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Background Visceral adipose tissue accumulates during antiretroviral therapy in many patients who are infected with the human immunodeficiency virus (HIV); this process is associated with an increased cardiovascular risk. We assessed the use of a growth hormone–releasing factor analogue, tesamorelin, to decrease visceral adiposity.
Methods We randomly assigned 412 patients with HIV (86% of whom were men) who had an accumulation of abdominal fat to receive a daily subcutaneous injection of either 2 mg of tesamorelin or placebo for 26 weeks. The primary end point was the percent change from baseline in visceral adipose tissue as shown on computed tomography. Secondary end points included triglyceride levels, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, the level of insulin-like growth factor I (IGF-I), and self-assessed body image. Glycemic measures included glucose and insulin levels.
Results The measure of visceral adipose tissue decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group; the levels of triglycerides decreased by 50 mg per deciliter and increased by 9 mg per deciliter, respectively, and the ratio of total cholesterol to HDL cholesterol decreased by 0.31 and increased by 0.21, respectively (P<0.001 for all comparisons). Levels of total cholesterol and HDL cholesterol also improved significantly in the tesamorelin group. Levels of IGF-I increased by 81.0% in the tesamorelin group and decreased by 5.0% in the placebo group (P<0.001). Adverse events did not differ significantly between the two study groups, but more patients in the tesamorelin group withdrew from the study because of an adverse event. No significant differences were observed in glycemic measures.
Conclusions Daily tesamorelin for 26 weeks decreased visceral fat and improved lipid profiles, effects that might be useful in HIV-infected patients who have treatment-associated central fat accumulation. (ClinicalTrials.gov number, NCT00123253
[ClinicalTrials.gov]
.)
Methods
Patients
Patients with HIV were recruited at 43 sites between June 2005 and April 2006. Eligibility criteria included the receipt of antiretroviral therapy for at least 8 weeks and an excessive accumulation of abdominal fat, which was defined as a waist circumference of at least 95 cm and a waist-to-hip ratio of at least 0.94 for men and a waist circumference of at least 94 cm and a waist-to-hip ratio of at least 0.88 for women. Other eligibility criteria were similar to those used in our previous phase 2 study of tesamorelin.3 The use of a stable lipid-lowering regimen within 3 months before randomization and of a stable physiologic testosterone regimen within 6 months before randomization was permitted. Patients who were receiving estrogen or growth hormone or related products within 6 months before randomization or who had a clinical history of pituitary disease were excluded. The study was approved by the institutional review board at each site, and all patients provided written informed consent before screening.
Study Design and Intervention
Patients were randomly assigned in a ratio of 2:1 to receive either 2 mg of tesamorelin or matching placebo, administered by subcutaneous injection daily between 6 a.m. and noon for 26 weeks. Randomization was stratified on the basis of the use of testosterone at baseline and the presence of diet-controlled impaired glucose tolerance or type 2 diabetes mellitus with the use of permuted blocks of 6. Patients and investigators were unaware of assignments to study groups. Assessments of body composition and metabolism were performed at baseline and at weeks 13 and 26. Tesamorelin and matching placebo were distributed as lyophilized powder for reconstitution in sterile water.
The initial 26-week study period was designed to assess the primary efficacy end point, the number of square centimeters of visceral adipose tissue as assessed by computerized tomographic (CT) scanning, and was followed by a 26-week extension phase to evaluate long-term safety. Patients who received tesamorelin in the main phase of the study underwent a second randomization to receive either tesamorelin or placebo in a ratio of 3:1 in the extension phase. Patients receiving placebo in the main phase were assigned to receive tesamorelin in the extension phase. A data and safety monitoring board met every 6 months to review safety data.
Theratechnologies funded and designed the study in consultation with Drs. Grinspoon and Falutz. The statistical analyses were performed by Quintiles Canada, and body-image outcomes were assessed by Phase V. The manuscript was drafted by Dr. Grinspoon. The decision to publish was made by Dr. Grinspoon and Theratechnologies. Dr. Grinspoon vouches for the accuracy and completeness of the data and the analyses.
Assessments
Visceral adipose tissue was determined on CT from a single 5-mm slice obtained between L4 and L5, which has been shown to correlate well with visceral fat volume.4 Scans were read at a central image reading center (Perceptive Informatics) in a blinded fashion. Lean body mass and the volume of fat in the trunk and limbs were determined from total-body dual-energy x-ray absorptiometry, with results also read centrally. Insulin-like growth factor I (IGF-I) was measured at Esoterix.
Self-perceived body image was determined by a validated questionnaire (Phase V Technologies).5 Patients rated their "belly size" by comparing their current appearance to their perceived healthy look, with scores ranging from much thinner (–100) to much bigger (+100); they also rated their "belly image distress" about their size, from extremely upsetting and distressing (0) to extremely encouraging (100) and their "belly profile" by choosing from among six silhouettes scored from normal (0) to very dysmorphic (5).
Statistical Analysis
The primary efficacy end point was the percent change in visceral adipose tissue from baseline to week 26. Secondary efficacy end points included the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, levels of triglycerides and IGF-I, and the patient's perception of body image. The safety end points included adverse events and effects on glucose, insulin, and hematologic and blood chemical analyses.
The efficacy end points were analyzed on the basis of data for patients who had received at least one dose of study drug with the last observation carried forward for those not completing the study. A secondary analysis was performed in patients who completed the study according to the protocol and received a study drug as instructed without a significant protocol violation (per-protocol population). Safety and baseline values are presented for patients who received at least one dose of a study drug. The treatment effect of tesamorelin was estimated according to the difference between placebo and tesamorelin in least-square means from the analysis of covariance.
Supportive analyses were also performed with the inclusion of covariates that were used in the stratification (i.e., testosterone use at baseline and the presence or absence of impaired glucose tolerance or type 2 diabetes mellitus) and the randomization center. The use of nonnucleoside reverse-transcriptase inhibitors was included in supportive models for visceral adipose tissue and lipid end points. The current use of lipid-lowering therapy was included in the model for lipid end points. Fisher's exact test was performed for adverse events observed in at least 10% of the patients. All serious adverse events, regardless of frequency, were reported. Baseline comparisons between groups were made by Student's t-test for continuous variables and Fisher's exact test for noncontinuous variables.
The study had a statistical power to detect a difference of 8% between the tesamorelin group and the placebo group in percent change in visceral adipose tissue on the basis of discussions with representatives of the Food and Drug Administration (FDA) to determine the clinical significance of a change in visceral fat, assuming a standard deviation of 18.5%, a power of 90%, a two-sided significance level of 0.05, and a 2:1 distribution ratio of tesamorelin to placebo. The randomization was weighted toward active therapy in order to permit the collection of safety data on the larger number of patients exposed to tesamorelin. An initial dropout rate of 33% was anticipated in the study plan. All reported P values are two-sided and were not adjusted for multiple testing.
Results
Patients
Of 412 patients who underwent randomization, 275 were assigned to receive tesamorelin and 137 to receive placebo. The discontinuation rate was 20.5% (22.7% in the tesamorelin group and 16.1% in the placebo group, P=0.12) (Figure 1). No significant differences in body composition or metabolic or chemical values were seen between the study groups at baseline, although significantly more patients in the tesamorelin group had received nonnucleoside reverse-transcriptase inhibitors (Table 1).
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The percent change from baseline to week 26 in visceral adipose tissue was significantly greater in the tesamorelin group, which had a decrease of 27.8 cm2, as compared with an increase of 5.1 cm2 in the placebo group (Figure 2A). Similar results were observed in the per-protocol population, as defined in the Methods section (data not shown). Results remained highly significant (P<0.001), with adjustment for the use or nonuse of testosterone at baseline, the presence or absence of impaired glucose tolerance or diabetes, sex, center location, and the use or nonuse of nonnucleoside reverse-transcriptase inhibitors. No significant covariate effects or covariate-by-treatment interactions were observed. The change in visceral adipose tissue in the tesamorelin group, as compared with the placebo group, was similar for men and women (data not shown). The change in visceral adipose tissue was larger for patients who had more visceral adipose tissue at baseline (Figure 2B).
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The changes in IGF-I levels were significant between groups: an increase of 109 ng per milliliter (81.0%) in the tesamorelin group and a decrease of 16 ng per milliliter (5.0%) in the placebo group. When the results were adjusted for age and sex, the mean changes in IGF-I levels represented a standard-deviation score of 2.69±2.51 in the tesamorelin group and –0.39±1.43 in the placebo group.
Lipids
The differences in the ratio of total cholesterol to HDL cholesterol and levels of triglycerides, total cholesterol, and HDL cholesterol were significant between the study groups (Table 2). These differences remained significant after adjustment for the use of both lipid-lowering drugs and non-nucleoside reverse-transcriptase inhibitors in a single model. With respect to the ratio of total cholesterol to HDL cholesterol, differences between the tesamorelin group and the placebo group were significantly greater among those who received lipid-lowering therapy than among those who did not receive lipid-lowering therapy (reductions of 0.74 and 0.30, respectively). No other significant treatment interactions were seen for the use of lipid-lowering drugs or nonnucleoside reverse-transcriptase inhibitors with respect to any lipid end points.
Body Image
Patients' mean changes in scores with respect to "belly image distress" and "belly profile" improved more in the tesamorelin group than in the placebo group, with increases of 11.6±26.9 and 6.2±25.8 (P=0.03), respectively, for distress and decreases of 0.67±1.25 and 0.34±1.25 (P=0.03) for the profile (data not shown). The difference in scores for "belly size" was not significant between the two groups (35.1±55.0 vs. 35.4±55.0, P=0.70).
Inflammatory and Other Biochemical Markers
Changes in levels of C-reactive protein did not differ significantly between the two groups. However, levels of adiponectin increased significantly more in the tesamorelin group (a relative difference of 10%, P=0.03) (Table 2).
Adherence and Adverse Events
The overall adherence as determined by a count of vials of medication used was 98.9% in the tesamorelin group and 99.5% in the placebo group.
There was no significant difference in levels of fasting blood glucose, 2-hour glucose, and insulin between the study groups after 26 weeks of treatment. Also similar in the two groups were CD4 cell counts and viral loads (Table 2). Clinically significant changes in safety measures were not seen in the tesamorelin group and the placebo group for liver function (alanine transaminase, –4±24 and –2±16 U per liter, respectively), kidney function (with nearly identical measures of creatinine), or blood pressure (diastolic, –2±10 vs. –0±10 mm Hg; and systolic, –2±14 vs. –2±12 mm Hg).
The overall percentages of patients with any adverse event or with a serious adverse event did not differ between the two groups (Table 3). Four serious adverse events were reported as possibly related to tesamorelin: peripheral neuropathy, febrile diarrhea with dehydration, loss of mobility, and congestive heart failure. A larger percentage of subjects in the tesamorelin group discontinued the study due to an adverse event (Table 3, and Table 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Adverse events resulting in discontinuation were most often related to arthralgias, swelling, and injection-site reactions.
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Among the injection-site reactions, urticaria reactions extending beyond the injection site were observed after 4 to 5 months of treatment in six patients in the tesamorelin group (2.2%) and in no patients in the placebo group; the drug was discontinued in all six patients. In one of these patients, systemic reactions (including nausea, tachycardia, shortness of breath, and sweating) with erythema at previous injection sites developed; these symptoms resolved spontaneously within 3 minutes. All six patients with urticaria tested positive for IgG antibodies against tesamorelin. In addition, IgG antibodies against tesamorelin were detected in 48.6% of patients in the tesamorelin group and 2.7% in the placebo group. The effects of tesamorelin on IGF-I and visceral adipose tissue did not differ significantly in patients with and without antibodies (Table 2 of the Supplementary Appendix).
Extension Phase
A total of 315 patients entered the extension phase (76.8%) and received at least one dose of a study drug: 204 in the tesamorelin group (74.7%) and 111 in the placebo group (81.0%). The overall dropout rate in the extension phase was 18.7%. Nine serious adverse events were recorded during the extension phase (Table 3), including two deaths in the tesamorelin group, one from complications of tonsillectomy and one from coronary artery disease in a patient with a known history of the condition. None of the serious adverse events were reported by investigators to be related to a study drug in the extension phase. Among patients receiving tesamorelin, 4% in the initial randomized phase had a serious adverse event, and less than 1% had events that were reported to be related to the drug. In the extension phase, 2.6% of patients in the tesamorelin group had a serious adverse event; none of these events were reported to be related to the drug.
Discussion
In this study, tesamorelin, a GHRH(1-44) analogue, significantly decreased visceral adiposity and concomitant dyslipidemia, without worsening overall glucose tolerance, in HIV-infected patients. Such patients who are treated with antiretroviral therapy often have changes in body composition, characterized by an excessive accumulation of visceral fat,6 a loss of fat in the limbs and in the abdominal subcutaneous tissues,7 dyslipidemia, glucose intolerance, and insulin resistance,8 which may increase cardiovascular risk.9 Such risk is increased with an extended duration of protease-inhibitor therapy, in association with an increased risk of diabetes and dyslipidemia.10,11 However, interventions to reduce the time that patients receive antiretroviral therapy (such as interruptions in treatment on the basis of CD4 cell counts) may actually worsen cardiovascular disease, as compared with continuous viral suppression.12 Thus, strategies to improve cardiovascular disease in patients with HIV infection should ideally target risk factors without the compromising of antiretroviral suppression or an interruption in antiretroviral treatment.
Visceral adiposity is associated with cardiovascular disease13,14,15 and selective expression of inflammatory adipocytokines.16,17 Small pilot studies involving patients who are not infected with HIV have suggested that selective reduction of visceral, but not subcutaneous, fat by surgical intervention may be associated with a reduction in cardiovascular risk factors.18,19 In addition, excess abdominal fat is associated with discomfort and poor self-image20 and may result in decreased adherence to antiretroviral therapy. Strategies to reduce visceral adiposity have been limited in HIV-infected patients. Insulin-sensitizing agents, lifestyle modification, and resistance training have not shown consistent effects in reducing visceral adiposity or in improving dyslipidemia in HIV-infected patients.21,22,23,24,25,26,27,28,29,30
Although growth hormone therapy is most often used to improve bone and muscle mass in patients with growth hormone deficiency caused by a pituitary tumor or exposure to radiation,31 it is approved by the FDA but not by the European Agency for the Evaluation of Medicinal Products to improve muscle mass in patients with AIDS-related wasting.32 Recent studies of pharmacologic doses of growth hormone have shown a consistent reduction in visceral adiposity in HIV-infected patients, but highly supraphysiologic levels of IGF-I and symptoms of growth hormone excess have occurred.33,34
The effects of tesamorelin appear to be highly specific for the visceral-fat compartment, with relatively little effect on subcutaneous fat or fat in limbs. Our study showed an estimated 1.0-kg selective loss in visceral fat after 6 months of treatment. As a comparison, a pilot study of surgical omentectomy of visceral fat in obese patients without HIV infection resulted in a net loss of 0.6 kg in visceral fat during a 24-month period and selective reduction in measures of cardiovascular risk.19 Among men without HIV infection, weight loss and exercise can reduce visceral fat by 1.1 kg but also reduce subcutaneous fat.35 However, patients in our study were not simply obese but also had a mixed pattern of lipodystrophy, with the majority having peripheral lipoatrophy in addition to abdominal obesity at baseline. The preferential reduction in visceral adipose tissue is important in this population, given their peripheral lipoatrophy. The reduction in visceral adiposity was associated with the degree of baseline visceral adiposity, suggesting that larger effects might be seen among patients with more accumulation of visceral fat. Patients receiving tesamorelin reported having a reduction in distress related to abdominal size, which might improve the quality of life and adherence to antiretroviral treatment.
The numbers of overall and serious adverse events were not significantly higher among patients receiving tesamorelin than among those receiving placebo, but were generally high in the two study groups, which is consistent with underlying medical illness. However, more tesamorelin-treated patients had adverse events that led to study discontinuation. The percentage of patients reporting symptoms of growth hormone excess — including arthralgias, peripheral edema, and myalgias — was lower than in previous large trials of growth hormone in HIV-infected patients.33,34 However, antibodies developed in almost 50% of patients receiving tesamorelin. Our study was of short duration, and the long-term side effects (including the presence of antibodies) and benefits (particularly in terms of cardiovascular outcome) remain unknown. Tesamorelin is not FDA-approved and is undergoing testing in phase 3 studies.
The use of nonnucleoside reverse-transcriptase inhibitors was more frequent among the tesamorelin-treated patients and may have influenced body composition and lipid end points.36 However, differences in end points for visceral fat and lipids remained significant after controlling for the use of nonnucleoside reverse-transcriptase inhibitors. The numbers of female patients were limited, but similar effects of tesamorelin were seen within each sex. Dropout rates did not differ significantly between the two groups and probably did not affect the results. Further studies to determine the long-term safety of tesamorelin are needed.
In summary, treatment with tesamorelin during a 6-month period resulted in a highly significant and selective reduction in visceral fat, with simultaneous improvements in dyslipidemia, without significant adverse effects on glycemic measures. Tesamorelin might be useful for the treatment of HIV-infected patients who have an increase in abdominal girth and dyslipidemia in the context of receiving antiretroviral therapy.
Presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 25–28, 2007.
Supported by Theratechnologies.
Dr. Falutz reports receiving consulting fees from Theratechnologies, Abbott Canada, and Boehringer Ingelheim Canada, lecture fees from Gilead, Bristol-Myers Squibb Canada, and Roche Canada, and grant support from Theratechnologies; Drs. Allas and Blot and Ms. Potvin, being employees of Theratechnologies and having an equity interest in the company; Dr. Kotler, receiving consulting and lecture fees from Serono Laboratories and grant support from Serono Laboratories and Theratechnologies; Drs. Somero, Brown, and Turner, receiving grant support from Theratechnologies; Dr. Berger, receiving consulting fees from Gilead, lecture fees from Gilead, GlaxoSmithKline, and Tibotec, and grant support from Theratechnologies and having an equity interest in Theratechnologies and Gilead; Dr. Richmond, receiving consulting fees from Abbott Laboratories, Achillion Pharmaceuticals, and GlaxoSmithKline, lecture fees from Boehringer Ingelheim and Pfizer, and grant support from Theratechnologies, Serono, GlaxoSmithKline, Bristol-Myers Squibb, Gilead, and Roche; Dr. Fessel, receiving grant support from Theratechnologies, Aguron, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron, Gilead, GlaxoSmithKline, Incyte, Merck, Pfizer, Roche, Serono, Tannox, and Tibotec; and Dr. Grinspoon, receiving consulting fees from Theratechnologies, Serono Laboratories, and Elixir Pharmaceuticals, lecture fees from Serono Laboratories and GlaxoSmithKline, and grant support from Theratechnologies, GlaxoSmithKline, Bristol-Myers Squibb, Immunex, Gilead, and Amgen. No other potential conflict of interest relevant to this article was reported.
We thank Jean-Claude Mamputu and Josée Morin for their help in the preparation of the manuscript.
Source Information
From Montreal General Hospital, McGill University Health Centre (J. Falutz), and Theratechnologies (S.A., K.B., D.P.) — both in Montreal; St. Luke's–Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York (D.K.); Palm Springs, CA (M.S.); Northstar Health Care, Chicago (D.B.); AIDS Research Alliance, West Hollywood, CA (S.B.); Fort Lauderdale, FL (G.R.); Kaiser Foundation Research Institute, San Francisco (J. Fessel); Phase V Technologies, Wellesley Hills, MA (R.T.); and Massachusetts General Hospital and Harvard Medical School — both in Boston (S.G.).
Address reprint requests to Dr. Grinspoon at the Program in Nutritional Metabolism, Massachusetts General Hospital, LON 207, Boston, MA 02114, or at sgrinspoon{at}partners.org.
References
In addition to the authors, the following investigators participated in the study: Clinique Médicale du Quartier Latin, Montreal — P. Côté; Montreal General Hospital, Montreal — J. Falutz; St. Paul's Hospital, Vancouver, BC, Canada — J. Montaner; Southern Alberta HIV Clinic, Calgary, AB, Canada — J.M. Gill; HIV Care Program, Windsor Regional Hospital, Windsor, ON, Canada — C. Quan; Sunnybrook and Women's College Health Sciences Centre, Toronto — A. Rachlis; New York University Medical Center, New York — J. Aberg; St. Luke's–Roosevelt Hospital, New York — J. Albu; Infectious Disease Physicians, Annandale, VA — S. Ambardar; University of Texas Medical School of Houston, Houston — R. Arduino; Northstar Healthcare, Chicago — D. Berger; Dallas Veterans Affairs Medical Center, Dallas — R. Bedimo; Central Texas Clinical Research, Austin, TX — C. Brinson; AIDS Research Alliance, West Hollywood, CA — S. Brown; Johns Hopkins University School of Medicine, Baltimore — T. Brown; Center for Special Immunology, Fountain Valley, CA — P. Cimoch; Fanno Creek Clinic, Portland, OR — G. Coodley; Community Research Initiative of New England, Boston — C. Cohen; UCLA School of Medicine, Los Angeles — J. Currier; University of Maryland Institute of Human Virology, Baltimore — C. Davis; Orlando Immunology Center, Orlando, FL — E. DeJesus; Indiana University Department of Medicine, Indianapolis — M. Dube; AIDS Community Research Initiative of America, New York — J. Ernst; Kaiser Permanente, San Francisco — J.W. Fessel; University of Cincinnati Medical Center, Cincinnati — J. Feinberg; Bach & Godofsky, Bradenton, FL — E. Godofsky; Massachusetts General Hospital, Boston — S. Grinspoon; Hennepin County Medical Center, Minneapolis — K. Henry; Rush University Medical Center, Chicago — H. Kessler; Body Positive, Phoenix, AZ — R. Myers; University of California San Diego Medical Center, San Diego — D. Lee; Treasure Coast Infectious Disease Consultants, Vero Beach, FL — G. Pierone; Capital Medical Associates, Washington, DC — B. Rashbaum; Fort Lauderdale, FL — G.J. Richmond; Care Resource, Miami — S. Santiago; Swedish Medical Center, Seattle — P. Shalit; Community Research Initiative of New England, Springfield, MA — D. Skiest; Drexel University College of Medicine, Philadelphia — P. Sklar; Infectious Disease, Palms Springs, CA — M. Somero; AIDS Research Consortium of Atlanta, Atlanta — M. Thompson; St. Vincent's Hospital and Medical Center, New York — A. Urbina; Infectious Diseases Associates, Sarasota, FL — W. Vega; Tufts New England Medical Center, Boston — C. Wanke.
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Related Letters:
Effects of Growth Hormone–Releasing Factor in HIV-Infected Patients
Malgarini R. B., Pimpinella G., Falutz J., Grinspoon S.
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N Engl J Med 2008;
358:969-970, Feb 28, 2008.
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