By Liz Highleyman

For reasons that are not fully understood, antiretroviral therapy and HIV infection itself are associated with lipodystrophy, a syndrome characterized by visceral adiposity (fat accumulation) and metabolic complications associated with an elevated risk for cardiovascular disease.

Hypothesizing that reduced growth hormone (GH) secretion -- which occurs in approximately one-third of HIV patients with fat accumulation -- might be a factor contributing to lipodystrophy, Steven Grinspoon and colleagues at Massachusetts General Hospital in Boston conducted a double-blind, placebo-controlled trial to investigate the effects of low-dose physiological GH administration on body composition, glucose levels, and cardiovascular parameters in HIV positive patients with abdominal fat accumulation and relative GH deficiency.

Results were presented at a media briefing in advance of the XVII International AIDS Conference taking place this week in Mexico City and published in the August 6, 2008 Journal of the American Medical Association.

A total of 192 HIV positive patients were screened between November 2003 and March 2006. Most (84%) were men, 74% were white, the mean age was 45 years, and the mean body mass index (BMI) was 26.6. Of these, 56 patients with abdominal fat accumulation and reduced GH secretion (peak GH < 7.5 ng/mL) were included in the study.

Patients were randomly assigned to receive either physiological replacement doses of subcutaneous GH -- meaning they were given enough to bring insulin-like growth factor 1 (IGF-1) levels within the normal range -- or else placebo. The starting dose of GH was 2 mcg/kg/day and increased to maximum dose of 6 mcg/kg/day (average 0.33 mg/d). Treatment continued for 18 months. Subjects in the GH and placebo groups were similar at baseline, including their use of antiretroviral drugs.

Changes in body composition were assessed using computed tomography (CT) scans and dual-energy x-ray absorptiometry (DEXA). Secondary outcomes included glucose levels, IGF-1 levels, blood pressure, and blood lipid levels. Quality of life was also assessed. In all, 55 patients (26 GH, 29 placebo) were included in the safety analyses and 52 (25 GH, 27 placebo) were included in the efficacy analyses.

Results

• As expected, IGF-1 levels increased in the GH group (treatment effect 129 ng/mL; P < .001).

• Improvements were seen in visceral adipose tissue area (P = 0.04), trunk fat (P = 0.04), diastolic blood pressure (P = 0.006), and triglycerides (P = 0.002).

• Abdominal fat decreased significantly more in the GH group compared with the placebo group (percentage change of -8.5% vs -1.6%, respectively).

• Total and HDL ("good") cholesterol levels were unchanged between the 2 groups.

• 2-hour glucose levels on glucose tolerance testing increased in the GH group vs the placebo group (P = 0.009), although hemoglobin A1c (a measure of long-term glucose levels) were similar.

• Adverse events were not increased in the GH arm compared with the placebo group (23% vs 28%; P = 0.70).

In conclusion, the study authors wrote, "In HIV-associated abdominal fat accumulation and relative GH deficiency, low-dose GH received for 18 months resulted in significantly reduced visceral fat and truncal obesity, triglycerides, and diastolic BP, but 2-hour glucose levels on glucose tolerance testing were increased."

In their discussion, they wrote, "Data from our randomized, placebo-controlled trial involving a long duration of observation inject a note of caution into the debate regarding the use of GH therapy in the HIV population. Large doses are highly effective to reduce VAT, but result in supraphysiological IGF-1 and many GH-related adverse events."

"Low-dose physiological GH is well-tolerated and results in significant but more modest reduction in VAT, but is nonetheless associated with increased glucose levels," they continued. "Therefore, the therapeutic window to achieve an optimal risk-benefit ratio of GH in individuals with HIV, abdominal fat accumulation, and insulin resistance may be very narrow and difficult to achieve."

Finally, they suggested that other more potent strategies to safely increase GH and reduce VAT -- including the use of GH-releasing hormone, or an analog such as tesamorelin (TH9507) -- may be more beneficial. Furthermore, "strategies using diet, exercise, and lifestyle change may be more cost-effective in the long run than GH, particularly in patients with HIV, visceral adiposity, and insulin resistance, in whom changes in glucose may be counterproductive."

Growth hormone - Normal Anatomy

The growth hormone (GH) is a protein hormone released from the anterior pituitary gland under the control of the hypothalamus. In children, GH has growth-promoting effects on the body. It stimulates the secretion of somatomedins from the liver, which are a family of insulin-like growth factor (IGF) hormones.

8/08/08

Reference
J Lo, SM You, B Canavan, and others. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. Journal of the American Medical Association 300(5): 509-519. August 6, 2008.