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Gay Men's Health Crisis
HIV-related Weight Loss and Wasting
David Pieribone
September 1, 1994
GMHC Treatment Issues 1994 Sep 1; 8(8): 2

HIV-associated weight loss, or wasting syndrome, is a major cause of illness and death in patients with late-stage HIV infection. It can be divided into two categories: acute weight loss, which often rebounds after an opportunistic infection is brought under control, and chronic weight loss, which is more difficult to reverse. Either decreased nutrient intake or alterations in metabolism can lead to weight loss. These factors can arise directly from HIV infection as well as from opportunistic infections, cancers or pre-existing gastrointestinal disease.

It is important to differentiate between mere loss in weight and the loss of protein stores (in lean tissue) that occurs during HIV infection. When acute weight loss is halted by treating an opportunistic infection, an individual may regain lost weight by adding fat rather than rebuilding lean tissue. Simply taking in more nutrients does not automatically produce recovery from wasting. AIDS-related wasting differs qualitatively from starvation. In starvation, the body's protein stores and muscle mass is conserved while basic metabolic rates slow and fat deposits are broken down for energy. During AIDS, the reverse happens. Studies by Kotler and others meanwhile indicate that death from wasting is related to the loss of lean body mass rather than just the amount of weight loss.[1] Alterations in Metabolism Primary infection with HIV or secondary opportunistic infections changes the body's metabolic pathways. Abnormal patterns of protein and lipid metabolism result, with nutrients transferred from lean to adipose (fat) tissue. Some inflammatory cytokines (intercellular immune regulators), such as tumor necrosis factor (TNF) and interleukin-1, have been associated with metabolic dysregulation and wasting.[2] Their chronic release during HIV infection seems to play a major role in HIV-related wasting. Endocrine abnormalities, including changes in gonadal, adrenal and thyroid function, have been noted in HIV-infected individuals and are another possible cause of weight loss and wasting.[3,4] One recent paper reported that people with AIDS-related wasting syndrome had significantly less testosterone and more prolactin and cortisol than similar people without wasting.[5] Testosterone promotes the growth and maintenance of muscle tissue. The decrease in testosterone may be related to the increased prolactin. Cortisol is an adrenal hormone that modulates stress. One of its functions is to free existing protein stores to repair tissue damage elsewhere in the body. Finally, progressive muscle weakness (myopathy), is an ill-defined condition that may be caused by HIV itself or extended use of AZT. It is reversible in the latter case.

Approved Treatments for Wasting Two appetite stimulants are the only FDA-approved therapies specifically for AIDS-related wasting syndrome.

Dronabinol (Marinol) is the psychoactive component of marijuana. In trials, dronabinol improved appetite and weight gain (mostly body fat) in about half of the participants. Side effects associated with Dronabinol include dizziness, thinking abnormalities, asthenia (weakness or loss of strength) and euphoria.

Megestrol acetate (Megace) is a synthetic progesterone (steroid hormone) in oral suspension. A twelve-week, placebo-controlled study conducted in patients with AIDS-related wasting provided the basis for its approval. Weight gains of five to seven pounds were observed in the megestrol acetate group, and two-pound losses were observed in the placebo group.[6] Phase II studies are underway to evaluate the combination of Marinol and Megace.

Side effects of Megace include high blood pressure, leg swelling, diabetes and impotence. (In addition, there was a trend toward a higher death rate in one study's treatment arm.) Megace, like Marinol, is widely considered to increase weight without adding to lean body mass (see article on the Tenth International Conference on AIDS). Appetite stimulants alone may not be able to overcome the basic metabolic changes wrought by the chronic response to HIV and the concurrent opportunistic infections. Reversing wasting may require "anabolic" agents that, like testosterone, promote muscle formation and discourage fat buildup.

Human Growth Hormone Recombinant human growth hormone (rHGH) and insulin-like growth factor (IGF-1) are two growth stimulators currently under study as therapies for wasting.

rHGH is a synthetic version of pituitary gland-derived human growth hormone. It is made by genetic engineering and used for the treatment of dwarfism. rHGH can induce positive nitrogen balance, promote protein sparing and increase weight gain and lean body mass in patients with AIDS-related wasting.[7] Side effects of rHGH include joint aches, fevers and high blood pressure.

Two preliminary studies published last year found that human growth hormone triggered significant weight gain in people with HIV wasting.[8,9] See the box on the International Conference on AIDS for the first analysis of a much larger, more extended trial of rHGH. The presentation on this trial was very encouraging.

IGF-1 is produced by the liver in response to human growth hormone. Many, but not all, of growth hormone's effects seem to really be the result of IGF-1. A trial comparing growth hormone and insulin-like growth factor is being conducted at the National Cancer Institute, but a trial examining the combination of the two yielded negative results (see below).

Anabolic Steroids Testosterone and the chemically similar synthetic anabolic steroids have been used by athletes and body builders to increase their muscle mass and stamina. Anabolic steroids can be dangerous, though, and medical supervision is desirable.

Community doctors have found that testosterone replacement therapy can improve patients' mood, sexual function, appetite and energy, although the long-term effects on immune function are not known. Testosterone replacement is generally not sufficient to manage weight loss and increasing testosterone levels to above normal can have adverse effects, including liver damage. A limited number of studies indicates that some of the newer synthetic oral testosterone derivatives have fewer side effects, and anecdotal reports claim that they increase immune cell populations (CD8 and CD4). Dr. Kotler, at St. Luke's/Roosevelt Hospital in New York, is conducting trials with oral oxandrolone, a synthetic anabolic. Early results indicate that patients taking oxandrolone experience weight gain. Upon termination of treatment, weight loss resumed, however. There was no evidence of CD8 or CD4 cell increases resulting from oxandrolone therapy. During short-term use, no overt side effects were noted but studies examining long- term use have not been done. The effects of anabolic steroids on women in particular need further monitoring, although oxandrolone is reputed to have few masculinizing effects.

Anabolic steroids such as deca-durabolin have become popular as an underground therapy among people with AIDS. Many feel that these compounds work much better when accompanied by a rigorous exercise program. Future studies should be conducted to evaluate the combination of anabolic steroids with growth hormone and testosterone replacement. The ideal therapy may well be an individualized one that includes hormone- and cytokine-modulating agents as needed but starts with such simple supportive measures as exercise and food supplements.

Cytokine Modulators Pentoxifylline is a medication for blood circulation disorders. It also inhibits the activity of TNF and might in this way help reverse wasting syndrome. An NIH-sponsored study has found that after eight weeks on pentoxifylline, triglycerides (lipids) in blood serum dropped significantly and TNF production went down.[10] Researchers at the Veterans Affairs Hospital in Brooklyn, New York studied the drug's effect on wasting syndrome in patients with AIDS but were not able to detect any weight gain or reversal of wasting.[11] Another recent study found that pentoxifylline at a dose of 800 mg three times daily did not affect the T-cell counts, viral load or TNF in eight patients treated for three weeks.[12] Thalidomide is enjoying a revival as a TNF blocker. Recently, two separate studies, one in France and another at Rockefeller University in New York City, have shown significant weight gain in patients receiving thalidomide. Thalidomide's abilities in this area are now the subject of further study. For the latest results, see the article on the AIDS Conference.

OP-1, a mixture of polypeptides, glycopeptides and glycosides, is another reputed TNF inhibitor. Its developer, Omega Pharmaceuticals, is just now beginning clinical trials of OP-1 for AIDS-related wasting.

Malabsorption Cells in the GI tract are particularly prone to damage during HIV infection, and this results in reduced absorption of nutrients. The HIV virus itself, intestinal parasites, and colitis induced by cytomegalovirus (CMV) are the main sources of tissue damage. The diarrhea connected with these conditions also may result in malabsorption. Fat, carbohydrate, protein and micronutrient (vitamin and mineral) malabsorption can occur. Malabsorption may also be a condition that pre-exists infection with HIV.

Infection by intestinal parasites triggers diarrhea and malabsorption in persons with AIDS by causing atrophy of the villi - the small threadlike projections on the interior of the small intestines which absorb nutrients when working properly. Given the variety of intestinal parasites, electron microscopic analysis of intestinal biopsy is required for a conclusive diagnosis. This procedure is both uncomfortable and expensive. It is also difficult to perform and may be unavailable in many places.

The protozoa Cryptosporidium parvum, the most commonly identified parasite in people with AIDS, causes massive secretory diarrhea. Paramomycin (Humatin) at 500 mg four times a day has demonstrated positive results in some patients although relapse is common after the drug is discontinued.[14] For persons with a more mild infection, a lactose-free, low-fat diet with a high calorie, protein-rich fluid supplementation is helpful. The large amounts of sugars or long-chain proteins found in some nutritional drinks tend to engender bloating and heightened diarrhea. Persons with severe untreatable diarrhea may also require parenteral (intravenous) fluid administration to maintain a normal state of hydration and electrolyte balance.

Among the drugs under investigation for cryptosporidiosis is intravenous azithromycin. This formulation of the drug is available directly from the manufacturer, Pfizer, on a compassionate use basis (call 800/742-3029 for further information). Side effects of IV azithromycin include nausea and abdominal pain. Oral azithromycin failed to show an effect on the frequency of bowel movements, parasite shedding in the stool or overall clinical response in a placebo-controlled study of 90 patients with cryptosporidiosis conducted at Cornell Medical Center.[15] Another anti-crypto agent in development consists of concentrated antibodies derived from cow's milk. Bioimmune Systems of Salt Lake City is just beginning preliminary human trials in HIV-negative individuals of its oral, milk-derived antibody product, known as Immuno-C. An efficacy trial for 40 people with AIDS-related cryptosporidiosis is expected later in the fall and will include six to eight sites around the country. More information may be obtained by calling Joy Erickson of Bioimmune Systems at 801/582-2345.

A second cow's milk preparation is called CryptoGAM. It is manufactured by Immucell and licensed by Univax. CryptoGAM failed as an oral agent in several early trials apparently because it was broken down in the stomach before it reached the intestines. A new open label trial is currently being conducted by Louis Fries, M.D., from Univax. Very high dose CryptoGAM (40 grams per day) is introduced directly into the duodenum via a nasogastric tube. Patients interested in the trial can contact Dr. Fries at 301/770- 3099.

Microsporidia (Enterocytozoon bieneusi or Septata intestinalis) is a second common GI parasite in people with AIDS. Infection can cause diarrhea and decreased intestinal absorption.[16] The drug albendazole has shown some promise and is currently the subject of an NIH- sponsored trial. A preliminary report on eight patients from Dr. Dominique Anwar of Grady Memorial Hospital in Atlanta indicates that atovaquone (an approved treatment for pneumocystis pneumonia) may be effective in reducing diarrhea.[17] As a preventive measure, HIV-infected people with low CD4 counts should be extremely careful about the water they consume. There are only three acceptable forms: distilled, deionized or boiled. Water filters, standing water (wells), spa waters and bottled spring water can be contaminated with intestinal parasites. Ice cubes and soda fountain-type drinks which mix tap water with syrup can also be contaminated. Use distilled, deionized or boiled water in all foods that will not be cooked and require water for their preparation. Because even the smallest amount of contaminated water can cause infection, fruits and vegetables rinsed with tap water could be a source of parasistes.

Nutritional Support Nutritional support is very important for individuals with HIV infection. Anabolic drugs will have little effect without sufficient diet. Studies also indicate that diets high in protein and complex carbohydrates, moderate in fats and sugars are important for good immune function.

Use of nutritional drinks such as Nutren, Ensure Plus, and Sustacal can increase caloric intake for individuals who are having trouble consuming enough calories. Because both individuals' needs and the products' compositions vary, one supplement may be better suited than another for a particular situation. Patients should consult their physicians or a nutritional counselor before adding nutritional drinks to their diets. Little data from controlled trials exist, though, so it is difficult to assess the actual benefit of supplementation. Lipisorb is a food supplement containing medium chain triglycerides that may benefit patients with fat malabsorption. Elemental (predigested) diets are comparatively easy to absorb in the GI tract and reportedly have helped lessen diarrhea and stabilize weight.[18] In patients unable to eat, data from two studies suggest that enteral gastrostomy feeding (feeding through a tube placed directly into the stomach through the skin) can result in weight gain and increased lean body mass.[19] Total parenteral nutrition (TPN) is a form of liquid nutrition infused directly into the bloodstream. Studies indicate that patients receiving TPN gain significant amounts of body cell mass and weight if they are free of systemic infections. Other studies have shown that administering TPN during secondary infection can increase weight gain and improve the quality of life by improving the individual's ability to fight infection.[20] Investigators also have reported that TPN has favorable effects on immune cell responsiveness.[21] But TPN can cost up to $13,000 a month in a home care environment. It is usually used to support someone through a limited period of acute illness but may be required for more lengthy periods.

Exercise Exercise can promote protein formation in tissues throughout the body. It is a helpful therapy when physical health permits. To build up lean body mass, resistance exercises (such as weight lifting) are more important than aerobic exercises, although aerobic exercise can also be beneficial. Exercise promotes muscle formation by increasing the number of testosterone receptors. Proper timing of food intake is also important in weight lifting. It is a good idea to eat well but not immediately prior to lifting weights and to eat a high protein food one to two hours after lifting.

Conclusion A variety of therapeutic strategies are available for different aspects of HIV-associated wasting. There is a strong correlation between proper weight, good nutritional status and survival.[22] Individuals should chart their weight, noting any significant change, and physicians should take determined steps to diagnose and treat major weight loss. Correct diagnosis and aggressive treatment can improve quality of life and prolong survival.

1 Kotler DP et al. American Journal of Clinical Nutrition. Sept 1989; 50(12):444-7.

2 Lombard RP et al. Clinical Immunology and Immunopathology. 1989; 50:374-84.

3 Jones PD et al. Journal of Acquired Immune Deficiency Syndromes. Dec 1992; 5:1266-71.

4 Landman A et al. Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

5 Coodley GO et al. Journal of Acquired Immune Deficiency Syndromes. Jan 1994; 7(1):46-51.

6 Flynn N et al Eighth International Conference on AIDS Jul 1992; 8(2): B205. abstract PoB3687.

7 Grunfeld C et al. Eighth International Conference on AIDS Jul 1992; 8(2): B230. abstract PoB3835.

8 Krentz AJ et al. Journal of Acquired Immune Deficiency Syndromes. Mar 1993; 6(3):245-251.

9 Mulligan K et al. Journal of Clinical Endocrinology and Metabolism. Oct 1993; 77(4):956-62.

10 Dezube BJ et al. Journal of Acquired Immune Deficiency Syndromes. Jul 1993; 6(7): 787-94.

11 Landman A et al. Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

12 Mole L et al. Journal of Acquired Immune Deficiency Syndromes. May 1994; 7(5):520-1.

13 Lahdevirta J et al. American Journal of Medicine. Sept 1988; 85(3):289-91.

14 Armitage K et al. Archives of Internal Medicine. Dec 1992; 152(12):2497-9.

15 Soave R et al. Thirty-third Interscience Conference on Antimicrobial Agents and Chemotherapy. October 1993; abstract 405.

16 Hecker LM et al. Nutrition Reviews. Nov 1990; 48(11):393-401.

17 Torres G, personal communication.

18 Hickey MS. Surgical Clinics of North America. Jun 1991; 71(3):645-64.

19 Kotler DP et al. American Journal of Clinical Nutrition. 1991; 53(1):149-54.

20 Campelli A et al Eighth International Conference on AIDS. Jul 1992; 8(2): 63.

21 Singer P et al. Journal of Parenteral and Enteral Nutrition. Jan- Feb 1991; 15(1):75-9.

22 Guenter P et al. Journal of Acquired Immunodeficiency Syndromes. Oct 1993; 6(10):1130-8.

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