Editorial: The Rational Use of Growth Hormone in HIV-Infected Patients

Steven Grinspoon and Marie Gelato

Neuroendocrine Unit (S.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and Division of Endocrinology (M.G.), SUNY Health Sciences Center–Stony Brook, Stony Brook, New York 11794

Address all correspondence and requests for reprints to: Dr. Steven Grinspoon, Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org

GH secretion and action is affected by nutritional status and changes in body composition. Acquired resistance to the action of GH is common in severe undernutrition as a result of impaired GH receptor and postreceptor signaling of IGF-I in the liver. In contrast, reduced GH secretion occurs in generalized obesity (1), most likely through inhibition by somatostatin. It is, therefore, not surprising that HIV disease is characterized by a number of abnormalities in the GH–IGF-I axis. In patients with AIDS wasting and loss of significant weight and muscle mass, a pattern of acquired GH resistance is seen, with increased GH and simultaneously decreased concentrations of IGF-I (2). In such patients, the expected GH-induced increase in IGF-binding protein-3 is diminished (3). In addition, increased proteolysis of IGF-binding protein-3 is seen in HIV-infected children with growth failure, which may affect the tissue concentration of free IGF-I (4). In contrast, recent data suggest reduced GH concentrations in HIV-infected patients with fat redistribution receiving highly active antiretroviral therapy, characterized by excess abdominal visceral fat and loss of sc fat (5). Although the mechanisms of these changes in fat redistribution have not been elucidated, recent data suggest a strong inverse correlation between increased visceral fat and reduced GH concentrations, determined from overnight frequent sampling (5). Taken together, these data suggest adaptive responses in GH secretion depending on changes in nutritional status and body composition in HIV-infected patients. In contrast, normal GH secretion has been reported in otherwise healthy HIV-infected patients, without demonstrated wasting or lipodystrophy (6).

The use of GH has been proposed both in the treatment of AIDS wasting to increase lean body and muscle mass, as well as in the HIV lipodystrophy syndrome, to reduce abdominal visceral fat. Use of the same hormone, GH, in these two seemingly disparate conditions, highlights the multiple effects of GH. On the one hand, GH is anabolic, improves nitrogen balance, and increases lean body mass. Data from a large randomized, placebo-controlled study of patients with advanced HIV disease and wasting demonstrate a significant 3-kg increase in lean body mass over 12 wk in response to GH (7). The dose of GH used in the study of Schambelan et al. (7), 0.1 mg/kg·day, was quite large (in comparison, GH may be initiated at doses as low as 0.002 mg/kg·day for adults with GH deficiency). Although the extracellular fluid component of fat-free mass increased, functional indices improved, suggesting a true anabolic effect of GH in patients with AIDS wasting (7). It remains unknown whether lower doses would be effective given the evidence for GH resistance in patients with AIDS wasting.

Although GH remains an option for patients with severe AIDS wasting, other strategies such as optimizing nutritional status and gonadal function and use of exercise should be considered as first-line therapies in such patients due to the proven benefit, minimal toxicity, and reduced cost of these strategies (8). Furthermore, a number of unanswered questions remain about the optimal use of GH in AIDS wasting. By what criteria of wasting should patients be identified? Should patients with normal or even increased absolute weight but with some weight loss be given GH. Should patients with normal weight but reduced muscle mass be considered for GH therapy? For example, it remains unknown whether HIV-infected patients receiving continued long-term, high-dose GH would suffer consequences of GH excess. When should GH be stopped, once initiated? Will symptoms of GH excess be more likely as GH resistance diminishes with improved weight from better antiretroviral therapy? To date, no long-term safety or dose-ranging studies of GH have been performed in patients with AIDS wasting. In this regard, concern arises regarding the diabetogenic potential of GH in light of recent studies showing insulin resistance and effects on glucose homeostasis in patients receiving highly active antiretroviral therapy, particularly protease inhibitors. In addition, concerns arise about stimulation of HIV-associated malignancies with long-term nonphysiological GH dosing. Another use of GH may be as an acute therapy to reverse losses in nitrogen associated with acute illness, such as opportunistic infections. Studies are now ongoing to determine the role of GH as an adjunctive metabolic therapy to spare protein losses during acute illness.

Recently, a number of studies have proposed the use of GH as a lipolytic agent in HIV-infected patients with fat redistribution (9). What is the rationale for this use of GH in HIV-infected patients with fat redistribution, and what are the potential safety concerns with the use of GH in this population? In non-HIV-infected patients, obesity is associated with reduced GH secretion (1). Although the mechanisms of fat redistribution in HIV infected patients receiving highly active antiretroviral therapy have not been determined, such patients demonstrate extreme visceral obesity without increases in total body fat. In such patients, excess visceral fat, not total body fat, predicts reduced GH secretion (5).

What is the effect of GH in patients with obesity? Johannsson et al. (10) have shown that GH administration (0.01 mg/kg·day) to abdominally obese men reduced visceral fat and improved glucose disposal rates. At first glance, such a hypothesis may seem contradictory, because GH is known to increase insulin resistance and antagonize the actions of insulin. However, use of low-dose GH may actually improve insulin resistance in association with reduced visceral adiposity. In such a scenario, the lipolytic effects might, therefore, prevail over the diabetogenic effects of GH.

In the initial studies of GH in HIV lipodystrophy, very large doses of GH (0.1 mg/kg·day) have been used (9, 11). Although these preliminary open label studies do suggest a potent lipolytic effect of GH to reduce visceral fat, increased glucose, and other side effects of GH excess, such as fluid retention, have been commonly reported using supraphysiological dosing. Although larger doses of GH may be expected to be more lipolytic, such doses are not rational and may not be necessary in light of the recent data suggesting reduced GH secretion in HIV-infected patients and the preexisting abnormalities in glucose homeostasis in a large majority of HIV-infected patients with the lipodystrophy syndrome. In this regard, the study by Lo et al. (12), in this issue of the JCEM, is an important first attempt to investigate lower doses of GH in patients with HIV lipodystrophy. Lo et al. (12) investigated a dose of 3 mg/d in patients with HIV lipodystrophy. Although such a dose is clearly still pharmacologic (as shown by the 4-fold increase in IGF-I to well above the normal range), important lessons can be learned from this study in the rational design of future studies to assess the efficacy of GH treatment in this population. Total body fat was reduced from GH, and a trend was observed in reduced visceral adipose tissue. Importantly, it seemed that GH was most lipolytic for visceral fat among the patients with the most increased visceral fat at baseline, suggesting a potential target population for future investigation. Insulin resistance, as assessed by euglycemic hyperinsulinemic clamp, worsened after 1 month, and then returned to baseline. However, 2-h glucose levels on oral glucose tolerance testing were increased at the end of the study compared with baseline, suggesting an overall impairment in glucose tolerance in response to GH. Furthermore, one patient with baseline-impaired glucose tolerance but a normal fasting glucose developed fasting hyperglycemia, and an additional patient required a dose reduction for arthralgias and developed diabetes mellitus based on the 2-h glucose level during the oral glucose tolerance test.

To know whether GH will be useful in patients with HIV lipodystrophy, placebo-controlled dose-ranging studies assessing physiologic GH administration need to be performed. It is also necessary to have strict inclusion criteria for such studies, targeting those patients with marked increased visceral adiposity as most likely to benefit from this therapy. The data from Lo et al. (12) suggest that lower doses of GH should be tested, to determine whether more physiologic dosing can reduce visceral fat without worsening glucose tolerance or insulin resistance. Furthermore, whether low-dose GH might actually improve insulin resistance is also an important question for HIV-infected patients with lipodystrophy. Another critical question regarding the efficacy of GH as a lipolytic strategy in HIV-infected patients relates to the appropriate surrogate marker(s) for efficacy in this population. Should the primary endpoints of such studies be a reduction in visceral fat, improvement in insulin sensitivity, lipids, or cardiovascular markers? In truth, all such markers may be important as endpoints of GH therapy, which must be safe and have an overall benefit, beyond the cosmetic, in such patients. Importantly, the beneficial effects of GH must be considered in light of other therapies being studied for such patients, including insulin sensitizers (13), which have the benefit of acting directly to improve insulin action, and by extension, body composition, cardiovascular markers, blood pressure, and other important endpoints. Finally, detailed investigation of the cause of fat redistribution and the contribution of antiretroviral agents to the lipodystrophy syndrome may allow a more direct modulation of cardiovascular markers and body composition without the use of additional hormones or metabolic therapies.

Received June 8, 2001.

Accepted June 8, 2001.

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