Von Roenn and Knopf provide a balanced review of the pathophysiology and treatment options for anorexia and cachexia associated with HIV and cancer. This is an important topic that cuts across subspecialty lines and typically frustrates clinicians. Fortunately, more has probably been learned about HIV-associated cachexia during the past decade than about cancer-associated cachexia during the previous three decades and a number of treatment options have emerged. The reader may therefore benefit from a summary of the practical implications of recent research on HIV-associated wasting. Several clinical guidelines can be recommended:
Monitor lean body mass (LBM), not just weight. It is now clear that the emphasis should be on preservation and restoration of LBM, not weight loss per se. Lean tissue represents the functional compartment of the body--liver, muscle, heart, intestines, spleen, kidneys, etc.--and is distinguished from body fat, extracellular fluid, and bone mineral, which also contribute to body weight. Reasons that LBM should be used as the therapeutic endpoint instead of weight follow: survival correlates better with LBM than with weight in AIDS [1,2] and other conditions; symptoms such as endurance, energy, strength, and mood, are related to LBM  and are unlikely to be altered by changing fat or extracellular fluid weight; and LBM can be measured easily and quickly with bioelectrical impedance analysis (BIA) instruments, which are portable, simple to operate, and inexpensive to purchase.
Be aware that weight loss most often occurs during acute opportunistic infections. The pattern of weight loss in AIDS is most often episodic, with acute bouts of rapid loss followed by partial recovery , rather than a linear and constant rate of weight loss. The episodes of weight loss are usually due to poor intake of food during an acute opportunistic infection. These simple clinical observations concerning natural history have important therapeutic implications. First, physicians who care for patients with AIDS during an opportunistic infection should not ignore nutrition, because the weight lost may not be regained and may ultimately contribute to morbidity and mortality associated with advanced wasting. Aggressive nutritional support--with liquid supplements, dietary consultation, peripheral parenteral nutrition, or even recombinant growth hormone (rGH [Serostim)--during episodes of Pneumocystis carinii pneumonia, for example, may prove useful. However, the efficacy of a preventative approach remains to be proven by clinical studies.
Second, during weight-stable periods, patients will exhibit a different pathophysiology and different treatment challenges than during episodes of actual weight loss. Therefore, I must disagree with Van Roenn and Knopf's comments about rGH studies. They state that "oral intake is the primary determinant of HIV-related weight loss" and concluded that exclusion of patients exhibiting reduced intake from clinical trials of rGH renders these studies broadly inapplicable. This is misleading because most weight-stable outpatients do not have reduced intakes [5,6], yet they are unable to replenish body weight and LBM. In fact, few clinically-stable patients with AIDS who see a physician hoping to reverse previous weight loss would be excluded from rGH use because their current intake is low, although it may have been low previously during an opportunistic infection.
Recognize that nutritional treatments (megestrol acetate, total parenteral nutrition) predominantly increase body fat, rather than LBM. The most disappointing finding from intervention trials in AIDS wasting has been the difficulty in repleting LBM, compared with body fat, when nutrient intake is increased. As Von Roenn and Knopf note, all studies to date with megestrol(Drug information on megestrol) acetate have observed 70% to 100% of weight gain as body fat . Home total parenteral nutrition also increased fat but not LBM when studied in patients with AIDS , although subsets of LBM responders were noted. The most likely explanation for the preference for fat deposition over LBM is the documented metabolic abnormalities that exist with HIV infection [9,10], which may divert nutrients away from LBM and into fat. The causes of the metabolic disturbances are not certain, but they may include hypogonadism , cytokines, lack of exercise, or other factors.
Megestrol acetate still has an important role in therapy for wasting, and I use it in my AIDS-Wasting Clinic at San Francisco General Hospital. Megestrol acetate is a remarkably effective appetite stimulant and increases intake by nearly 600 kcal/day. The pleasures of meals, the cosmetic and psychologic benefits of gaining body fat, and the prevention of further losses of LBM justify the use of megestrol acetate. However, its limitations should be recognized: many patients will be disappointed by their body changes, and no effect on survival or performance has been documented or can be expected in the absence of LBM changes.
Understand the available anabolic therapies and their pros and cons. Several options for anabolic therapies are worth considering.
rGH--The only treatment that clearly increases LBM in AIDS wasting is rGH [3,12]. This agent overcomes the resistance of lean tissue to anabolism that characterizes patients with AIDS, most likely by direct actions on muscle and other tissues. At present, rGH is not approved by the Food and Drug Administration, although approval is likely by the fall of 1996. A large treatment protocol sponsored by the company (Serono) is available through which patients with AIDS can obtain rGH in many cities in the United States. The main problem is the extremely high cost, which is nearly $12,000 for a 12-week course. Because rGH probably should be given continuously or patients return to previous LBM levels, this represents a substantial annual cost. Because it is effective but expensive, I use rGH at San Francisco General Hospital only after all other treatment options have failed.
Androgens and 'Anabolic' Steroids--Hypogonadism is the most common endocrine abnormality in HIV-infected men . Replacement of this potent LBM-anabolic hormone makes obvious sense if testosterone deficiency is present; all patients with AIDS wasting should undergo a serum total testosterone measurement. We are willing to provide testosterone replacement when borderline-low values are present (eg, less than 450 to 500 ng/mL, with the normal range being 225 to 1,100 ng/mL), assuming that most patients with low-normal levels are likely to have had much higher values most of their lives. Intramuscular injections of testosterone (200 mg every 2 weeks or 100 mg weekly) can be given, although this results in supraphysiologic levels followed by deficient levels in the period following each injection. Skin patches provide a better pharmacologic profile, but the scrotal patch often is associated with poor patient acceptance, and the currently-available systemic skin patch results in a high degree of local irritation, requiring frequent discontinuation.
Oral or parenteral "anabolic" steroids are also an option. However, I suggest caution before accepting the "anabolic to androgenic" ratios that Von Roenn and Knopf quote. The theoretic and practical existence of anabolic selectivity for any agent that interacts with the testosterone receptor is still uncertain . Nevertheless, studies with putatively "anabolic" steroids are underway to establish their utility in wasting disorders, and preliminary or anecdotal evidence suggests some promise for these agents.
Exercise--Although exercise is an attractive theoretic option for restoring LBM and improving patients' functional status, it should be recognized that most patients with wasting associated with HIV or cancer will not be able to exercise. Many patients with AIDS wasting can no longer work out because they feel worse afterward. Some of my patients have even described fever after exercise. Thus, any agent that helps patients return to exercising (eg, rGH, androgens, anabolic steroids) can be of a great clinical benefit for this reason alone.
Anticytokine Agents--The role of cytokines in clinical wasting syndromes remains intriguing but difficult to prove. At present, thalidomide(Drug information on thalidomide) is being tested in AIDS wasting for its potent inhibitory effects on the production of tumor necrosis factor by monocytes. I share the concerns about this agent noted by Von Roenn and Knopf. We  tested a less potent anticytokine intervention (n-3 fatty acids in the form of fish oil) in AIDS wasting. Although clinically stable patients tended to increase body weight and reduce metabolic abnormalities, fish oil apparently could not prevent episodes of weight loss associated with an opportunistic infection. The role of anticytokine agents in wasting disorders remains uncertain.
Combination Therapies--As Von Roenn and Knopf suggest, combination therapies may prove advantageous. One particularly useful combination may be megestrol acetate plus an androgen or anabolic steroid, because megestrol acetate induces a profound drop in the serum testosterone level . This combination is currently being tested in several clinical trials. Other combinations might include an appetite stimulant plus a growth hormone, an androgen or anabolic steroid plus a growth hormone, or an anticytokine plus an appetite stimulant. However, no clinical trials have yet been performed for any of these drug combinations.
Attempt to categorize patients into etiologic subgroups for selection of appropriate therapy. The fundamental distinction in cachexia syndromes is between patients who simply need more nutrients (starved subset) and those who also need anabolic agents (metabolic disorder subset) to increase LBM. At present, there is no definitive way to classify patients, but some clues are helpful. Patients with a slow, steady pattern of weight loss; clearly reduced appetite (due to oropharyngeal lesions, gastrointestinal symptoms, depression, etc.); low food intake documented by a dietician; very low body fat (eg,less than 10% to 12%); and no evidence of altered metabolism (increased energy expenditure or triglycerides) are most likely to be in the starved group. These patients need nutrients and may respond by increasing LBM and functional status. Megestrol acetate (perhaps with an androgen combination), oral supplements, or tube feedings should be considered in these patients. Patients with intermittent bouts of weight loss; fevers and sweats; a diagnosed opportunistic infection (such as Mycobacterium avium-intracellulare); currently adequate food intake documented by a dietician; relatively preserved body fat stores (eg, more than 15%); low serum testosterone levels; or documented metabolic abnormalities [9,16] are more likely to fall into the "metabolic disorder" subgroup. The alternative anabolic therapies noted previously can be considered for repletion of LBM and improvements in functional status .