Treatment Issues, Vol 11, No. 4/5; April 1997
Dave Gilden

It may be that once the conditions for wasting exist, the syndrome persists even when HIV levels decline. Several small surveys presented at April's Nutrition and HIV Infection conference in Cannes, France found that about a fifth to a quarter of those on aggressive antiviral therapies continue to lose weight or lean body mass. One of the studies observed that there was little correlation between viral load response to therapy and changes in weight. Serono Laboratories has made similar findings in an ongoing survey it is conducting. And the initial results from a study at Tufts University indicate that over the first seven to nine months on HAART, patients gain significant amounts of weight as they eat more, but it is all fat (presented by Sherwood Gorbach, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

An inability to restore lean body mass (muscle in particular) after acute or chronic weight loss has been the hallmark of wasting syndrome. That inability remains even when a person recovers from an opportunistic infection that triggered the weight loss episode. Another on going study at Tufts University is observing that, at least in people with high HIV levels, even strenuous exercise programs do not improve body composition. Trial participants did increase their weight by an average 3.8% after eight weeks, but the percent increase in fat and lean tended to be the same (presented by Ronenn Roubenoff, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

(A more definitive word on recovery after successfully suppressing viral load may come from the weight gain substudy that is part of the recently concluded ACTG 320, a trial of AZT (or d4T) plus 3TC with or without indinavir. The substudy will try to determine whether adding the protease inhibitor and obtaining greater reductions in viral load result in greater increases in lean body mass, and whether increased lean body mass is associated with changes in appetite and the body's pro-inflammatory agents (such as TNFa, see below). Until now, drug companies have either not collected or refused to release much information on weight changes in their protease inhibitor trials.)

Growth Hormone Hits the Market

It seems that in addition to potent antiviral therapy, an anabolic (muscle-enhancing) or anti-inflammatory agent may be necessary to reset the body's chemistry after chronic HIV plays havoc with it. Developments in this area continue to make news. December 2 marked the introduction of Serono's brand of human growth hormone (Serostim), which was granted accelerated approved for treating AIDS wasting system in August after a rough ride through the FDA. (For the details of the FDA's critique of Serostim, see Treatment Issues article Growth Hormone Cut Down at the Pass, March 1996, page 6 and Treatment Briefs: Human Growth Hormone, August 1996, page 9.)

One of the oddest things about the Serostim approval is that the duration of therapy and a precise definition of what population will benefit remain elusive. Controlled trials of growth hormone lasted only 12 weeks. Average weight gain in these trials was about 2.5 pounds. In the most exhaustive trial, a 178-person affair that included body composition analysis, the weight gain was found to consist of an average lean body mass increase of 6.8 pounds and a 4.3 pound loss in body fat. But, 22% of the participants dropped out or were noncompliant, and of the rest, 26% of those on growth hormone continued to lose weight. Participants in the open-label continuation phases of the trials maintained their weight gains while on growth hormone, but it was difficult to say what would have happened had they stopped. There were many trial dropouts here too, and these people may or may not have resumed their weight loss.

The FDA-approved package insert that comes with Serostim limits itself to recommending that treatment be initiated when a patient's unintentional weight loss reaches 10% of normal body weight. If weight loss continues after two weeks of treatment, the patient's condition should be reevaluated. The insert notes that any acute opportunistic infection may need to be cured, or at least suppressed, before restoration of weight or body composition is possible.

Serostim, injected subcutaneously once a day, is hideously expensive, costing $210 or $252 retail for a daily dose of five or six milligrams. Serono has established a yearly price cap of $36,000 for those who must keep taking Serostim indefinitely to prevent a recurrence of loss in weight and lean body mass. A patient assistance program will also provide free drug to a limited number of people with restricted financial means. For more information on Serostim distribution and financial assistance call the "Serostim Access Line," 800/714-2437.

The enormous expense is not the only reason to use Serostim judiciously. The doses of growth hormone administered for AIDS wasting syndrome (about 0.1 mg/kg of body weight) are very high compared to what is used for other conditions. In the brief AIDS wasting trials, rates of muscle pain (53.7% of those on growth hormone), tissue swelling and stiffness (27.3%), and carpal tunnel syndrome (relatively infrequent) were markedly elevated.

Much of the confusion around growth hormone stems from the fact that AIDS wasting is really a collection of syndromes. The variety of factors at work range from lack of appetite to malabsorption in the gut to metabolic derangement triggered by generalized inflammation, and the precise mix differs from individual to individual. Many of these factors must be treated in tandem. Growth hormone cannot work without sufficient nutrient intake, for example.

The confusion concerning Serostim's therapeutic role may be resolved by an FDA-imposed post-marketing trial. That trial will enroll over 700 volunteers to check on changes in lean body mass, body weight, physical function and quality of life after 12 to 48 weeks on therapy. A series of changes in study design have caused this study to be postponed several times, unfortunately. Some of the existing uncertainties in the protocol may be cleared up by an FDA conference on evaluating wasting syndrome described at the end of this article.

Testosterone Replacement Therapy

Since wasting is multifactorial in origin, then treatment probably should be individually tailored, acting on whatever suitable targets present themselves. There may be many therapies that are more appropriate for wasting than growth hormone in individual cases. For one thing, wasting has frequently been found to be associated with low sex hormone levels (hypogonadism), particularly low testosterone. Steven Grinspoon, M.D., has found that half the men with AIDS-related weight loss have low free testosterone levels (see Journal of Clinical Endocrinology and Metabolism, Nov. 1996; 81(11):4051-8). Parallel findings have been reported for women with HIV, even though women's normal testosterone levels are ten-fold lower than those of men (see Ellen Engelson et al., Eleventh International Conference on AIDS, abstract Tu.B.2382).

Testosterone has a strong stimulating effect on muscle tissue, and replacing lost testosterone might help reverse the attrition of lean body mass. In fact, the Alza Corporation has been implying that its testosterone skin patch (brand name: Testoderm) is useful for AIDS wasting since it was approved last year as testosterone replacement therapy for those with low levels of the hormone. Results from two trials for men and one open-label follow-up are now in, and they show no benefit for the Alza patch as far as weight and body composition are concerned. The patch did substantially increase the male volunteers' testosterone levels, which may have other benefits in terms of libido and overall energy. Alza officials and outside researchers are interpreting these results to mean that testosterone levels were not raised sufficiently to have a detectable anti-wasting effect.

Judith Rabkin, Ph.D., of the New York Psychiatric Institute, argues, "With injectable testosterone, you get a bigger bang for your buck. The patches are hard to stick, so delivery may be a problem. Also compliance could be an issue -- you have to stick a new Alza patch on your scrotum each day." Dr. Rabkin's trial of injectable testosterone is now being written up. Also, Dr. Steven Grinspoon's group at Massachusetts General Hospital (Boston) should soon finish analyzing a trial of intramuscularly injected testosterone in 50 men with AIDS wasting syndrome. Like the Alza trials, this is a six-month testosterone replacement study -- it seeks to restore testosterone to normal in those with low untreated levels. Dr. Grinspoon comments, "Our study will definitively answer the question" of whether mere testosterone replacement is sufficient to reverse AIDS-related weight loss. Finally, the University of Southern California is nearing completion of a trial that specifically compares the Alza patch to injected testosterone.

A competing testosterone patch can be placed on any part of the body, not just the scrotum. It was developed by the TheraTech Corporation and is marketed by SmithKline Beecham under the brand name Androderm. A Los Angeles trial with this patch in men with intermediate HIV infection recently ended. Of special interest, TheraTech has developed a skin patch geared specifically to replace the small amounts of testosterone normally produced by women. A trial of the women's patch is taking place at Massachusetts General Hospital in Boston, and results should be available this summer.

The Grinspoon paper cited above also presented findings that men with AIDS-related wasting actually had higher than normal levels of natural growth hormone, but their bodies did not seem to be responding to it. (In particular, there were insufficient levels of insulin-like growth factor 1 (IGF-1), which is produced by liver cells in response to growth hormone.) "Our data support the case for using very high levels of growth hormone," says Dr. Grinspoon. The recommended dose for Serostim is indeed very high, and the cost is a certain number of generally tolerable side effects. With testosterone, safety may be more of an issue, in part because of its masculinizing side effects. Possible adverse events include acne, increased irritability and, over time, cardiovascular and prostate problems.

A recent paper, however, found achieving supernormal testosterone levels was safe over the short-term as well as highly effective in stimulating muscle development among HIV-negative volunteers (see Shalender Bhasin et al., New England Journal of Medicine, July 4, 1996; 335(1):1-7,52). The New England Journal paper found that adding weight training to testosterone was even more effective.

Dr. Bhasin, who is from Charles R. Drew University in Los Angeles, argues that testosterone might be preferable to growth hormone. Testosterone acts to raise IGF-1 locally, within muscle tissue, whereas the IGF-1 produced by the liver in response to growth hormone spreads throughout the body. He is currently investigating the use of testosterone with and without resistance weight training in men with HIV-associated weight loss, but the testosterone dose administered, 100 mg/week, is only one-sixth that used in the HIV-negative trial. Dr. Bhasin estimates that the cost of testosterone therapy could amount to a mere $150 per year.

Aside from adding exercise to testosterone, Dr. Grinspoon and others are considering combining human growth hormone and testosterone. Other possible combinations include the use of testosterone plus Megace, an appetite stimulant that on its own tends to increase fat stores, with little effect on lean tissue. Megace is a derivative of the female hormone progesterone and actually suppresses testosterone production. ACTG trial 313 is testing whether testosterone replacement in both men (200 mg every two weeks) and women (100 mg every two weeks) can overcome Megace's drawbacks. And in New York, Dr. Rabkin is testing testosterone therapy along with a high amino acid nutritional supplement.

Exploring Anabolic Steroids

An alternative approach is to employ one of the synthetic anabolic steroids that mimic testosterone's muscle-building effects while minimizing its virilizing aspects. In theory, higher doses could be used with little concern for safety. This theory remains to proved, however, and the exact extent of anabolic steroids' muscle-building capacity needs further rigorous exploration.

The most tested anabolic steroid so far has been oxandrolone, which is produced by Bio-Technology General under the brand name Oxandrin. Oxandrolone is an oral drug approved by the FDA in 1962 as a general remedy for weight loss in a variety of conditions including chronic infection. The agent is now being touted in advertisements that strongly imply its efficacy for AIDS wasting syndrome. Oxandrolone's usefulness in AIDS has yet to be established, and an early trial utilizing a 5 mg/day dose found that oxandrolone had no appreciable benefit in AIDS.

Recent trial data suggest that higher doses will be more effective, though. In a paper published last December describing a trial in AIDS wasting syndrome, administration of 15 mg of oxandrolone per day resulted in statistically significant weight gain over those taking placebo through 14 weeks. At week 16, however, this difference (a gain of 1.32 pounds versus a loss of 2.42 pounds in the placebo group) failed to reach statistical significance. Body composition was not measured in this trial. Two studies of oxandrolone were reported last winter at the Fourth Conference on Retroviruses and Opportunistic Infections, and both looked at the effect of oxandrolone at 20 mg a day on body composition (see abstracts 692 and 695). The initial results of each of these studies (after an average of about a month) found about a 6.6 pound increase in weight. Body cell mass (a measure of increased protein stores) averaged 2.6 and 3.3 pounds higher in the two studies. Both these small, open-label trials are continuing, with further improvements noted in the trial participants who have already been on treatment for more than a month.

Two major ongoing oxandrolone trials are following a blinded, placebo-controlled protocol with higher doses. One study is trying 20, 40 and 80 mg per day in men with AIDS-related weight loss. Another is administering 20 and 40 mg per day to women. These trials will enroll about 300 men and 200 women, observing them for 12 weeks to compare oxandrolone versus placebo. In a second 12-week period, everyone will receive active treatment.

At 20 mg/day, it would cost more than $12,000 for a year's supply of oxandrolone at today's prices. A definitely cheaper substitute is the injectable anabolic steroid nandrolone decanoate. Nandrolone is made by Organon Teknica under the brand name Deca Durabolin, and there are also several generic versions. On a per milligram basis, nandrolone costs a sixth to a twelfth of what oxandrolone costs. Unfortunately, no one is pursuing a development strategy for nandrolone the way Bio-Technology General is for oxandrolone.

Some data are available, though. At the Eleventh International Conference on AIDS, Gary Bucher, M.D., and colleagues at the Center for Special Immunology in Chicago described gains in weight and fat-free mass in HIV-positive male volunteers receiving 100 mg/week of nandrolone for 12 weeks (abstract Mo.B.423). These volunteers had not necessarily experienced previous weight loss, however. In another report (see AIDS, June 1996, 10(7):745-52), a group from Sydney, Australia noted gains averaging 8.8 pounds over 16 weeks in 24 men who did have HIV-associated wasting. These men had not gained weight when enrolled in a program consisting of resistance exercise and dietary counseling. (Note that these 24 were from a cohort of 220 men, of whom the rest did succeed in gaining weight from the exercise and dietary counseling alone). The volunteers received 100 mg of nandrolone injected every other week in four months on/one month off cycles. The investigators estimated that the total yearly cost for such treatment would be just $600. A new San Francisco study of nandrolone using 100 or 200 mg/wk has found equivalent results -- a gain of 8.8 pounds at 12 weeks, of which two-thirds was ascribed to increased body cell mass (presented by Marc Hellerstein, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

Summing up his experience with nandrolone, Dr. Bucher said, "The anabolic effect seems equal to growth hormone, but there may be fewer side effects with deca [nandrolone] in terms of joint pain and tissue swelling." The AIDS Clinical Trials Group is at present sponsoring a small trial of nandrolone in women with greater than 5% HIV-associated weight loss. The women will receive 100 mg of nandrolone or placebo every other week for 12 weeks and then everyone will receive nandrolone for another 12 weeks. A second study at the University of Southern California is testing nandrolone with and without resistance weight exercise in men with HIV-associated weight loss. In this trial, the high dose of 600 mg/week will be administered. A third trial is being sponsored by the American Foundation for AIDS research for both men and women with moderate weight loss. This 120-person, 16-week trial will test biweekly nandrolone doses of 200 and 400 mg in men and 100 and 200 mg in women.

Thalidomide: New Results

All these therapies aim at overwhelming the signs of wasting with large amounts of protein-building agents. Rather than reversing the obvious wasting effects, why not aim for the underlying cause? Attempts have been made to do this with thalidomide, which blocks production of tumor necrosis factor alpha. TNFa is prominent among the several immune system's inflammatory agents that have been blamed for the depletion of protein stores during HIV infection. In January, a thalidomide developer, Celgene, of Warren, New Jersey, announced that the data from its trial in 99 people with AIDS wasting showed a statistically significant weight gain. The company seems to have "jumped the gun," as one person close to the trial put it. No data were yet available from the trial to justify Celgene's press release.

In April, a preliminary analysis of this trial was unveiled at a conference on TNFa blockers in Santa Fe. Commenting on the state of data, the study's principal investigator, Morris Schambelan, M.D., of San Francisco General Hospital, said, "The primary efficacy data are pretty solid, but the rest needs careful scrutiny." The results are a little curious in that the higher dose had less effect than the lower one: During the first eight weeks, participants gained on average 4.5 pounds (3.3% of their mean weight) on 100 mg/day of thalidomide, compared 2.2 pounds (1.2%) on 200 mg/day and 0.7 pounds (0.5%) on placebo. Participants continued to gain weight in the eight-week continuation phase. Dr. Schambelan estimates that about half the total weight gained was in lean body mass, although the complete body composition analysis has not been done.

One surprise is that HIV viral load went up slightly (an average of 0.3 logs, or two-fold) in the course of the trial. Reducing TNFa levels should have slowed HIV replication by lessening CD4 cell activation. But then, does thalidomide really reduce TNFa? TNFa levels are still to be assessed in this trial, but Dr. Schambelan noted that in a newly released study of thalidomide in oral aphthous ulcer treatment, the level of both TNFa and its cellular receptors rose somewhat. Thalidomide also failed to reduce IL-2 induced increases in TNFa levels or relieve side effects reputedly associated with the TNFa increases during a trial of IL-2 plus thalidomide (reported at the Fourth Conference on Retroviruses and Opportunistic Infections, abstract 36).

It may be that total TNFa is hard to quantify because blood levels are not necessarily indicative of cells' exposure to the substance in lymph tissue or that some sort of rebound effect occurs in response to thalidomide. Alternatively, thalidomide's primary anti inflammatory property, the key to its effectiveness, may not really be related to TNFa. Another surprise in this trial was how poorly tolerated was the 200 mg per day dose. Seventeen of the 31 people receiving the 200 mg dose dropped out, most complaining of somnolence or skin rash. Otherwise the results are in line with, though more modest than, two recently published articles: one describing a small six-month trial in Mexico City (Gustavo Reyes-T ran et al., AIDS, December, 1996 10(14):1501-7), which administered 400 mg/day and a three-week, 300 mg/day Thai study in 32 men with HIV, half of whom also had tuberculosis (Jeffrey Klausner et al., Journal of Acquired Immune Deficiency Syndromes, March, 1996; 11(3):247-57). In the Mexican study, no effect of thalidomide on plasma HIV or TNFa was observed, but the Thai study did find reductions in both these values among the study participants who were co-infected with HIV and TB.

Among the Thai volunteers, baseline TNFa plasma levels seemed to correspond with HIV viral load, with the TB infected group tending to have higher levels of each. Other studies have observed that tuberculosis hastens HIV disease progression, and the enhancement of TNFa production may be related to this acceleration.

Celgene has filed a New Drug Application with the FDA for use of thalidomide for treating a type of aggressive leprosy. Based on the latest results concerning weight gain, it plans to do the same for AIDS wasting syndrome. Further investigation is also taking place concerning thalidomide's ability to reduce oral aphthous ulcers and diarrhea, both of which can interfere with food intake and lead to weight loss. Until the drug is on the market, it is available through a compassionate use protocol for those with uncontrollable AIDS-related weight loss. For more information, call Celgene at 800/801-8328.

Of course, thalidomide is notorious for causing birth defects, and distribution of the substance will have to take place within the context of a rigorous education program to prevent its use during pregnancy. A program that could serve as a model is the one involving Hoffmann-La Roche's widely used acne medication Accutane, which also causes severe birth defects. Aside from the literature it distributes, the Accutane program requires a signed consent form and a negative pregnancy test for women starting Accutane. Roche also recommends that doctors obtain a pregnancy test from their female patients before they renew the Accutane prescription each month. Although Accutane is administered for just five months, pregnancies are still known to occur in women taking it, at a rate of 3.4 per 1,000 female patients according to a Roche survey. Eight percent of these pregnancies were carried to term and resulted in live births.

Evaluating Effectiveness

The relative merits of the anti-inflammatory and anabolic approaches to wasting could be tested this fall in a trial proposed by Dr. Schambelan and others. The trial would compare thalidomide to human growth hormone in people with acute opportunistic infections. In addition, the investigators would try to further unravel the two agents' exact mechanism of action (especially thalidomide's). But, as Dr. Schambelan commented, "Let's not forget about the thalidomide-growth hormone combination." As in the Megace plus testosterone trial mentioned above -- or the often proposed combination of anabolic steroids with exercise programs -- combining wasting treatments may be more effective than any single strategy.

One difficulty in combining approaches is that the evaluation of wasting treatments is still in its infancy. Until last summer, the FDA was insisting that the prime standard for approving an effective anti-wasting therapy was proof that it prolonged patients' lives or at least reduced the incidence of opportunistic infections. Even weight gain was not necessarily sufficient for the FDA: We know that losing weight predicts further disease progression and death, but does gaining weight improve survival? Measures such as improved quality of life or physical performance are extremely subjective or inconclusive, although one could argue that a therapy that makes people function better is worthy of approval. The accuracy of methods for measuring body composition also remain controversial, with many fearing that growth hormone and other anabolic agents largely increase intracellular water or blood proteins rather than the protein content of muscle tissue.

In the case of Serostim, the FDA was faced with considerable pressure from AIDS activists and physicians who insisted that indications of increased lean body mass should be sufficient to allow sales of an anti-wasting treatment. The begrudging approval, granted without evidence of a positive effect on survival or disease progression and conflicting data on weight gain and improved functioning, is evidence of the agency's increasing confusion in this therapeutic area. Last year, the researcher in charge of oxandrolone's clinical trials, Rudolfo Ferraresi, M.D., complained, "When we tried to pin down the FDA on what data we should collect, they didn't come up with anything. They just indicated that if we come to them with compelling data, they might approve the drug. They said wait for the public meeting we are going to have to develop a consensus."

That public meeting finally took place on May 22 and 23, at Treatment Issues' press time. Cosponsored by the Federation of American Societies for Experimental Biology, it featured workshops on wasting syndrome in AIDS and other chronic diseases. At the end, small discussions groups focusing on specific diseases were to formulate guidelines for measuring wasting in patients as well as for evaluating wasting therapies during clinical trials. This meeting is a sequel to the two-day NIH conference referred to above that was devoted to reviewing current knowledge on the causes and treatment of AIDS wasting syndrome.

Bill Thorne, who has kept track of AIDS wasting therapies for ACT UP/Golden Gate, summed up his expectations for the FDA meeting by saying "Similar to the exploration of HIV viral load as a tool for clinical trials, the introduction of body composition measurements will lead to faster approval of therapies and a significant modification of treatment for AIDS-related wasting."

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