Treatment with an investigational drug that induces the release of growth hormone significantly improved the symptoms of HIV lipodystrophy, a condition involving the redistribution of fat and other metabolic changes in patients receiving combination drug therapy for HIV infection.
A team led by researchers from Massachusetts General Hospital (MGH) and McGill University Health Centre found that treatment with tesamorelin, a growth-hormone-releasing factor, significantly reduced deep abdominal fat deposits and improved the metabolic aspects of HIV lipodystrophy in a group of patients with the syndrome. The report of a six-month Phase 3 clinical trial of tesamorelin appears in the December 6 New England Journal of Medicine.
"This appears to be the most promising strategy to date for a safe, effective method of reducing excess visceral fat deposits and improving lipid abnormalities in HIV-infected patients, thereby improving their risk for cardiovascular disease," says Steven Grinspoon, MD, of the MGH Neuroendocrine Unit and Program in Nutritional Metabolism, the report's senior and corresponding author.
A significant number of HIV-infected individuals who receive antiviral therapy develop lipodystrophy. Symptoms of the syndrome include a loss of subcutaneous fat in the face, arms, and legs and increased fat deposits in the abdomen. The metabolic aspects of the syndrome -- changes in cholesterol and other blood lipids, and development of insulin resistance -- could increase the risk of cardiovascular disease in HIV-infected patients.
Earlier studies found that growth hormone secretion is reduced in men with lipodystrophy. Since directly injecting growth hormone can have significant side effects, researchers at the MGH previously investigated the use of growth-hormone-releasing hormone (GHRH) to increase levels in a way that mimics natural control of hormone levels. In a 2004 study, they showed that patients receiving GHRH injections appeared to have more normal growth hormone levels and improvements in fat distribution.
The current study followed up an earlier Phase 2 study of tesamorelin, a growth-hormone-releasing factor that can be dosed only once a day instead of twice. Study participants -- HIV lipodystrophy patients recruited from 43 sites around the U.S. and Canada -- were randomly assigned to receive either tesamorelin or a placebo, self administered daily for six months. At the end of the study period, researchers measured participants' visceral fat -- deposits around organs deep in the abdomen -- and subcutaneous fat in arms and legs. They also recorded key lipid measurements and levels of the hormone IGF-1, which reflects the release of growth hormone. In addition, participants were surveyed at the beginning and end of the study on their perceptions of their bodies and any distress they felt.
Among the more than 325 participants who completed the study, those receiving tesamorelin had significant reductions in abdominal fat, measured by CT scan, resulting in a 20 percent difference from those in the placebo group. Lipid measurements -- including triglycerides, total cholesterol, HDL, and the ratio of total cholesterol to HDL -- also improved significantly; IGF-1 levels reflected increased release of growth hormone in the tesamorelin group. Participants receiving the drug also reported significant improvements in their body image and reduced levels of distress.
"Patients treated with tesamorelin saw their abdominal fat decrease by 15% on average, compared to a 5% average increase for the placebo group", explained Dr. Falutz. "Also, the side-effects are minimal."
"Longer-term studies are necessary to confirm our results, and another confirmatory Phase 3 trial needs to be completed to comply with FDA requirements," says Grinspoon. "But this study shows clearly that the novel strategy of inducing the release of endogenous growth hormone can improve symptoms of lipodystrophy, relieving patient distress -- which may improve their compliance with therapy -- and reducing several cardiovascular risk factors." Grinspoon is an associate professor of Medicine at Harvard Medical School.
The study was supported by Theratechnologies, a biopharmaceutical company based in Montrιal that is developing tesamorelin, and the data were analyzed by Quintiles, Canada. Julian Falutz, MD, of McGill University Health Center, is the first author. Additional co-authors are Soraya Allas, MD, PhD, Koenraad Blot, MD, and Diane Potvin, MSc, Theratechnologies; Donald Kotler, MD, Columbia College of Physicians and Surgeons; Michael Somero, MD, Palm Springs, Calif.; Daniel Berger, MD, Northstar Health Care, Chicago; Stephen Brown, MD, AIDS Research Alliance, Los Angeles; Gary Richmond, MD, Ft. Lauderdale, Fla.; Jeffrey Fessel, Kaiser Foundation Research Institute, San Francisco; and Ralph Turner, MD, PhD, Phase V Techologies, Wellesley, Mass.
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