw all medications and cautiously reinstitute HIV medications (avoiding the suspected NRTI) when metabolic abnormalities have resolved
HAART = highly active antiretroviral therapy; AZT = zidovudine; NRTI = nucleoside analog reverse transcriptase inhibitor

Diet. The long-term diet in individuals infected with HIV who have normal body weight and do not have severe weight loss or protein-calorie malnutrition should conform to recommendations from the ADA (33) and National Cholesterol Education Program (NCEP III) (34). These include reducing the lipid content to 30% of total calories with saturated fat less than 10%, 10% to 20% of calories as protein, and the remainder as carbohydrate (34). These dietary recommendations are especially important in patients treated with PIs who develop metabolic dysregulation. A substantial portion of patients with HIV who are receiving HAART therapy have cholesterol or triglyceride levels that exceed the current NCEP guidelines (table 5) (34,35).

TABLE 5. National Cholesterol Education Program Guidelines for CAD Risk Factors (34,35)

Total cholesterol > 200 mg/dL

Triglyceride level > 200 mg/dL

2 or more risk factors for CAD including:
    Man > 45 years old or woman > 55 years old
    Strong family history for CAD
    Cigarette use
    Hypertension
    Diabetes mellitus
    Low HDL cholesterol (< 40 mg/dL)
    High LDL cholesterol (> 130 mg/dL)*

CAD = coronary artery disease; HDL = high-density lipoprotein;

LDL = low-density lipoprotein

Aerobic exercise. Used as an adjuvant therapy to improve functional status and stimulate the immune system in both uninfected (36) and HIV-infected individuals (37-44), aerobic exercise training may have a positive effect. In individuals with HIV, bicycle or treadmill exercise done in 1-hour sessions, three times per week, for 6 to 12 weeks at a moderate rate (below the lactic acidosis threshold [LAT]), or heavy rate (above the LAT), has been shown to improve aerobic capacity (LAT and maximal oxygen uptake), functional status, lean body mass, weight, mood (reduced depressive symptoms), and quality of life.

Aerobic exercise training does not appear to have harmful effects on the immune system of an individual with HIV. No increase in opportunistic infection, decrease in CD4 count, or increase in HIV PCR titers was noted in the above studies. Immune indices (increased candida skin test reactivity and small increases in CD4 counts) may improve (45). The changes observed in immune function with exercise training are quite small and probably not clinically significant; however, the lack of a detrimental effect is clearly important. Therefore, regular aerobic exercise can be recommended with confidence as an important adjunctive therapy.

Aerobic exercise may also have a role in mitigating metabolic dysregulation associated with HIV and HIV therapy, although future research will be required to resolve this issue. Specifically, the adverse changes in glucose, insulin levels, insulin resistance, lipids, weight, and waist-to-hip ratio may be improved in both uninfected (19,41,46,47) and HIV-infected individuals (44,45) who perform aerobic exercise; however, regional changes in adipose tissue may not be ameliorated. Studies are currently underway to confirm the role of aerobic exercise training on metabolic syndromes in individuals with HIV, both in those receiving HAART, and in those about to start.

Lipid-lowering medication. Initial attempts to achieve lipid goals should include a low-fat, low-cholesterol diet combined with aerobic exercise. However, if these attempts fail to achieve the expected result within 6 months, medications to reduce lipids (cholesterol and/or triglycerides) should be considered, especially if other risk factors for coronary artery disease are present.

To reduce cholesterol in individuals who are HIV+, the Adult AIDS Clinical Trials Group (see table 2) recommends statins as excellent first-line agents for lowering cholesterol. PIs may increase serum statin drug levels (eg, simvistatin: 31-fold increase, atorvastatin calcium: 4.5-fold increase) or decrease them (pravastatin sodium: 0.5-fold decrease); therefore, initial dosage and monitoring of lipid-lowering effects are important. In addition, the statins might also lower PI drug levels since all of these are metabolized by CYP3A4, the same cytochrome P-450 enzymes that are induced by all of the statins except pravastatin. Until more data are available on the interactions of these classes of drugs, statin therapy should be instituted only after aggressive attempts have been made to lower levels of LDL cholesterol by other means, such as diet and exercise.

The preferred approach for lipid-lowering therapy is to begin with 20 mg of pravastatin or 10 mg of atorvastatin calcium given each evening at bedtime. If triglycerides are also elevated, fibrates such as gemfibrozil (600 mg twice a day) or micronized fenofibrate (200 mg once a day) are effective and have minimal risk for adverse effects. Of course, concern exists that the concomitant use of statins and fibrates may increase the risk for rhabdomyolysis. Niacin should be avoided because its use has frequent side effects and may increase insulin resistance, and bile sequestering resins may affect gastrointestinal absorption of other HIV drugs.

Risk-factor modification. Long-term smoking cessation and control of hypertension (defined as >140 mm Hg systolic and > 90 mm Hg diastolic) should also be a part of adjuvant therapy for HIV+ individuals. Efforts to achieve and sustain these goals are very important to modify long-term CAD risk.

Anabolic therapies. Additional adjunctive therapies, used specifically to improve lean body mass and weight while decreasing fat mass, have focused primarily on the syndrome of HIV-associated wasting (defined as more than 10% loss in body weight). These interventions are primarily anabolic agents such as recombinant human growth hormone, testosterone, anabolic steroids such as oxandrolone (28), or possibly insulin-like growth factor-1 (29-32). Testosterone replacement therapy appears especially promising in patients with low serum testosterone levels and weight loss, although it may not have an additive effect beyond resistance exercise training alone (48). In studies using anabolic androgens, however, the effects of the androgen and progressive resistance training were additive in augmenting lean body tissue and strength (28,49).

High levels of immunoglobulin with specificity to the antivasoactive intestinal peptide/NTM region of the HIV GP120 protein (50,51) may improve long-term survival (52). High levels can be achieved either through passive infusion (53,54) or possibly as a result of exercise training—a potent inducer of this immunoglobulin (55,56).

Vaccine. A final adjunctive therapy that may hold promise is a vaccine to prevent HIV infection or stimulate immune function if HIV infection exists (57). Unfortunately, it is not immediately forthcoming (58).

Evaluating the Effects of Therapy

Several specialized tests are available for clinical and research use to determine the current metabolic status and assess the benefits of HAART, nutritional and medical therapies, aerobic exercise training, and other adjuvant therapies. The tests supplement the history and physical exam (questions and exam focused on weight loss or gain, changes in body habitus and image, dietary habits, drug regimen and schedule, functional capacity, regular exercise activity, etc), and laboratory evaluation of metabolism (fasting insulin, fasting lipid panel, lactic acid level, and, in cases of wasting, total testosterone level). Documentation and quantification of the current physiologic, anatomic, and nutritional status can be used singularly or in combination to assess the current status of the patient with HIV and to evaluate the response to medical and adjuvant therapies.

Cardiopulmonary exercise testing (CPXT) is an integrative physiologic test that continuously measures oxygen uptake, lactic acidosis threshold, ventilation, heart rate, 12-lead electrocardiogram, and oxygen saturation during exercise. CPXT can be used to evaluate exercise limitation in patients with HIV (59,60) and document the effects of aerobic exercise, medical intervention, or other adjunctive therapy, from the level of the respiratory system to the muscle mitochondria.

Strength testing evaluation (48) can be effort-dependent (maximal voluntary muscle strength) or effort-independent (amount of electromyogram signal at a specific work intensity). It objectively evaluates the effects of a strength training program.

Bioelectrical impedance (BIA) (61) is used to assess body composition by determining fat-free mass (FFM) and fat mass. The test measures electrical conductivity through ionically charged liquid media. When validated against established measures of body composition, differential equations can be generated to estimate body cell mass or FFM, which are indirect measures of muscle and other components of lean tissue. Fat is derived by subtracting FFM from total weight. BIA may not be optimal to assess changes in body fat in HIV+ patients because the test is insensitive to regional changes in body composition.

Dual-energy x-ray absorptiometry (DEXA) is used to evaluate the changes in body composition of muscle, fat, and bone using the differential absorption of two different electron energy sources by tissues of different density (18,62).

Computerized axial tomography and magnetic resonance imaging are perhaps the most anatomically precise clinical methods to determine body composition, allowing quantification of fat, muscle, bone, and visceral and regional fat accumulation or loss (63). Although expensive, the tests are readily available.

In Summary

HIV infection and HAART can result in various metabolic syndromes. These can range from weight loss with AWS and sarcopenia, to redistribution of body fat, metabolic dysregulation, or drug-induced lactic acidosis. Recognition of these individual syndromes is important for optimal and timely treatment with applicable drug and nondrug therapies. Finally, HIV infection should now be considered a chronic disease, and both drug and nondrug therapy should be offered to mitigate the long-term risk of the metabolic complications of HIV and HAART.

References

1. Department of Health and Human Services, Henry J Kaiser Family Foundation: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Ann Intern Med 1998;128(12 Pt 2):1079-1100
2. Carpenter CC, Cooper DA, Fischl MA, et al: Antiretroviral therapy in adults: Updated recommendations of the International AIDS Society-USA Panel. JAMA 2000;283(3):381-390
3. Slom TJ, Murphy RL: Advances in antiretroviral therapy in HIV-1 disease. Drug Benefit Trends 1999;11(12):22-24, 33-36, 39-42, 44-47
4. Palella FJ, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998;338(13):853-860
5. Chmait S, Lee S, Yih J, et al: Anti-HIV therapy pocket guidelines. Harbor-UCLA Pharmacy News Capsule 2000;16(2):3-4
6. Wolfe PR: Practical approaches to HIV therapy. Postgrad Med 2000;107(4):127-136
7. Babameto G, Kotler DP: Malnutrition in HIV infection. Gastroenterol Clin North Am 1997;26(2):393-415
8. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Morb Mortal Wkly Rep MMWR 1987;36(suppl 1):1S-15S
9. Grunfeld C, Feingold KR: The role of the cytokines, interferon alpha and tumor necrosis factor in the hypertriglyceridemia and wasting of AIDS. J Nutr 1992;122(suppl 3):749-753
10. Chlebowski RT, Grosvenor MB, Bernhard NH, et al: Nutritional status, gastrointestinal dysfunction, and survival in patients with AIDS. Am J Gastroenterol 1989;84(10):1288-1293
11. Nemechek PM, Polsky B, Gottleib MS: Treatment guidelines for HIV-associated wasting. Mayo Clin Proc 2000;75(4):386-394
12. Grunfeld C, Feingold KR: Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992;327(5):329-337
13. Hommes MJ, Romijn JA, Endert E, et al: Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asytmptomatic stage. Am J Clin Nutr 1991;54(2)311-315
14. Wald JJ: The effects of toxins on muscle. Neurol Clin 2000;18(3):695-718
15. Safrin S, Grunfeld C: Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999;13(18):2493-2505
16. Lo JC, Mulligan K, Tai VW, et al: 'Buffalo hump' in men with HIV-1 infection. Lancet 1998;351(9106):867-870
17. Kotler DP: Lipodystrophy: Return of the Splitters. 7th Conference on Retroviruses and Opportunistic Infections 2000; http://primarycare.medscape.com/medscape/cno/2000/retro/Story.cfm?story_id=1009. Accessed 2/15/01
18. Carr A, Samaras K, Thorisdottir A, et al: Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353(9170):2093-2099
19. Meigs JB, Nathan DM, Wilson PW, et al: Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance: the Framingham Offspring Study. Ann Intern Med 1998;128(7):524-533
20. Lewis W, Dalakas MC: Mitochondrial toxicity of antiviral drugs. Nat Med 1995;1(5):417-422
21. Brinkman K, ter Hofstede HJ, Burger DM, et al: Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998;12(14):1735-1744
22. Dalakas MC, Illa I, Pezeshkpour GH, et al: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322(16):1098-1105
23. Mhiri C, Baudrimont M, Bonne G, et al: Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 1991;29(6):606-614
24. Honkoop P, Scholte HR, de Man RA, et al: Mitochondrial injury: lessons from the fialuridine trial. Drug Saf 1997;17(1):1-7
25. Roy PM, Gouello JP, Pennison-Besnier I, et al: Severe lactic acidosis induced by nucleoside analogues in an HIV-infected man. Ann Emerg Med 1999;34(2):282-284
26. Miller KD, Cameron M, Wood LV, et al: Lactic acidosis and hepatic steatosis associated with the use of stavudine: report of four cases. Ann Intern Med 2000;133(3):192-196
27. Tsai CH, Doong SL, Johns DG, et al: Effect of anti-HIV 2'-beta-fluoro-2',3'-dideoxynucleoside analogs on the cellular content of mitochondrial DNA and on lactate production. Biochem Pharmacol 1994;48(7):1477-1481
28. Strawford A, Barbieri T, Van Loan M, et al: Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA 1999;281(14):1282-1290
29. Grinspoon S, Corcoran C, Askari H, et al: Effects of androgen administration in men with AIDS wasting syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129(l):18-26
30. Schambelan M, Mulligan K, Grunfeld C, et al: Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med 1996;125(11):873-882
31. Mulligan K, Tai VW, Schambelan M: Effects of chronic growth hormone treatment on energy intake and resting energy metabolism in patients with human immunodeficiency virus-assoicated wasting: a clinical research center study. J Clin Endocrinol Metab 1998;83(5):1542-1547
32. Ellis KJ, Lee PD, Pivarnik JM, et al: Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone. J Clin Endocrinol Metab 1996;81(8):3033-3038
33. American Diabetes Association: Clinical practice recommendations 1997. Diabetes Care 1997;20(Suppl 1):S1-S70
34. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-2497
35. American College of Physicians: Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults: part 1. Ann Intern Med 1996;124(5):515-517
36. Shephard RJ, Shek PN: Exercise, immunity, and susceptibility to infection: a J-shaped relationship? Phys Sportsmed 1996;27(6):47-66
37. Rigsby LW, Dishman RK, Jackson AW, et al: Effects of exercise training on men seropositive for the human immunodeficiency virus-1. Med Sci Sports Exerc 1992;24(1):6-12
38. LaPerriere A, Fletcher MA, Antoni MH, et al: Aerobic exercise training in an AIDS risk group. Int J Sports Med 1991;12(suppl l):S53-S57
39. Johnson JE, Anders GT, Blanton HM, et al: Exercise dysfunction in patients seropositive for the human immunodeficiency virus. Am Rev Respir Dis 1990;141(3):618-622
40. Lawless D, Jackson CG, Greenleaf JE: Exercise and human immunodeficiency virus (HIV-1) infection. Sports Med 1995;19(4):235-239
41. MacArthur RD, Levine SD, Birk TJ: Supervised exercise training improves cardiopulmonary fitness in HIV-infected persons. Med Sci Sports Exerc 1993;25(6):684-688
42. Lox CL, McAuley E, Tucker RS: Exercise as an intervention for enhancing subjective well-being in an HIV-1 population. J Sports Exerc Psychol 1995;17(4):345-362
43. Perna FM, LaPerriere A, Klimas N, et al: Cardiopulmonary and CD4 changes in response to exercise training in early symptomatic HIV infection. Med Sci Sports Exerc 1999;31(7):973-979
44. Stringer WW: HIV and aerobic exercise: current recommendations. Sports Med 1999;28(6):389-395
45. Stringer WW, Berezovskaya M, O'Brien WA, et al: The effect of exercise training on aerobic fitness, immune indices, and quality of life in HIV+ patients. Med Sci Sports Exerc 1998;30(l):11-16
46. Schwartz RS, Shuman WP, Larson V, et al: The effect of intensive endurance exercise training on body fat distribution in young and older men. Metabolism 1991;40(5):545-551
47. Ross R, Dagnone D, Jones PJ, et al: Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men: a randomized, controlled trial. Ann Intern Med 2000;133(2):92-103
48. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 2000;283(6):763-770
49. Sattler FR, Jaque SV, Schroeder ET, et al: Effects of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with human immunodeficiency virus. J Clin Endocrinol Metab 1999;84(4):1268-1276
50. Veljkovic V, Metlas R, Raspopovic J, et al: Spectral and sequence similarity between vasoactive intestinal peptide and the second conserved region of human immunodeficiency virus type 1 envelope glycoprotein (gp120): possible consequences on prevention and therapy of AIDS. Biochem Biophys Res Commun 1992;189(2):705-710
51. Fust G: Enhancing antibodies in HIV infection. Parasitology 1997;115(suppl):S127-S140
52. Veljkovic V, Metlas R, Jevtovic D, et al: The role of passive immunization in HIV+ patients: a case report. Chest 2001;120(2):662-666
53. Jacobson JM, Colman N, Ostrow NA, et al: Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection. J Infect Dis 1993;168(2):298-305 [published erratum appears in J Infect Dis 1993;168(3):802
54. Levy J, Youvan T, Lee ML: Passive hyperimmune plasma therapy in the treatment of acquired immunodeficiency syndrome: results of a 12-month multicenter double-blind controlled trial. The Passive Hyperimmune Therapy Study Group. Blood 1994;84(7):2130-2135
55. Paul S, Said SI: Human autoantibody to vasoactive intestinal peptide: increased incidence in muscular exercise. Life Sci 1988;43(13):1079-1084
56. Woie L, Kaada B, Opstad PK: Increase in plasma vasoactive intesinal polypeptide (VIP) in muscular exercise in humans. Gen Pharmacol 1986;17(3):321-326
57. D'Souza MP, Cairns JS, Plaeger SF: Current evidence and future directions for targeting HIV entry: therapeutic and prophylactic strategies. JAMA 2000;284(2):215-222
58. Veljkovic V, Metlas R, Kohler H, et al: AIDS epidemic at the beginning of third millennium: time for a new AIDS vaccine strategy. Vaccine 2001;19(15-16):1855-1862
59. Wasserman K: Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications, ed 3. Philadelphia, Lippincott Williams & Wilkins, 1999
60. Stringer WW: Mechanisms of exercise limitation in HIV+ individuals. Med Sci Sports Exerc 2000;32(7 suppl):S412-S421
61. Kotler DP, Burastero S, Want J, et al: Prediction of body cell mass, fat-free mass, and total body water using bioelectrical impedance analysis: effects of race, sex, and disease. Am J Clin Nutr 1996;64(3 suppl):489S-497S
62. Hadigan C, Miller K, Corcoran C, et al: Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 1999;84(6):1932-1937
63. Grinspoon S, Corcoran C, Rosenthal D, et al: Quantitative assessment of cross-sectional muscle area, functional status, and muscle strength in men with the acquired immunodeficiency syndrome wasting syndrome. J Clin Endocrinol Metab 1999;84(1):201-206

The authors wish to acknowledge the National Institutes of Health for its support of Dr Sattler's work (DK-49308 and NCRR GCRC MOI RR-43).

Dr Stringer is the acting chair of the Department of Medicine and chief of General Internal Medicine at Harbor-UCLA Medical Center in Torrance, California. Dr Sattler is a professor of medicine in the Division of Infectious Diseases at Keck School of Medicine at the University of Southern California in Los Angeles. Address correspondence to William W. Stringer MD, Dept of Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Box 459, Torrance, CA 90509; e-mail to stringer@ucla.edu.