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[learn_more caption=”By Mariel Selbovitz”]
Mariel_Selbovitz_ViroChannelMariel Selbovitz, MPH is Senior Research Program Coordinator at Johns Hopkins School of Medicine and President at The Bio Diversity Group.

She is also a member of the International AIDS Society (IAS), American Public Health Assocciation (APHA) and Campaign to End AIDS (C2EA) and serves as Co-Chair of the Cornell AIDS Clinical Trials Group Community Advisory Board.

She received her BA from Cornell University and her Master in Public Health from the Johns Hopkins School of Public Health.[/learn_more]

Following a review and recommendations of a reconsideration panel of Health Canada, the Canadian regulatory agency has agreed to resume an NDS review of tesamorelin (Egrifta), a Growth- Hormone Releasing Factor (GHRF) analog, used for the treatment of excess visceral fat.

Tesamorelin was approved for use in the U.S. in November of 2011 and is awaiting regulatory approval in Canada and other countries. It is the only drug with the ability to decrease visceral fat accumulation in HIV patients with lipodystrophy. Tesamorelin acts on the pituitary gland to stimulate the release of Human Growth Factor (HGF). As an analog of GHRF, tesamorelin releases the appropriate amount of HGF, which has been found to be reduced in HIV patients with lipodystrophy.

A significant number of HIV patients experience lipodystophic effects from early protease inhibitors including Crixivan and Viracept. A significant increase in intra-abdominal fat is associated with a higher risk of cardiovascular disease1,2 and diabetes2.

In two clinical trials3,4 involving 806 HIV-infected adults with lipodystrophy and excess abdominal fat, patients treated with tesamorelin experienced greater reductions in abdominal fat as measured by CT scan compared to patients receiving a placebo. Improvements in self image were reported by some study participants.

A Phase III study5 was conducted with 550 patients receiving 2 mg of tesamorelin once daily and 266 receiving placebo. All patients had CD4 counts above 300 and 3 out of 4 patients had an undetectable viral load. Average waist size was 41 inches. Adherence was 99% or higher in both groups. During the second 26 weeks of the study, the patients on placebo were given tesamorelin and those in the treatment arm were randomized to continue therapy or placebo. Body scans were done prior to initiating treatment, throughout the study period and at 52 weeks. The aim of the study was to assess the amount of fat loss that occurred with the utility of tesamorelin as compared to placebo.

At 26 weeks, there was a 13% reduction in deep belly fat in the treatment arm as compared to placebo. At 52 weeks, patients who continued on treatment experienced an 18% reduction. Those who were assigned to the placebo arm at 26 weeks demonstrated a reverse in the gains made in deep belly fat reduction within three months. Tesamorelin had no significant effect on cholesterol levels but reduced triglycerides. A small increase in lean body fat also occurred.

Tesamorelin was also found to reduce inflammation in a study6 published in the April 20, 2011 issue of AIDS, suggesting it may also help reduce the risk of CVD in patients who achieve significant visceral fat loss. Dr. Takara Stanley and colleagues from Harvard Medical School tested stored blood samples from previous studies of tesamorelin and measured the inflammation marker PAI-1 antigen and tPA, both of which have been associated in CVD in HIV patients. The analysis looked at samples from 410 subjects, 273 of who had received tesamorelin for at least 26 weeks and 137 who received the placebo. The researchers found that reductions in deep belly fat were accompanied by reductions in PAI-1 and tPA, which persisted even when controlled for age, sex, race and the protein insulin-like growth factor (IGF-1), which can independently affect inflammation. They concluded that, “These data also have potential clinical implications and suggest that use of tesemorelin in patients with HIV and excess abdominal fat accumulation may result in an overall improvement in critical inflammatory and fibrinolytic markers, which may improve overall cardiovascular risk.”

In placebo-controlled Phase III studies, the most common side effects reported were injection site reactions (9%), joint stiffness and pain (13%) and muscle pain (6%). Twenty-eight patients experienced a hypersensitivity reaction, which was described by researchers as “extended skin reactions” in 41% of these patients, with symptoms including nausea, rapid heart beat, feeling dizzy or light-headed, sweating, shortness of breath and headache, none of which were life threatening. These symptoms disappeared when patients were treated with antihistamines or corticosteroid creams and discontinuation of the study drug.

Theratechnologies, the makers of tesamorelin, petitioned Health Canada after review of a tesamorelin NDS was halted and a notice of non-compliance/withdrawal was issued after Theratechnologies’ original NDS was submitted in June of 2011. The notice of non-compliance/withdrawal was based on Health Canada’s determination that the risks of tesamorelin outweighed the benefits of the drug under the proposed conditions for use.

Tesamorelin is an injectable medication taken daily. Discontinuation of therapy has been shown to reverse the benefits back to baseline measurements.

REFERENCES
1. South Med J. 2003 Feb;96(2):180-8; quiz 189. Lipodystrophy, insulin resistance, diabetes mellitus, dyslipidemia, and cardiovascular disease in human immunodeficiency virus infection. Tanwani LK, Mokshagundam SL.

2. Curr Med Res Opin. 2008 Mar;24(3):609-24. doi: 10.1185/030079908X272742. HIV lipodystrophy and its metabolic consequences: implications for clinical practice. Wierzbicki AS, Purdon SD, Hardman TC, Kulasegaram R, Peters BS.

3. J Acquir Immune Defic Syndr. 2010 Mar;53(3):311-22. doi: 10.1097/QAI.0b013e3181cbdaff. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension.
Falutz J, Potvin D, Mamputu JC, Assaad H, Zoltowska M, Michaud SE, Berger D, Somero M, Moyle G, Brown S, Martorell C, Turner R, Grinspoon S.

4. J Clin Endocrinol Metab. 2010 Sep;95(9):4291-304. doi: 10.1210/jc.2010-0490. Epub 2010 Jun 16.
Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. Falutz J, Mamputu JC, Potvin D, Moyle G, Soulban G, Loughrey H, Marsolais C, Turner R, Grinspoon S.

5. Effect of Tesamorelin (TH9507), a Growth Hormone-Releasing Factor (GRF) Analogue, on Visceral Adipose Tissue (VAT) in HIV-Infected Patients with Excess Abdominal Fat: Impact of Antiretroviral Therapy Regimen
Falutz J, Mamputu JC, Marsolais C, Potvin D, Zoltowska, M, Aeschliman D, Kotler D and Grinspoon S. Abstract P-19 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV Nov. 2008 http://www.intmedpress.com/lipodystrophy/data/File/10th_Lipo_Abstract_Booklet.pdf

6. Effects of Tesamorelin on Inflamation Markers in HIV Patients with Excess Abdominal Fat: Relationship with Visceral Adipose Reduction Takara L. Stanley, M.D., Julian Falutz, M.D., Jean-Claude Mamputu, Ph.D., Graziella Soulban, Ph.D., Diane Potvin, M.Sc, and Steven K. Grinspoon, M.D. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673013/