AIDS TREATMENT NEWS Issue #187, November 19, 1993
Dave Gilden

Obviously, the first thing to do to minimize weight loss is to treat the underlying infections that trigger it. But people with AIDS may not regain the weight dissipated during acute illness. And wasting may occur without any apparent opportunistic infection.

Karl Grunfeld, M.D., Ph.D., is an endocrinologist based at the San Francisco Veterans Administration Medical Center who has researched and written extensively on HIV-associated wasting. He says "Wasting is not inevitable, but a reflection of disease complications. People who rapidly lose weight almost always have opportunistic infections. And two-thirds of those with slow weight loss have gastrointestinal disorders. Everyone with HIV should have their weight charted, and when things change, the physician should look very carefully at the underlying condition."

There are two therapies approved specifically for HIV-related weight loss, Marinol (or THC, the active ingredient in marijuana) and Megace (a progesterone analog), which are both appetite stimulants. There also are a number of dietary supplements, both oral and intravenous, for people with problems absorbing enough nutrients to maintain the heightened level of metabolic activity that occurs during HIV infection. (See AIDS TREATMENT NEWS #133 for a review of gastrointestinal conditions affecting nutrient intake.)

Although appetite stimulation and nutritional supplementation are effective when the sole problem is insufficient nutrition, in people with HIV they usually contribute added pounds of fat, not the desperately needed protein stores in lean tissues such as muscle.

Wasting in AIDS is not like starvation, where the body reduces its metabolic rate and utilizes fat stores to make up for reduced food intake. Marc Hellerstein, M.D., Ph.D., a University of California Berkeley endocrinologist who frequently works with Dr. Grunfeld observed, "In AIDS, and other diseases, too, the body switches to preferring to metabolize protein over fat. And it's hard to put lean tissue back on just by consuming more nutrients."

As far as wasting is concerned, AIDS acts like any chronic disease. The body mobilizes its resources to meet the needs of emergency immune response and repair critical damaged tissue. This response, which includes breaking down existing cellular protein, is appropriate in the short-run but becomes literally self-destructive when extended in reaction to a chronic stressor like HIV.(2)

Tumor necrosis factor and a number of other immune system activation chemicals (cytokines) as well as changes in hormonal balance, such as increased production of cortisol,(3) are thought to influence the shift to a wasting mode. Researchers more and more are turning to hormone-based therapies that overcome these basic wasting factors while, it is hoped, leaving valuable immune activity intact.

Human Growth Hormone

Recombinant human growth hormone (rHGH) has been approved for several years now to correct small stature in children. This synthetic biotechnology product, which mimics the natural hormone produced by the pituitary gland, has a two-fold mode of action. It reduces protein breakdown and nitrogen excretion while increasing fat metabolism. The availability of rHGH has led to considerable research into its use in adults to treat a wide variety of problems involving either lean tissue loss or obesity.

Two preliminary studies published this year found that human growth hormone triggered significant weight gain in people with HIV wasting. The first was a University of New Mexico trial(4) comparing high dose versus low dose rHGH in a total of ten people with AIDS or ARC. The 12-week trial found that weight loss was reversed in the high-dose group, with trial participants gaining an average of 3.8 kg of lean body mass and losing an average of 1.3 kg in fat mass. (Including extra water retention, total average weight gain was 3.2 kg.) Muscle power and endurance also improved significantly. Six weeks after the trial's completion, most of these gains had disappeared, however.

In a San Francisco trial published just last month,(5) six HIV-positive men and six HIV-negative controls were kept in a metabolic hospital ward for two weeks, where they were fed a uniform, controlled diet and received rHGH for a week. In the course of the treatment week, the HIV-positive men, who previously had lost nearly 20 percent of their original body weight, averaged a gain of 2.0 kg, compared to 1.6 kg in the HIV-negative men. Protein use as fuel decreased significantly in the HIV-positive group, while their use of fat increased -- hopefully sparing the body's protein.

The San Francisco research group is now part of a new national trial that involves 160 men and women at ten sites. After an initial, placebo-controlled three-month period, all the trial participants will receive open-label rHGH for an indefinite period.

"The FDA is calling this study 'pivotal,'" said Morris Schambelan, M.D., one of the study's investigators. "Besides being of longer duration and placebo-controlled, it will include endurance testing, better measurements of body composition, and quality of life data." There will also be immunological measurements -- several reports have indicated that human growth hormone has immune-stimulating effects. [Note: This study, sponsored by Serono Laboratories, Inc., of Narwell, Massachusetts, is now recruiting at two sites in San Francisco -- San Francisco General Hospital, and the VA Medical Center -- and at eight other sites in the U.S. Recruiting is expected to continue through 1993.]

The University of New Mexico group is now conducting one of several studies that combine human growth hormone with insulin-like growth factor (IGF-1). IGF-1 is produced by the liver in response to human growth hormone. Many, but not all, of growth hormone's effects seem to be really the result of IGF. "We're just in the early data-gathering phase for IGF," said Dr. Grunfeld. "We started with growth hormone because it has a track record. Once we get preliminary data we can try combinations of the two in order to avoid particular side effect profiles."

Side effects of rHGH can include swelling in the limbs, joint stiffness and increases in blood sugar and fat levels. Reversible carpal tunnel syndrome has been seen in people taking high doses of rHGH. Growth hormone is also reported to stimulate immune cell proliferation, but one group found that, in the test tube at least, rHGH also enhanced HIV replication.(6) For this reason, volunteers in the national ten-site rHGH study are required to be taking AZT or a similar antiviral medication.

Among the reported side effects of IGF are jaw tenderness and low blood sugar. But long-term use of either of these drugs is an uncharted area.

Anabolic Steroids

It is noteworthy that the two completed growth hormone trials took two years to get into print after they were completed. This was true despite the fact that rHGH and IGF are both hi- tech, high-visibility products with very active corporate sponsors.

As growth hormone research grinds on, alternatives exist at the grassroots level that cost one-tenth of what rHGH does. These are anabolic steroids, which body builders and other athletes use to increase their muscle mass and stamina. The anabolic steroid family includes testosterone and synthetic derivatives with fewer androgenic (masculinizing) effects.

A number of knowledgeable AIDS specialists have been prescribing testosterone to patients complaining of weight reductions plus loss of libido [see the interview with Lisa Capaldini, M.D., in AIDS TREATMENT NEWS #184]. But just correcting the frequent mild testosterone deficiencies is often not enough, and boosting testosterone levels above normal can have adverse consequences, including liver toxicities. This is where the synthetic anabolic steroids come in.

Despite anabolic steroids' "schedule III" legal status (they are controlled substances on the same level as aspirin- codeine combinations), a considerable anabolic steroid lore has accumulated in the sports world,(7) and HIV-positive body builders have brought that information to the AIDS community.

One such bridge is Brian Chadsey, M.D., a Los Angeles physician who is a former football player and body builder. Chadsey has been looking at anabolic steroids' effect on HIV wasting for eight years. He currently has almost 100 patients using the substances. "I've had phenomenal results," said Dr. Chadsey, "with patients commonly gaining 20 or 30 pounds. Anabolic steroids are useful when people have unintentional weight losses of ten percent, low testosterone levels and decreases in daily functioning. Most doctors tell their patients to just live with weight loss, that it's part of the disease process. But wasting syndrome is probably an escalating event that leads to early death." [See AIDS TREATMENT NEWS #150 and #166 for two other physicians' experience with anabolic steroids.]

Dr. Chadsey also reports significant improvements in his patients' immune cell populations while on anabolic steroids. Three-quarters of his patients witnessed rises in their CD8 (cytotoxic lymphocyte) counts and 40 percent have had increases in CD4, or T-helper cell levels.

In Sacramento, California, Michael Dullnig, M.D., a psychiatrist, also drew on his weightlifting past when trying to control his own HIV-associated weight loss. Dr. Dullnig started personally taking anabolic steroids last spring, when a bout of mycobacterium avium left him 50 pounds below normal weight, extremely weak, and disabled in one leg. After following an individual regimen since May that includes anabolic steroids, extensive use of nutritional supplements, and a rigorous weight-training schedule, Dullnig said, "I'm back to the way I looked before, and my energy has returned. I feel like my life was given back to me."

Dullnig thinks that "exercise is the key. Steroids make cells receptive to building tissue, but you need exercise to stimulate the anabolic process. The right nutrients are also very important. This is like another period of adolescence." He does warn against overtraining, though. People need to pay attention to their physical limitations. Dr. Chadsey says that not all his patients are on exercise programs, although those who are get better results.

The murky social and legal atmosphere surrounding anabolic steroids makes it difficult for people with HIV to obtain the substances or even reliable information about their proper use. Expert supervision when using anabolic steroids is especially important for women, who should take lower doses than men and need to follow a regimen with little potential for androgenic side effects.

And following an extensive exercise and food supplementation program is an obstacle for many people who are sick and lack stamina or digestive capacity. These are just the people who need the most protection from wasting.

Researchers justify focusing their attention on growth hormone because of such objections, but more clinical trials of anabolic steroids could also provide important information. Dr. Kotler, at St. Luke's/Roosevelt Hospital in New York, is in a unique position in that he is conducting separate clinical trials on both anabolic steroids and human growth hormone. Dr. Kotler says that, although the data has not been analyzed yet, the results of the two trials seem similar, with about half the people showing considerable improvement in body composition. Those who do not are people who come down with severe opportunistic infections. Meanwhile, no major side effects with either the anabolic steroid (in this case oral oxandrolone) or rHGH have been observed.

So which therapy is more appropriate? Dr. Kotler said, "We can't tell yet whether anabolic steroids, human growth hormone, or just testosterone replacement, is best. I don't even know whether any of these are good long term or have hidden side effects."

Dr. Chadsey is also looking into using growth hormone to combat wasting. He thinks a combination of anabolic steroids and growth hormone may be desirable. "You need some androgenic effect to increase the reaction to growth hormone," he said.

Future therapies may well be tailored to the individual, based on an analysis of each person's hormonal and immune activity as well as overall disease state. Personal tolerance to the different therapies would be a factor, too.

Dr. Hellerstein speculated, "We may use a mixture of approaches depending on what people need: anabolic steroids for those with low testosterone, human growth hormone to correct metabolic imbalances, immune modulators to balance the immune system's effects, nutritional supplementation for malabsorbers, plus exercise for those who are able to do it."

References

1. Kotler DP, Tierney AR, Wang J, and Pierson RN Jr. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. American Journal of Clinical Nutrition. September 1989; volume 50, number 3, pages 444-447.

2. Grunfeld C, and Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. The New England Journal of Medicine. July 30 1992; volume 327, number 5, pages 329-337.

3. Christeff N, Gharakhanian S, Thobie N, Rozenbaum W, and Nunez EA. Evidence for changes in adrenal and testicular steroids during HIV infection. Journal of Acquired Immune Deficiency Syndromes. August 1992; volume 5, number 8, pages 841-846.

4. Krentz AJ, Koster FT, Crist DM, and others. Anthropometric, metabolic and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. Journal of Acquired Immune Deficiency Syndromes. March 1993; volume 6, number 3, pages 245-251.

5. Mulligan K, Grunfeld C, Hellerstein M and others. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. Journal of Clinical Endocrinology and Metabolism. October 1993; volume 77, number 4, pages 956-962.

6. Laurence J, Grimison B, and Gonenne A. Effect of recombinant human growth hormone on acute and chronic human immunodeficiency virus infection in vitro. Blood. Jan 15 1992; volume 79, number 2, pages 467-72.

7. Phillips WN. Anabolic reference guide. Mile High Publishing, Golden Colorado, 1991.

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