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The HIV Wasting Syndrome

Wasting syndrome is a common complication of HIV disease. Wasting can be secondary to HIV infection itself, but is also commonly associated with opportunistic infections (OIs) and HIV-related cancers. Weight loss often foreshadows the onset of an AIDS-defining illness before other clinical manifestations are apparent.

Wasting in AIDS is similar to wasting in cancer cachexia and other serious illness. These syndromes involve dysregulation of metabolism, characterized by catabolism, preferential loss of lean body mass over fat, and, conversely, preferential gain of fat over lean mass when enteral or parenteral therapy is used. This continuous loss of cell mass and negative nitrogen balance promotes progression of AIDS and can hasten death.

Treatment of wasting syndrome in HIV involves appropriate antiretroviral therapy, a careful search for and treatment of OIs, and adequate nutrition. The clinician must also address the metabolic abnormalities that promote wasting.

Prevalence and Clinical Significance

Wasting syndrome is defined as weight loss in excess of 10% from baseline that is associated with chronic diarrhea, fever, or weakness. Between 1987 and 1991, wasting was the second most common AIDS-associated condition reported to the CDC and the only AIDS-associated illness noted in 7.1% of reported cases. Unpublished data from the CDC's Adult-Adolescent Spectrum of Disease Program, which studied AIDS deaths in 10 cities, found that between 1990 and 1994, wasting occurred in 21.6% of cases. This was the fourth most common AIDS-associated condition, after PCP, MAC, and esophageal candidiasis. CDC statistics from 1995 document wasting as the third most common AIDS-indicator condition, after severe immunosuppression and PCP. Wasting is more prevalent in people of low socioeconomic status and women.

For a variety of reasons, clinicians often treat wasting syndrome inadequately. They can be overwhelmed by the difficulties and competing side effects of antiretroviral regimens and OI therapies. Physicians receive very little nutrition education as part of their formal training. Additionally, effective pharmacologic intervention in wasting is just beginning to evolve.

The degree of wasting and malnutrition correlates with progression of AIDS. Data from the Multicenter AIDS Cohort Study showed that development of AIDS, fever, thrush, and a CD4 lymphocyte count of less than 100/mm³ were independently associated with continuing loss of body mass. Another study found that measurements of lean body mass, albumin, and transferrin predict survival, independent of CD4 count. Starvation causes death when people reach 66% of ideal body weight or 54% of ideal body cell mass; patients with AIDS die at a similar level of weight loss. Because wasting is associated with disease progression, prevention and treatment of wasting should be an integral part of the care of patients infected with HIV. Studies are in progress to document the effect of reversing wasting on disease progression, morbidity, and mortality.

Pathophysiology of Wasting

Not all pathogenetic mechanisms of wasting in HIV have been fully elucidated, but many factors that promote progressive weight loss are understood. Wasting is a product of: (1) perturbations of metabolism and resting energy expenditure caused by the body's immunologic response to HIV and its secondary infections; (2) inadequate nutrition, secondary to poor oral intake, and malabsorption of nutrients, caused by diarrhea; and (3) alteration of levels of endogenous anabolic hormones, especially in men.

Perturbations of Metabolism

Resting energy expenditure (REE) increases with HIV infection. Even asymptomatic individuals with early infection have been shown to have an REE of 9% to 12% above seronegative controls. In HIV-associated hypermetabolism, maintenance of body weight requires an increase in caloric intake but, in the absence of OIs, most HIV-positive individuals can maintain adequate intake. Patients with AIDS have REEs of 25% to 34% above controls in some studies, and REE increases even when nutritional intake is poor. Paradoxically, in normal subjects REE decreases when caloric intake declines.

The development of an OI, with its concomitant rise in REE, usually leads to loss of weight, mostly lean body mass. Conversely, weight gain achieved through alimentation alone is mostly adipose tissue. This physiologic preference for fat over lean body mass is more acute in men than women, but all patients with AIDS face a persistent loss of lean body mass that is difficult to replace. The body, instead of reacting to a scarcity of nutrients by preserving lean body mass, combines hypermetabolism with accelerated protein breakdown and negative nitrogen balance to produce wasting.

Limited data are available on the potential role of cytokines in patients with AIDS and more research is needed. However, the mechanism of metabolic dysregulation that inappropriately increases REE and favors adipose tissue over lean body mass may in part be related to the cytokines elaborated in response to HIV and OIs. Tumor necrosis factor (TNF), interleukin (IL) 1, 2, and 6, and interferon alpha, beta, and gamma have all been implicated in metabolic dysregulation. TNF induces weight loss and suppresses appetite in animal models. In addition, these various cytokines may act synergistically to cause futile cycling and inappropriate use of substrates.

Futile cycling of fat occurs in HIV infection, contributing to increased REE as well as hypertriglyceridemia. Peripheral lipolysis releases free fatty acids from adipose tissue. The free fatty acids are re-esterified into triglycerides in the liver and then packaged into very low density lipoproteins (VLDLs), which are released into circulation. The VLDLs are broken down in the periphery by lipoprotein lipase, resulting in storage of the triglycerides in peripheral adipose tissue again. Each of these steps requires adenosine triphosphate (ATP), thus wasting energy, shuttling fat between the periphery and the liver and back again. Current research concludes that TNF, IL-1, IL-6, and interferon alpha play a role in futile cycling of fat.

Inappropriate use of substrate contributes to increased REE and protein wasting seen in HIV. An example of this is the liver utilizing glucose to synthesize triglycerides, instead of protein, in individuals with negative nitrogen balance. This step consumes energy needed to maintain body cell mass. Using energy to make fat is inappropriate in a patient losing body cell mass. The body should be oxidizing fat, not synthesizing it, in this situation. Bodily energy reserves and substrate such as glucose should be employed to restore lean body mass. TNF, IL-1, IL-6, and interferon alpha appear to be involved in the transformation of glucose into triglycerides in the liver.

Malnutrition

Malnutrition occurs in HIV for many reasons. Both illness and inactivity suppress appetite. Many of the medications used to treat HIV and OIs cause anorexia and a variety of GI side effects. Candidiasis, aphthous ulcers, and CMV disease involving the mouth and esophagus make eating difficult and decrease oral intake.

Many secondary infections including MAC, CMV, cryptosporidium, microspora, protozoa, and bacterial pathogens cause diarrhea and secondary malabsorption of nutrients. HIV causes diarrhea through villous atrophy, crypt hyperplasia, lymphocyte infiltration of bowel epithelium, viral infiltration of the mucosae, and the development of an enteric autonomic neuropathy. Many of the well-known hepatic complications associated with HIV, as well as abnormalities of the pancreas caused by ddI, ddC, pentamidine, CMV, MAC, cryptococcus, toxoplasmosis, and TB contribute to diarrhea and malnutrition. Malnutrition is further exacerbated when patients decrease oral intake in an effort to reduce diarrhea.

Androgen Deficiency

One of the roles of androgenic hormones is to help generate and maintain lean body mass. More than half of men with AIDS have low or inadequate androgenic hormone levels due to HIV's interference with the hypothalamus-pituitary axis, adrenal glands, and the testes. Total and free testosterone levels are both suppressed. This lack of endogenous anabolic stimulation is particularly important in light of the metabolic shift away from preservation of lean body mass. HIV's effect on endogenous androgens in women has not been well studied. Given the high prevalence of wasting syndrome in women, both viral effects on female metabolism and the impact of hormone supplementation need further study.

Treatment of Wasting

Optimally, clinicians should try to prevent wasting syndrome as well as treat it when it occurs. Weight loss is often the first sign of a new AIDS-defining illness. Patients should be weighed at every visit and their weight trends recorded on a graph. Because lean body mass is lost in preference to fat, weight alone can be a misleading indicator of nutritional status and clinical course. Laboratory markers of nutritional status include albumin, transferrin, and cholesterol levels. Some clinicians also use bioelectric impedance analysis, which measures lean body mass, to track nutritional status.

Treating Underlying Illness

A crucial first step is to provide appropriate antiretroviral therapy as well as meticulous prophylaxis and treatment of OIs. Two early studies documented clinical and biochemical improvement in individuals treated with AZT monotherapy; one documented an average 2- to 3-kg weight gain and a second demonstrated rapid, significant, and sustained declines in interferon and triglyceride levels in subjects treated with AZT. A later study documented a decrease in REE of 650 kcal/day in patients with CMV colitis who were treated with ganciclovir. Several studies have documented that patients with active, untreated secondary infections are often unable to gain weight even with hyperalimentation.

Patients with untreated secondary infections involving the mouth and GI tract tend to have poor oral intake, since they often have dysphagia and odynophagia as well as diarrhea and malabsorption. Addressing oral and esophageal complications can improve caloric intake and reduce discomfort (see ACC, March 1995 for a complete discussion of esophageal lesions in HIV).

Nutrition

Maintenance of good nutrition is essential. Lost weight can be very difficult to replace. Calorie needs are in the 25 to 60 kcal/kg/day range; 20% should be protein. Working with a nutritionist is helpful. Patients often have deficiencies of micronutrients. One study found a 31% decrease in progression to AIDS in patients taking regular multivitamins with minerals. This finding may be confounded by a bias in favor of more compliant patients with better diets.

Oral feeding is clearly the nutritional route of choice. Emphasizing intake that is high in calories, protein, and fat is important. Over-the-counter nutritional supplements can help patients who are having difficulty with meals, or while they are being treated for oral or esophageal ulcers. Enteral alimentation can be used if oral or esophageal disease or disabling systemic illness makes eating temporarily impractical.

Total parenteral nutrition (TPN) has been hotly debated in AIDS. Using TPN in patients with inadequately treated, active OIs and end-stage disease is of little value. Weight gained, if any, will be primarily fat. TPN is occasionally useful as temporary "bridge" therapy for a discrete period during treatment of intercurrent illness. The clear goal should be a restoration of full oral feeding once the patient can eat again. TPN is generally inappropriate in the terminal care of patients with AIDS.

Pharmacologic Approaches

Several pharmacologic approaches have been tried. Megestrol acetate and dronabinol are FDA approved and have defined but limited usefulness. Megestrol acetate was initially found to stimulate appetite and increase weight in patients with breast cancer, and it does the same for patients with AIDS, but the weight gained is mostly adipose tissue -- 67% in one study and nearly all in another; in the second study there was a concomitant slight loss of lean body mass. Megestrol's side effects include hyperglycemia and suppression of testosterone and cortisol levels. It may be most helpful when used briefly in severely wasted patients who can benefit from initial replacement of fat. Other strategies directed at increasing lean body mass should be used when patients are taking megestrol.

Dronabinol, a synthetic form of tetrahydrocannabinol (marijuana's active ingredient), has FDA approval as an appetite stimulant. It is effective, but sedation and confusion are common, dose-limiting side effects.

Because wasting is characterized by a preferential loss of lean mass, many researchers have focused on reversing the pathophysiologic conditions that promote such loss. Anabolic agents such as recombinant human growth hormone and anabolic steroids have received attention, as have thalidomide and pentoxifylline, which interfere with some of the cytokines thought to be involved with wasting.

In clinical trials, recombinant human growth hormone injected daily increased lean body mass, reduced fat, and improved muscle function in patients with wasting. Growth hormone promotes insulin resistance, however, and may produce clinically significant hyperglycemia. It is also costly. In preliminary studies, 5 mg was used every other day, at $250 per dose, or $3750 per month wholesale. It is hoped that several current trials of recombinant growth hormone will define the effect of this agent on disease progression and mortality.

Anabolic steroids have been studied minimally in the setting of HIV. They have historically been abused by some athletes and bodybuilders to increase strength and muscle mass. A recent article in the New England Journal of Medicine (Bhasin S et al, New Engl J Med 96; 335:1-7) confirmed the efficacy of supplementary superphysiologic doses of testosterone in promoting development of lean body mass and weight gain in normal male subjects.

One recent trial of an oral anabolic steroid, oxandrolone (20 mg daily), showed a mean weight gain of 10.7 lbs over two months in a group of predominantly gay men with advanced HIV disease (64 CD4/mm³ or less). On average, more than twice as much lean body mass as fat was gained. Another study, pending publication, examined the effects of oxandrolone in hospitalized men and women with severe burns, which promote protein wasting and catabolism much like that seen in HIV. Patients treated with oxandrolone and a high protein diet gained an average of 14.5 lbs. in three weeks, primarily lean body mass, and gained muscle function and strength.

These studies support the experience of many AIDS clinicians who have been prescribing anabolics for the past several years because these agents bring about significant weight gain and improved clinical status and sense of well-being in HIV patients. Current trials are assessing the effect of these improvements in clinical status on disease progression and mortality.

At this time, randomized controlled trials have not established a standard treatment regimen for the use of anabolic steroids in HIV. Regimens clinicians commonly use in men provide physiologic replacement doses of testosterone (enanthate or cypionate) equal to 100 mg per week. Using this drug in men is logical for treating hypogonadism and reversing catabolism, although the efficacy of this approach has not been proved. Nandralone, a less masculinizing anabolic agent, is used in women as well as men to increase anabolic activity. Again, most clinicians use approximately 100 mg per week. Testosterone enanthate and nandralone intramuscularly can be administered once or twice a month. At $4 to $10 per dose, they are relatively inexpensive. After patients gain weight, they can often go without injections for several months, receiving occasional supplemental doses as needed. Of note is the potential for liver toxicity with testosterone or nandralone.

A new, reformulated testosterone patch has recently been approved for use in testosterone deficiency. Unlike the previous patch, this formulation does not need to be placed on the scrotum. The usual dose is one or two 2.5 mg patches daily. The wholesale price of the testosterone patch is $97.50 for a box of 60.

Some clinicians prescribe anabolic steroids prophylactically to a patient who develops a new OI, reasoning that, since secondary infections augment hypermetabolism and protein wasting, pre-emptive doses of anabolics will prevent the loss of difficult-to-replace weight. The efficacy of this practice needs to be confirmed by careful studies.

Introducing anabolic steroids into treatment for HIV disease raises certain concerns. These include the potential for abuse and the possibility of developing malignancies and severe gonadal dysfunction. These adverse physical effects, seen in athletes who abuse anabolics with pharmacologic doses, may be much less common in AIDS patients using physiologic replacement doses. Another concern is that gains in fat-free mass include visceral organ tissue as well as skeletal muscle. Studies are needed to confirm that anabolics are not creating new problems by causing organomegaly. At this time, anabolic steroid use by patients with AIDS should be undertaken with caution.

Regular exercise, which increases both appetite and lean body mass, is an important part of therapy for wasting, especially when anabolic agents are used.

Finally, thalidomide and pentoxifylline have gained attention because they modulate some of the cytokines that appear to play a role in wasting. Both agents decrease production of TNF alpha, which has been broadly implicated in the pathophysiology of wasting.

One study of 18 patients taking thalidomide or placebo found that 8 of 9 thalidomide-treated patients gained or maintained weight, whereas only two of nine controls did; more studies are under way. Thalidomide has also been helpful for aphthous ulcers, and may help increase patients' oral intake of nutrients.

One small study of pentoxifylline raised concerns about its safety and the consequences of suppressing TNF and other mediators of inflammation in patients who are immune-compromised. Of five patients, three who had elevated TNF alpha at baseline had no weight loss with pentoxifylline, but two patients without elevated TNF alpha had weight loss during the study. Of concern was the fact that the two patients without elevated TNF alpha levels developed severe bacterial pneumonia within three weeks of entering the study.

At the recent XI International AIDS Conference in Vancouver, Drs. Jay Levy and Robert Gallo presented findings on the role of various cytokines in HIV pathogenesis. It is clear that a better understanding of the role of these cytokines in HIV disease will be helpful in developing further treatments. Our current understanding of the intricacies of these various cytokines' interactions is incomplete and, as was demonstrated in the pentoxifylline trial above, the use of agents that alter cytokine levels has potential dangers.

Summary

Wasting syndrome is a common, disabling feature of HIV disease. Wasting and malnutrition have been shown to predict disease progression. Current studies are assessing the effect of reversal of wasting on disease progression. Treatment and prevention of wasting syndrome requires a multidisciplinary approach: antiretroviral therapy, treatment and prophylaxis of OIs, proper nutrition, and correcting metabolic dysregulation.

— Gary S. Reiter, MD, FACP

Dr. Reiter is assistant clinical professor at Tufts University School of Medicine and medical director and associate director, respectively, of the River Valley HIV Clinic and Hospice LifeCare of Holyoke, Massachusetts.

Published in AIDS Clinical Care November 1, 1996

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