In this study, we demonstrate that tesamorelin significantly improves body composition, with a highly significant, but selective reduction in VAT and body image among HIV-infected patients with abdominal fat accumulation. These benefits occurred without any significant increases in glucose or insulin levels, a major concern for any strategy to augment GH secretion in the HIV population. Moreover, from the design of the current study, with a 6-month extension phase beyond the 6-month primary efficacy phase, we were able to show that the decrease in VAT persists in those patients treated continuously for 12 months, with a total reduction of 17.5% in VAT in this group amounting to a 3.8-cm loss in WC, that was comprised entirely of loss of VAT. Although this effect is largely lost in patients switching off therapy for 6 months, residual benefits in body image persisted which may be important to patients.
Increased abdominal fat accumulation, particularly visceral fat, is increasingly recognized as contributing to increased coronary heart disease.18 Selective surgical removal of a small amount of visceral fat improves metabolic risk factors, whereas liposuction to remove considerable SC fat has little effect.19,20 Moreover, in the general population, WC has been shown to be independently associated with myocardial infarction risk in the Interheart Study,9 controlling for traditional risk factors and more recently, to independently contribute to increased mortality above and beyond BMI.10 HIV-infected patients beginning ART demonstrate a loss of peripheral fat and a relative sparing or increase in central fat.2,3 Moreover, recent studies demonstrate a significant increase in VAT among ART-naive patients beginning a PI, NNRTI, or combined PI/NNRTI strategy.21 Increased upper trunk and visceral fat have been shown to correlate most strongly with insulin resistance and dyslipidemia in HIV-infected patients.6-8 Moreover, recent data in HIV-infected patients receiving ART suggest increased VAT is significantly related to coronary calcium progression.22 The adverse effects of increased WC shown in non-HIV-infected patients may be even larger among HIV patients, in whom WC is made up of increased VAT with loss of SAT, as opposed to non-HIV-infected patients, with obesity and excess VAT and SAT. Therefore, there may be a particularly strong logic to selectively reducing VAT in the HIV population. The data from the current randomized placebo-controlled study add to the growing body of literature on the effects of tesamorelin on VAT. In randomized placebo-controlled studies enrolling almost 900 patients, there has been a very consistent reduction in VAT in response to tesamorelin.
In contrast to prior studies with GH, treatment with tesamorelin was again shown in this study not to reduce SC fat. The selective effect to reduce visceral fat is important among HIV-infected patients, the majority of whom also demonstrate SC fat loss with long-term ART, as seen in the current study in which two-thirds of the subjects noted lipoatrophy and baseline extremity fat by DEXA was low. Indeed, recent studies suggest that the SC depot may be protective in terms of metabolic abnormalities23 and a strategy which does not contribute to a further loss in SC fat is ideal for the HIV population.
A number of studies have now shown GH secretion to be relatively reduced among HIV-infected patients with increased abdominal fat accumulation.12,13 These studies show normal GH pulsatility, but reduced pulse height and width, suggesting a reduction in GHRH-stimulated GH pulsatility.13 Prior studies have begun to investigate the effects of a novel strategy, using a GRF analogue, to augment endogenous GH pulsatility and thus address a fundamental metabolic abnormality in HIV-infected patients with excessive central fat accumulation.24
In contrast to GHRH, which results in more physiological increases in GH and IGF-I, dosing with exogenous GH requires careful titration to avoid significant GH excess. Large Phase III studies using GH at high doses resulted in pharmacological increases in GH, with concomitant increases in glucose,25,26 not seen with tesamorelin. Importantly, in the current and prior studies with tesamorelin, glucose was not disturbed even among patients with IGT or diet-controlled diabetes, who were permitted to enroll and constituted 15%-20% of the study population. Indeed, even low dose GH, carefully titrated to maintain physiological levels of IGF-I, significantly increased 2-hour glucose, achieving a comparable, but smaller 9% reduction in VAT over a longer period of 18 months compared with a 17.5% reduction over 12 months in response to tesamorelin in the current study.27
Although it is reassuring that tesamorelin does not significantly adversely affect glucose homeostasis, it is important to consider why glucose was not improved given the significant reduction in VAT in this study. The mechanism of action of tesamorelin is a highly specific effect on the pituitary to increase endogenous GH release. GH is known to be directly antagonistic to insulin and low dose GH itself, as opposed to tesamorelin, worsens glucose in the setting of improved visceral fat among HIV-infected patients.27 In contrast, tesamorelin improves VAT but is neutral to glucose. One potential hypothesis is that there is some mild aggravation of insulin action, as a result of increased pituitary GH secretion, but of a degree that is counterbalanced by the improvement in VAT, so that the net effect is neutral. It is also possible that concomitant use of insulin antagonistic antiretroviral drugs counters the improvements in glucose that would ordinarily be expected with reductions in VAT among HIV-infected patients.
In contrast to a prior study of tesamorelin, the current study did not show a significant decrease in triglycerides, but rather a trend, amounting to a net reduction in triglycerides of 26 mg/dL compared with placebo over 6 months. The treatment effect was larger in the prior study, 59 mg/dL, but entry triglyceride levels were higher in that study.14 One explanation may be that the current study included European sites, where dietary and lifestyle patterns may differ. Importantly, a similar proportion of patients were receiving PIs in both studies. TC was reduced significantly for subjects receiving tesamorelin for 12 months in the current study suggesting at least 1 additional cardiovascular benefit beyond that of a reduction in VAT.
The effects of tesamorelin on body image are important and consistent between the 2 Phase III studies. Patients receiving tesamorelin in this double-blinded placebo-controlled study reported less distress regarding abdominal hypertrophy, and physician rating of the abdominal profile also improved. This reduction in stress related to body image may contribute to increased compliance with ART. At a minimum, the significant reduction in belly distress suggests that the benefit in VAT reduction and WC were clinically significant to patients. We also assessed the important question as to whether effects on body image persist over 12 months. In the current study, we demonstrate data that the improvement in body image indeed persisted in those receiving 12 months of treatment in the T-T group, but also persisted, in those in the T-P group who switched off tesamorelin. The persistence of these effects after discontinuation of tesamorelin was stronger in the current study than in the prior study.15
Overall, AE rates and SAEs did not differ between tesamorelin and placebo in the primary efficacy phase and did not increase further with continuing treatment over 12 months in the safety extension phase. The development of lung cancer in one of the tesamorelin-treated patients was most likely unrelated to study medication, given the short exposure period of 3 months and physiological IGF-I during treatment. A small percentage of patients experienced a hive-like rash that did extend beyond the injection site in some patients. These patients were discontinued and improved, without further consequence. A small percentage of patients treated with tesamorelin can be expected to have such a reaction, and for such patients, treatment discontinuation is prudent.
How does tesamorelin compare with other strategies to reduce visceral fat in HIV-infected patients? Neither metformin nor lifestyle modification including, thrice weekly exercise, significantly reduce visceral fat to the degree of tesamorelin,28-30 but these strategies improved markers of glucose homeostasis, whereas tesamorelin was neutral to glucose. Effects of tesamorelin on lipids are stronger than that seen with metformin and lifestyle modification. Body image was not assessed in response to metformin and or lifestyle modification and was significantly improved in response to tesamorelin.
Tesamorelin is not yet approved for use in North America or Europe. However, we now report completion of a second Phase III study, again demonstrating significant efficacy of tesamorelin (18% reduction in VAT) and good safety with ongoing treatment to 12 months in a randomized placebo-controlled study of over 400 patients. With these new data, there are now consistent results from 2 large Phase III, randomized placebo-controlled studies to suggest that this is a potentially useful clinical strategy to selectively reduce VAT and improve body image among HIV-infected patients with abdominal fat accumulation in the context of ART treatment.
We would like to thank the patients for their participation.
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APPENDIX I: STUDY INVESTIGATORS
The following investigators participated in the study: Ottawa Hospital, Ottawa, Ontario, Canada-J. Angel; Hospital CU de Santiago, Unidad de Enfermedades Infecciosas, Santiago de Compostela, Spain-A. Antela López; Hendry Glades Department of Health, Labelle, FL-J. Beal; Northstar Medical Center, Chicago, IL-D. Berger; Central Texas Clinical Research, Austin, TX-C. Brinson; AIDS Research Alliance, West Hollywood, CA-S. Brown; Hôpital de l'Hôtel Dieu Lyon, Lyon Cedex 02, FRANCE-L. Cotte; CHU St-Pierre, Clinique des Maladies Infectieuses, Brussels, BELGIUM-N. Clumeck; UCLA School of Medicine, Los Angeles, CA-J. Currier; ACRIA, New York, NY-J. Ernst; Clínico San Carlos, Enfermedades Infecciosas, Hospital de Dia, Madrid, SPAIN-V. Estrada; Montreal General Hospital, Immune Deficiency Treatment Centre, McGill University Health Centre, Montreal, Quebec, CANADA-J. Falutz; Kaiser Permanente, Clinical Trials Unit-Dr. Dillon, San Francisco, CA-W. J. Fessel; BSUH NHS Trust, HIV/GUM Research Department, Elton John Centre, Brighton, United Kingdom-M. Fisher; Therapeutic Concepts, Houston, TX-J. C. Gathe; Massachusetts General Hospital, Program in Nutritional Metabolism, Boston, MA-S. Grinspoon; UCSF/VA Medical Center, San Francisco, CA-C. Grunfeld; Indiana University School of Medicine, Division of Infectious Diseases, Indianapolis, IN-S. Gupta; University of Texas Southwestern Medical Center at Dallas, Dallas, TX-M. Jain; Royal Free Hospital, Ian Charleson Day Centre, London, United Kingdom-M. A. Johnson; St. Georges Hospital, Department of GU Medicine (Courtyard Clinic), London, United Kingdom-D. Macallan; The Research Institute, Springfield, MA-C. Martorell; University Hospitals of Cleveland, Cleveland, OH-G. A. McComsey; Hospital Ramón y Cajal, Servicio de Enfermedades Infecciosas, Madrid, Spain-S. Moreno; CHU Sart-Tilman, Maladies Infectieuses, Liège, BELGIUM-M. Moutschen; St Paul's Hospital, Canadian HIV Trials Network, Vancouver, British Columbia, Canada-J. Montaner; University of California San Francisco, San Francisco, CA-K. Mulligan; Chelsea and Westminster Hospital, St Stephen's Clinic, London, United Kingdom-G. J. Moyle; Southwest Center for HIV/AIDS, Phoenix, AZ-R.A. Myers; ID Associates, Hillsborough, NJ-R. G. Nahass; Centre Hospitalier Universitaire de Santé de l'Estrie, Département de microbiologie et d'infectiologies, Sherbrook, Quebec, Canada-A. Piché; Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris, FRANCE-C. Piketty; Sunnybrook Health Sciences Centre, Toronto, Ontario, CANADA-A. Rachlis; Hôtel Dieu, Services des Maladies Infectieuses, Nantes Cedex 1, FRANCE-F. Raffi; Fort Lauderdale, FL-G. J. Richmond; CHUM-Hôpital Notre-Dame, Pavillon L-C Simard-UHRESS, Montreal, Quebec, CANADA-D. Rouleau; University of Alabama at Birmingham, Center for AIDS Research, Birmingham, AL-M.S. Saag; St. Mary's NHS Trust, London, UK- G. Scullard; Swedish Medical Center, Seattle, WA-P. Shalit; Denver Public Health Department, Terry Beirn Community Programs for Clinical Research on AIDS, Denver, CO-J.C. Shlay; Hamilton Health Sciences Center - McMaster University Health Sciences Centre, Hamilton, Ontario, CANADA-F. Smaill; Infectious Disease, Palm Springs, CA-M. S. Somero; AIDS Research Consortium of Atlanta, Inc. Atlanta, GA-M.A. Thompson; Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Quebec, QC, CANADA-S. Trottier; UZ Gasthuisberg, Leuven, BELGIUM-E. H. Van Wijngaerden; Hôpital Necker, Service des Maladies Infectieuses, Paris Cedex 15, France-J. P. Viard; University Health Network, Toronto General Hospital, Toronto, Ontario, Canada-S. Walmsley; Tufts New England Medical Center, Nutrition Infection Unit, Boston, MA-C. Wanke; University of North Carolina at Chapel Hill, AIDS Clinical Trials Unit, Chapel Hill, NC-D. Wohl; and Infectious Disease Research Institute, Inc, Tampa, FL-B. G. Yangco.