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Manipulation of the Growth Hormone Axis in Patients with HIV Infection EDITORIAL
 
 
  NEJM Dec 6, 2007
 
Marc R. Blackman, M.D.
From the Research Service, Veterans Affairs Medical Center, Washington, DC.
 
Patients with human immunodeficiency virus (HIV) infection often have a reduced mass of skeletal muscle and bone and a maldistribution of body fat. Loss of muscle mass, strength, and function are integral to the AIDS wasting syndrome and are associated with resistance to the anabolic effects of growth hormone. Administration of growth hormone in relatively high daily doses for 12 weeks improves muscle mass, strength, and function but leads to excess salt and water retention, the carpal tunnel syndrome, glucose intolerance, and insulin resistance, whereas the use of somewhat lower doses or an alternate-day regimen elicits similar beneficial effects with fewer side effects.1
 
It is uncertain whether growth hormone, growth hormone-releasing hormone (GHRH), or other means of stimulating the growth hormone axis will find a place in the therapeutic armamentarium of such patients. In this issue of the Journal, Falutz et al.2 report on the use of tesamorelin, a GHRH analogue, for the treatment of HIV-related abnormalities in fat storage and metabolic function.
 
Why should such an approach work? Growth hormone, produced by the somatotropic cells of the anterior pituitary gland, is an important anabolic and lipolytic hormone that increases muscle and bone mass and decreases body fat.3 Approximately two thirds of the daily, pulsatile release of growth hormone occurs at night, particularly during slow-wave sleep. Growth hormone secretion is modulated by two stimulatory peptides - GHRH, which is produced in the hypothalamus, and ghrelin, which is produced in the stomach, small intestine, and hypothalamus - and by the inhibitory peptide somatostatin. GHRH is derived from a 108-amino-acid protein, which is processed into the final bioactive form containing 40 or 44 amino acids that stimulates the production of growth hormone through the GHRH receptor.4 Ghrelin, an octanoylated 28-amino-acid peptide, stimulates the secretion of growth hormone through an endogenous growth hormone secretagogue receptor.5 Most tissue effects of growth hormone are mediated by insulin-like growth factor I (IGF-I), which is produced in response to growth hormone at various tissue sites. In turn, IGF-I exerts feedback inhibitory effects on growth hormone secretion. Circulating IGF-I is produced mainly in the liver, and its blood levels correlate closely with the daily release of growth hormone in nonelderly adults. Tissue IGF-I acts as a paracrine or autocrine factor to mediate local effects of growth hormone.3 IGF-I exists in blood and tissue both free and combined with one or more of six IGF-I-binding proteins (IGFBPs). The predominant circulating IGFBP is IGFBP-3, which is responsive to growth hormone. IGFBPs modulate the bioavailability and action of IGF-I. Thus, serum IGF-I levels do not completely account for tissue effects mediated by IGF-I.
 
The HIV lipodystrophy syndrome is characterized by increased abdominal visceral adiposity, a loss of subcutaneous fat in limbs, insulin resistance, and dyslipidemia. Lipodystrophy occurs in many patients who are receiving highly active antiretroviral therapy (HAART), particularly combination therapy with protease inhibitors and nonnucleoside reverse-transcriptase inhibitors.6 Lipodystrophy is more common in women, older persons, and patients with lower CD4 counts and body weights; its severity is influenced by the type, duration, and use of HAART. The relative risk of cardiovascular disease increases with the duration of HAART,7 yet absolute risks of cardiovascular morbidity and mortality appear to be low for most HIV-infected patients, except those with other cardiovascular risk factors. Patients with HIV lipodystrophy have diminished nocturnal secretion of growth hormone and IGF-I, closely related to their increased visceral adiposity,1 as in obese people who are not infected with HIV.3
 
Low doses of growth hormone that are administered to generally healthy men with abdominal obesity reduce visceral adiposity and improve insulin sensitivity.8 Administration of relatively high doses of growth hormone to patients with HIV-associated lipodystrophy decreases abdominal visceral fat and serum cholesterol levels but is accompanied by frequent adverse effects, whereas lower doses of growth hormone maintain the lipolytic effect with fewer adverse effects.6
 
To evaluate the potential use of more physiologic replacement of growth hormone in patients with HIV lipodystrophy, several investigators have examined the effects of various analogues of GHRH. In 31 patients with HIV lipodystrophy, twice-daily injections of GHRH(1-29) at a dose of 1 mg every 12 hours for 12 weeks increased IGF-I levels and lean body mass and decreased truncal fat.9 The decrease in abdominal visceral fat was not significant, and levels of glucose, insulin, and lipids were unaltered. In another, placebo-controlled study, tesamorelin, a GHRH analogue modified to prevent protein cleavage by the serum enzyme dipeptidyl aminopeptidase IV, was administered subcutaneously to 61 HIV-infected patients at doses of either 1 mg or 2 mg once daily for 12 weeks.4,10 As compared with the group receiving 1 mg, the group receiving 2 mg had higher IGF-I levels and less truncal fat; they also had less abdominal visceral fat, but the difference between the tesamorelin group and the placebo group was not significant. There were no significant changes in fasting-glucose levels, and there were few adverse effects.
 
In their multicenter study involving 412 patients, Falutz et al. report on data from patients with HIV lipodystrophy who received either 2 mg of tesamorelin or placebo once daily for 26 weeks. This phase was followed by a second 26-week extension phase in which 77% of all patients underwent a second randomization to receive either tesamorelin or placebo; these patients were followed for longer-term safety. During the initial study period, in the tesamorelin group, there was a highly significant decrease (15%) in abdominal visceral fat, the primary outcome. IGF-I and lipid profiles improved, as did patients' indexes of body image; there were no significant between-group differences in levels of glucose or insulin, CD4 counts, viral load, inflammatory markers, headache, arthralgias, or other adverse effects. IgG antibodies against tesamorelin developed in nearly half the patients who received the drug, of whom six had urticarial skin reactions, one with associated transient systemic atopic symptoms. There were no drug-related serious adverse events during the extension phase.
 
Is there a role for tesamorelin or other growth hormone secretagogues in the treatment of patients with HIV lipodystrophy? Data from the study by Falutz et al. and from previous trials suggest that this question is a compelling one, particularly because trials of other potential therapeutic approaches - such as insulin sensitizers, hypolipidemic agents, exercise, and diet - have yielded inconclusive results.6 Although discontinuation of HAART could attenuate or reverse the lipodystrophic abnormalities, the underlying HIV infection could be exacerbated; thus, such an interruption in therapy is not a practical remedy.
 
Numerous questions remain about the long-term administration of tesamorelin or other growth hormone-releasing analogues.
 
--Would such a regimen lower cardiovascular morbidity and mortality;
--overstimulate the pituitary gland or central nervous system, with an increased risk of pituitary neoplasms or neurobehavioral dysfunction;
--augment the risk of cancer in susceptible patients;
--improve the quality of life;
--elicit different response profiles according to age, sex, race, and atopic or genetic predisposition;
--or be supplanted by orally active growth hormone secretagogues, which might exert a better risk-benefit profile and be less expensive?
 
The findings of Falutz et al. suggest that without answers to these questions, the treatment of HIV lipodystrophy remains unresolved.
 
No potential conflict of interest relevant to this article was reported.
 
References
 
1. Grinspoon S, Gelato M. The rational use of growth hormone in HIV-infected patients. J Clin Endocrinol Metab 2001;86:3478-3479. [Free Full Text]
 
2. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med 2007;357:2359-2370. [Free Full Text]
 
3. O'Connor KO, Stevens TE, Blackman MR. Growth hormone and aging. In: Juul A, Jorgensen JOL, eds. Growth hormone in adults. Cambridge, England: Cambridge University Press, 1996:323-66.
 
4. Tomlinson B. Drug evaluation: tesamorelin, a synthetic human growth hormone releasing factor. Curr Opinion Investig Drugs 2006;7:936-45. 5. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-660. [CrossRef][Medline]
 
6. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005;352:48-62. [Free Full Text]
 
7. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349:1993-2003. [Erratum, N Engl J Med 2004;350:955.] [Free Full Text]
 
8. Johannsson G, Marin P, Lonn L, et al. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab 1997;82:727-734. [Free Full Text]
 
9. Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth-hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA 2004;292:210-218. [Free Full Text]
 
10. Falutz J, Allas S, Kotler D, et al. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS 2005;19:1279-1287. [ISI][Medline]
 
 
 
 
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