Treatment Issues; Vol. 9, No. 5 - May 1995
Theo Smart

The two drugs approved for AIDS-related wasting, Megace and marinol, increase appetite and help people gain weight, but they do not confront the metabolic changes that lead to loss of lean body mass. The weight gained on these drugs is mostly fat.

Other treatments such as steroids and TNF inhibitors -- as well as human growth hormone may better address the metabolic changes that precede wasting. We described the state of research on thalidomide, the most prominent TNF inhibitor, above. Here, we report on some more possible alternatives to human growth hormone therapy.

Ketotifen

Ketotifen, an anti-histamine approved in Europe, is also a TNF inhibitor that may be useful in AIDS-related wasting. Studies report that the drug has potent anti-inflammatory activity and reduces edema, rashes and allergy-associated dermatitis. It may have activity against ulcerative colitis. A study of ketotifen for eosinophilic gastroenteritis, a wasting syndrome of unknown cause, reported substantial weight gains.2 A number of studies note that the drug's chief side effects are appetite stimulation and weight gain. German studies report that ketotifen reduces TNF secretions from peripheral white blood cells of people with HIV.3,4 A pilot study of ketotifen in people with AIDS was presented at the Ninth International AIDS Conference in 1993.5 Another study using ketotifen in combination with oxymetholone was also reported at the conference (see combination therapy section below).

In the monotherapy study, eight people with HIV and elevated TNF were treated with ketotifen for three months. TNF levels decreased on therapy and increased after treatment discontinuation. Patients gained a mean of about six pounds on treatment, and lean body mass also increased significantly. Both weight and lean body mass decreased after going off therapy.

The Germans believe the suppression of TNF is ketotifen's mechanism of action, but the drug may simply be treating malabsorption by virtue of its anti-inflammatory activity in the gut. To our knowledge, there are no ongoing studies of ketotifen by itself, which is unfortunate as the drug is extremely safe. Dose-ranging studies might find greater activity at higher doses. At present, the drug's maker, Sandoz, has no plans of marketing the drug in the US. It is available through the PWA Health Group in New York.

Anabolic Steroids

Anabolic steroids are testosterone derivatives designed to increase strength and muscle mass. Testosterone performs these functions in the body, but its masculinizing effects make it an inappropriate therapy for men who already have normal testosterone levels, or, clearly, for women. The synthetic anabolic steroids were designed to be less masculinizing than testosterone. Two of them, nandrolone and methandrostenolone, are used to treat women with osteoporosis in Europe. Oxymetholone (an oral steroid used to treat anemia) reportedly has only mild masculinizing effects, too.

Men with AIDS often have low testicular function, creating testosterone deficiency that may precede wasting syndrome. In New York, Howard Grossman, M.D., finds testosterone deficiencies in about 80 percent of his patients with advanced AIDS. He prescribes testosterone plus varying doses of nandrolone. He periodically takes some patients off steroids for a time, since continuous administration of steroids may reduce the number of steroid receptors on cells, thereby reducing their effect.6 Continuous steroid administration may also depress production of natural steroids, but this may not apply to people with AIDS who have chronic adrenal imbalances.

Anabolic steroids have the advantage of being dramatically cheaper than most therapies being studied for AIDS-related wasting. Deca-durobolin, a brand of nandrolone made by Organon, costs as little as $30 a month. A generic brand is even cheaper but currently unavailable.

The ability of anabolic steroids to increase muscle mass and break down fat in healthy, exercising people is well documented,7 and doctors can legally prescribe therapeutic doses. However, despite the numerous anecdotal reports of steroid use in people with AIDS-related wasting, their long- term safety and efficacy have yet to be established in placebo-controlled studies. The American Federation for AIDS Research and the Community Consortium in San Francisco, are both considering placebo-controlled studies of anabolic steroids. Given the exorbitant costs of human growth hormone, and the fact that many AIDS drug assistance programs are strapped for cash, these studies need to start as soon as possible.

One oral steroid, oxandrolone, was studied in a standard randomized trial, but the results were disappointing. Patients in both the treatment and placebo arms of the study gained weight. Activists have criticized the study for not including a regimen of resistance exercise such as weight- lifting. According to body builders, exercise is necessary to provoke the anabolic effect.

A study using higher doses of oxandrolone is waiting for FDA approval, which may come in the next several months. Higher doses of oxandrolone have been safely used in people with alcoholic hepatitis and children with growth disorders. An Australian trial combining resistance exercise with nandrolone (100 mg injected intramuscularly every two weeks) was presented at a conference in Glasgow last November.8 The participants had lost five to fifteen percent of their usual body weight. Treatment was open-label because the investigators thought that a placebo-controlled study would not enroll enough participants. The trial did exclude people who might regain weight spontaneously by providing applicants with a month of nutritional counseling and support. Only those who continued to lose weight were enrolled into the study.

Preliminary data from eight patients after eight weeks of therapy showed a weight gain of almost four pounds. The increase was mostly lean body mass as measured by increases in mid-arm muscle areas, with no increase in fat. Participants reported improvement in their quality of life. They felt much less fatigue and could again participate in vigorous activities. There was no change in CD4 cell counts. (Some individual steroid users have reported improvements in their immune status.)

Complete data from this study should be published in the next few months. Julian Gold, M.D., the primary investigator, claims to have treated over 150 patients with nandrolone in addition to those in the study. He plans to conduct a placebo-controlled study to prevent wasting in people with HIV and less than 200 CD4 cells and normal weight.9 Judith Rabkin, Ph.D., of Mt. Sinai Hospital in New York has treated over 150 patients with testosterone and reports dramatic improvements in energy while on treatment. She is now studying testosterone's effect on lean body mass and weight in a placebo-controlled trial involving people with subnormal natural testosterone. After six weeks, patients are offered open-label testosterone. Patients need not have wasting syndrome to enter the study, which is primarily monitoring testosterone's effect on energy and libido. Although recovery from wasting is not a primary goal of the study, Dr. Rabkin has already seen a statistically significant effect on lean body mass in the first twelve men to complete the study.10 She hopes to enroll 50 to 100 more patients. Anyone interested should call 212/960-5762. Besides masculinization, anabolic steroids have such possible side effects as acne, high blood pressure, cancers of the liver and personality changes. Their immunologic effects seem to differ, but some steroids may have the potential to stimulate proliferation of KS and lymphoma.

DHEA

DHEA (dehydroepiandrosterone) is a hormone produced by the adrenal gland. Its role in the body is poorly understood. Some of it is converted into testosterone and other androgens. It may have immunologic effects -- in one study it doubled the life span of laboratory rats, which produce little or no DHEA naturally. It also may have an effect on mood and energy levels, and it appears to influence metabolism.11

The exact role of DHEA in metabolism is unclear. Studies in rodents and dogs suggest that the hormone reduce obesity. One placebo-controlled study in ten young men supported this, finding that DHEA increased muscle while depleting fat. Other studies in obese men and women did not confirm these results. As with anabolic steroids, though, resistance exercise may be necessary to stimulate the anabolic effect.

Levels of DHEA are extremely low in people with AIDS.12 The underproduction of DHEA may be the key change that precedes the development of AIDS-related wasting. There have not been any studies of DHEA's effect on weight or body composition in people with AIDS-related wasting, but a study of DHEA as an antiviral and immune modulator in people with HIV found no consistent change in weight.13

Combination Therapy

A study combining ketotifen and oxymetholone,14 the oral anabolic steroid, in 24 people with HIV who had lost at least ten percent of their pre-illness weight also was presented at the Ninth International AIDS Conference. Patients with active opportunistic infections for the six months prior to treatment were excluded from the study since weight lost during an infection may be quickly regained. Preliminary data from 22 patients observed showed that 18 out of 22 gained an average of 11.4 pounds after treatment for an average of 3.9 weeks. Appetite increased in 20 out of 22 of the patients, weakness improved in most patients, and TNF levels went down. Two patients reported fatigue, and one became impotent during treatment. The study did not report whether the treatment increased lean body mass.

A German double-blind placebo controlled study of the combination of oxymetholone and ketotifen is in progress. If this study finds a significant increase in lean body mass, a similar combination strategy using anabolic steroids plus thalidomide may be worth evaluating.

References

1 Kotler DP et al. American Journal of Clinical Nutrition. Sep 1989; 50(3):444-7.

2 Melamed I et al. American Journal of Medicine. Mar 1991; 90(3):310-314.

3 Ballmaier M et al. Eighth International Conference on AIDS. July 1992; 3(abstract PuA 6009):12.

4 Schedel I et al. J Interferon Research. Oct 1994; 14(5):291-2.

5 Herbarth L et al. Ninth International Conference on AIDS. June 1993; 1(abstract PO-B29):2189.

6 Grossman H. Personal Communication. May 8, 1995.

7 Kopera H. Acta Endocrinologica Supplementum. 1985; 271:11- 18.

8 Gold, J et al. Second International Congress on Drug Therapy and HIV Infection; November 1994; (abstract P68):S35.

9 Gold J. Personal Communication. January 14, 1995.

10 Rabkin J. Personal Communication. May 10, 1995.

11 Morales A et al. Journal of Clinical Endocrinology and Metabolism. 1994; 90(6):1360-1367.

12 Jacobson MA. J Infect Dis. Nov 1991; 164(5):864-8.

13 Dyner TS et al. J AIDS. May 1993; 6(5):459-465.

14 Hengge UR et al. Ninth International Conference on AIDS. June 1993; 1(abstract PO-B19-1844):442.

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