(PDF) Effects of Tesamorelin (TH9507), a Growth Hormone

HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT). Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat. Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension. A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197). Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily. We evaluated percent change in VAT by computed tomography scan at wk 26. At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52. Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

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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

Julian Falutz, Jean-Claude Mamputu, Diane Potvin, Graeme Moyle,

Graziella Soulban, Helen Loughrey, Christian Marsolais, Ralph Turner,

and Steven Grinspoon*

Context: HIV patients treated with antiretroviral therapy (ART) often develop increased visceral

adipose tissue (VAT).

Objective: Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin

in ART-treated HIV patients with excess abdominal fat.

Design and Setting: Two multicenter, international studies were conducted; a 26-wk randomized,

placebo-controlled primary intervention phase was followed by a 26-wk safety extension.

Patients: A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1

fashion to receive tesamorelin 2 mg (n ⫽543) or placebo (n ⫽263) sc daily. At wk 26, patients initially

on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n ⫽246) or placebo (T-P, n ⫽135)

for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n ⫽197).

Interventions: Tesamorelin (GHRH

1–44

) at a dose of 2 mg or identical placebo, sc, was given daily.

Main Outcome Measure: We evaluated percent change in VAT by computed tomography scan at wk 26.

Results: At wk 26, VAT decreased significantly in tesamorelin-treated patients (⫺24 ⫾41 vs. 2⫾35 cm

tesamorelin vs. placebo, P⬍0.001; treatment effect, ⫺15.4%). No significant changes were observed

in abdominal sc adipose tissue (⫺2⫾32 vs. 2⫾29 cm

,P⫽0.08; treatment effect, ⫺0.6%). Treatment

with tesamorelin resulted in significant decreases in triglycerides (⫺37 ⫾139 vs. 6⫾112 mg/dl, P⬍

0.001; treatment effect, ⫺12.3%) and cholesterol to high-density lipoprotein ratio (⫺0.18 ⫾1.00 vs.

0.18 ⫾0.94, P⬍0.001; treatment effect, ⫺7.2%) vs. placebo. Tesamorelin improved body image [belly

appearance distress (P⫽0.002)], patient rating of belly profile (P⫽0.003), and physician rating of belly

profile (P⬍0.001). Mean IGF-I increased 108 ⫾112 vs.⫺7⫾64 ng/ml (P⬍0.001 vs. placebo). At wk 52,

decreases in VAT 关⫺35 ⫾50 cm

(⫺17.5 ⫾23.3%)兴, waist circumference (⫺3.4 ⫾6.0 cm), triglycerides

(⫺48 ⫾182 mg/dl), cholesterol (⫺8⫾38mg/dl), and non-high-density lipoprotein (⫺7⫾38 mg/dl) were

maintained (all P⬍0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was

generally well tolerated. No clinically meaningful differences were observed between groups in glu-

cose parameters at wk 26 and 52.

Conclusions: Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk,

preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without

clinically meaningful changes in glucose parameters. (J Clin Endocrinol Metab 95: 0000– 0000, 2010)

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.

doi: 10.1210/jc.2010-0490 Received March 1, 2010. Accepted May 24, 2010.

* Author Affiliations are shown at the bottom of the next page.

Abbreviations: AE, Adverse event; ANCOVA, analysis of covariance; ART, antiretroviral

therapy; BMI, body mass index; CI, confidence interval; HbA

, glycated hemoglobin; HDL,

high-density lipoprotein; HRQOL, health-related quality of life; IFG, impaired fasting glu-

cose; SAE, serious AE; SAT, sc adipose tissue; SDS, SD score; VAT, visceral adipose tissue.

ORIGINAL ARTICLE

Endocrine Care

J Clin Endocrinol Metab, September 2010, 95(9):0000–0000 jcem.endojournals.org 1

J Clin Endocrin Metab. First published ahead of print June 16, 2010 as doi:10.1210/jc.2010-0490

HIV-infected patients treated with antiretroviral ther-

apy (ART) often develop significant changes in

body composition with excess abdominal visceral fat and

reduction in abdominal sc fat (1). These changes may con-

tribute to distress over body dysmorphia and reduced

quality of life (2). In addition, these changes are associated

with metabolic abnormalities including dyslipidemia (3)

and may contribute to increased cardiovascular disease in

this population (4, 5). HIV-infected patients with in-

creased visceral adiposity demonstrate reductions in GH

secretion (6), and we hypothesized that administration of

a GHRH (tesamorelin) may induce increased endogenous

GH secretion, reduce excess abdominal fat, and improve

metabolic and body image abnormalities in this patient

population (7). Two similar, but independent phase-3

studies have now been completed with tesamorelin (8–

10). The results of these two large studies demonstrated

consistent effects to reduce visceral adipose tissue (VAT)

and improve body image. Effects on lipids were significant

in the first study and trended but did not reach statistical

significance in the second study. The primary data from

these two studies have now been pooled to further inves-

tigate primary and secondary endpoints as well as to de-

termine the effects in specific subgroups, e.g. ART class

and baseline impaired fasting glucose (IFG), which were

not previously performed. Moreover, the pooled analysis

investigated the relationship of change in VAT to specific

body image and quality of life endpoints and gives more

comprehensive data on the effects among women and

safety.

Materials and Methods

Design

Two similar randomized placebo-controlled phase-3 trials

were performed to assess the efficacy and safety of tesamorelin

(8 –10). In brief, each study included a randomized placebo-con-

trolled 6-month primary phase followed by a safety extension,

whereby patients originally randomized to placebo were switched

to tesamorelin and those originally randomized to tesamorelin were

randomized to continue on tesamorelin or receive placebo for an

additional 26 wk.

Entry criteria for both studies were identical. HIV-infected

patients, age 18– 65 yr, with CD4 cell counts higher than 100

cells/mm

and viral load less than 10,000 copies/ml, receiving a

stable ART for at least 8 wk and with evidence of abdominal fat

accumulation (waist circumference ⱖ95 cm and waist to hip

ratio ⱖ0.94 for males and waist circumference ⱖ94 cm and

waist to hip ratio ⱖ0.88 for females) were recruited (11). Sub-

jects were excluded with 1) fasting glucose of 150 mg/dl or higher

or known history of type I or type II diabetes mellitus requiring

medication or 2) history of malignancy or active neoplasm. For

a detailed list of exclusion criteria, see Refs. 8–10. Each study

was approved by the Institutional Review Board at each site, and

participants provided written informed consent.

Study procedures

The primary efficacy phase included assessments at wk 6, 13,

19, and 26 (8 –10). Subjects completing the 26-wk efficacy phase

were asked to participate in a 26-wk extension phase. Continued

eligibility was confirmed based on glucose less than 150 mg/dl.

Assessments occurred at wk 32, 39, 45, and 52.

Intervention, randomization, and blinding

Subjects were randomized in a 2:1 fashion (tesamorelin or pla-

cebo) to tesamorelin 2 mg sc daily or identical placebo for the pri-

mary efficacy phase. Active drug and placebo were provided by

Theratechnologies Inc. Randomization was stratified on the basis

of the use of testosterone and the presence of IFG (glucose ⬎110

mg/dl and ⬍126 mg/dl) or diet-controlled diabetes (glucose ⬎126

mg/dl but ⬍150 mg/dl) at screening (first study) or by site and

diabetes condition at screening (second study). Investigator, spon-

sor, and patients were blinded to treatment assignment in all phases

of the study. Tesamorelin and placebo were provided as lyophilized

powder in two 3.0-ml vials of identical appearance. Subjects were

instructed to reconstitute each vial with 1.1 ml sterile water and

self-administer by sc injection once a day until the end of the study.

Eligible subjects entering the extension phase were rerandomized in

a blinded fashion. Subjects initially randomized to tesamorelin were

rerandomized in a 1:3 ratio (first study) or 1:1 ratio (second study)

to receive tesamorelin (T-T) (2 mg sc daily) or identical placebo

(T-P). Subjects receiving placebo were switched to tesamorelin (P-

T), using identical doses as in the first phase of the study (see Fig. 1).

Compliance

Treatment compliance was assessed by recording the number

of vials (used, unused, or broken) returned at the study visits.

Safety

Subjects were discontinued if asymptomatic with fasting glu-

cose higher than 180 mg/dl or symptomatic with fasting glucose

lower than 180 mg/dl or for hypersensitivity reaction beyond the

local injection site (8 –10). A data safety monitoring board mon-

itored adverse events (AEs) for each study.

Laboratory methods

Body composition, biochemical testing, and body image pa-

rameters were determined as previously described (8, 10) (see

Supplemental Methods, published on The Endocrine Society’s

Journals Online web site at http://jcem.endojournals.org).

Statistical analysis

Statistical analyses were performed by Octagon Research So-

lutions (Wayne, PA). The minimum difference needed to detect

a clinically relevant difference between tesamorelin and placebo

Montreal General Hospital (J.F.), McGill University Health Centre, Montreal H3G 1A4, Canada; Theratechnologies Inc. (J.-C.M., D.P., G.S., H.L., C.M.), Montreal H4S 2B4, Canada; St.

Stephen’s Center (G.M.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Phase V Technologies Inc. (R.T.), Wellesley, Massachusetts 02481; and Massachusetts

General Hospital and Harvard Medical School (S.G.), Boston, Massachusetts 02114

2Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000

in VAT, the primary endpoint, was considered to be 8% after

consultation with the U.S. Food and Drug Administration (FDA)

and based on the recommendation of an expert panel hosted by

the Forum for Collaborative Research (12) for each study. Sec-

ondary endpoints included IGF-I, triglycerides, total cholesterol

to high-density lipoprotein (HDL) cholesterol ratio, and patient-

reported outcomes related to body image

Because each study used similar inclusion and exclusion cri-

teria, endpoint assessments, study design, and statistical analy-

ses, the primary data from each study were pooled for analysis.

The pooled statistical analysis was a prespecified analysis, which

was part of the Integrated Summary of Efficacy report (requested

by the FDA for a New Drug Application Submission) after the

individual studies were completed. For each study, there was no

effect of enrollment site in the model. Secondary models for VAT

and trunk fat were constructed with use of testosterone, IFG/

diabetes, age, gender, ART regimen at baseline, and change in

ART therapy as covariates. Inclusion of these covariates did not

alter the results of the analysis.

The safety and intent-to-treat populations were defined as all

randomized subjects who were exposed to study drug. (i.e. in-

jection of at least one dose of study drug). These analyses used all

available data on patients including partial

data from patients who discontinued. Com-

parison of variables at baseline was made

using an ANOVA model including treat-

ment group and study. The treatment effect

in the primary efficacy endpoint was tested

using an analysis of covariance (ANCOVA)

on the natural log ratio of VAT at wk 26 to

baseline VAT. The primary ANCOVA

model included treatment, natural log base-

line VAT, and study. Using a highly strin-

gent analysis to account for type I error in

the pooling of two previously analyzed stud-

ies, a Pvalue of ⱕ0.001 would be considered

statistically significant.

The treatment effect of tesamorelin for

primary and secondary variables was esti-

mated by the placebo vs. tesamorelin differ-

ence in least-squares means from the

ANCOVA described above, using the in-

tent-to-treat population and the last-obser-

vation-carried-forward method for imputa-

tion of missing data as accepted by the FDA

in the prespecified statistical analysis plan.

Additional sensitivity analyses were per-

formed using the mixed-model repeated-

measures method. The change from baseline

to wk 26 in lipid levels was analyzed using

an ANCOVA model to account for baseline

level, the use of lipid-lowering treatments,

and study. Ranked ANCOVA models were

fitted for belly size evaluation change score,

belly appearance distress, and belly profile.

For the safety extension phase, compari-

sons were made for VAT and secondary vari-

ables between those patients originally as-

signed to tesamorelin and then randomized to

stay on tesamorelin (T-T group) or switch to

placebo (T-P group) with ANCOVA. With-

in-group changes from baseline to wk 52 for

each treatment group (T-T, T-P, and P-T)

were tested with repeated-measures ANOVA.

For the safety analyses in both the primary efficacy phase

and the safety extension phase, all clinical laboratory values

were summarized by treatment group using descriptive sta-

tistics. For the primary efficacy phase, the 95% confidence

intervals (CIs) are presented for overall AE and serious AE

(SAE) rates as well as for AEs seen in more than 10 and 5% of

patients, respectively.

Results

For the first study, 570 subjects were screened and 412

were randomized. For the second study, 599 subjects were

screened and 404 were randomized. In the primary effi-

cacy phase (0 –26 wk), subjects were randomized 2:1 tesa-

morelin to placebo, resulting in 543 patients receiving

tesamorelin and 263 receiving placebo (Fig. 1). Of these

subjects, a similar percentage, 207 in the placebo group

FIG. 1. Enrollment and outcomes.

J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000 jcem.endojournals.org 3

(79%) and 413 in the tesamorelin group (76%), com-

pleted 26 wk of treatment (Fig. 1).

The baseline characteristics of the study subjects are

shown in Table 1. One hundred twenty-one subjects

(15%) were female. Twenty-two percent of the subjects

had IFG tolerance, and 7.4% had mild diet-controlled

diabetes with a fasting glucose higher than 126 and lower

than 150 mg/dl at baseline. The proportion of patients

receiving specific ART regimens was comparable between

groups and was as follows: nucleoside reverse transcrip-

tase inhibitor (NRTI) plus non-NRTI (NNRTI) (33%),

NRTI plus protease inhibitor (45%), NRTI plus NNRTI/

protease inhibitor (10%), NRTIs alone (5%), and other

(7%). Demographic, metabolic, and body composition

parameters were not different at baseline between the

groups (Tables 1 and 2).

Primary efficacy phase (wk 0–26)

VAT decreased significantly in tesamorelin-treated pa-

tients [⫺24 ⫾41 (⫺13.1%) vs. 2⫾35 (⫹2.3%) cm

tesamorelin vs. placebo, P⬍0.001, equivalent to a

⫺15.4% treatment effect of tesamorelin relative to pla-

cebo], whereas no significant changes were observed in

abdominal sc adipose tissue (SAT) [⫺2⫾32 (⫹0.7%) vs.

2⫾29 (⫹1.3%) cm

,P⫽0.08, ⫺0.6% treatment effect]

(Fig. 2 and Table 2). Similar results were seen using the

mixed-model repeated-measures approach. Trunk fat sig-

nificantly decreased in subjects receiving tesamorelin (Ta-

ble 2). Limb fat differed between the tesamorelin- and

placebo-treated patients at wk 26, but the change in the

tesamorelin group was not different from baseline, and the

change from baseline was equivalent to 0.2%. Lean body

mass increased significantly (Table 2). Waist circumfer-

ence decreased significantly in the tesamorelin- vs. place-

bo-treated patients (Table 2). No significant differences in

body mass index (BMI) were observed between the

groups.

The effect of tesamorelin on VAT was similar among

subjects stratified by baseline ART regimen (Supplemental

Fig. 1), and there was no treatment-by-ART interaction

(P⫽0.82). In addition, the effect of tesamorelin in males

was similar to that in females at 26 wk, with no statistically

significant treatment-by-gender interaction [percent

change in VAT for males was ⫺13.2 vs. 2.5% (P⬍0.001)

and for females was ⫺12.5 vs. 1.4% (P⫽0.001) for tesa-

morelin vs. placebo, respectively].

In the pooled analysis, significant effects to reduce trig-

lycerides [treatment effect, ⫺43 mg/dl (95% CI ⫽⫺54 to

⫺21), ⫺12.3%, P⬍0.001] and total cholesterol to HDL

[treatment effect, ⫺0.36 (95% CI ⫽⫺0.46 to ⫺0.19),

⫺7.2%, P⬍0.001] were observed. Less significant but

favorable effects of tesamorelin relative to placebo were

seen for total cholesterol (⫺2.3%, P⫽0.01), HDL

(⫹3.0%, P⫽0.06), and non-HDL (⫺3.9%, P⫽0.001)

(Table 2 and Supplemental Fig. 2). No significant effects

on fasting glucose, fasting insulin or 2 h glucose on oral

glucose tolerance testing were seen in tesamorelin- vs. pla-

cebo-treated patients (Table 2). Similar results were ob-

tained with an ANCOVA controlling for IFG/diabetes

condition at screening. There was no interaction between

IFG/diabetes condition and treatment. Mean glycated he-

moglobin (HbA

) increased 0.14% from baseline in the

tesamorelin-treated group compared with 0.02% in the

placebo group [treatment effect, 0.12% (95% CI ⫽0.05–

0.17), P⬍0.001]. This change amounted to an increase

from 5.26 to 5.39% in the tesamorelin-treated patients.

Mean IGF-I levels increased generally within the physio-

logical range of young adults in tesamorelin-treated pa-

tients (84.1 ⫾101.3%, P⬍0.001 vs. placebo) (Table 2).

Sixty-four percent of patients treated with tesamorelin for

26 wk had an age- and gender-based IGF-I SD score (SDS)

of 3 or less.

Treatment with tesamorelin was associated with im-

provement in body image, which was at P⬍0.001 for

physician-rated belly profile, P⫽0.002 for belly appear-

ance distress, and P⫽0.003 for patient-reported belly

profile (Table 2). On the health-related quality of life

TABLE 1. Baseline demographics and clinical

characteristics of the patients entering the primary

randomized study (n ⫽806) (0–26 wk)

Variables

Tesamorelin

(n ⴝ543)

Placebo

(n ⴝ263)

Age (yr) 47.5 ⫾7.4 47.9 ⫾7.6

Male/female ratio (%) 85.6/14.4 83.7/16.3

Race (%)

White 77.0 74.1

Black 13.1 12.9

Other 10.0 13.0

Weight (kg) 89.3 ⫾13.8 88.6 ⫾14.6

BMI (kg/m

) 29.0 ⫾4.2 29.0 ⫾4.2

Waist circumference (cm) 105 ⫾9 105 ⫾9

Waist-to-hip ratio 1.00 ⫾0.07 1.00 ⫾0.07

Viral Load (%)

Undetectable 75.0 78.3

50– 400 copies/ml 16.9 15.2

⬎400 copies/ml 8.1 6.5

CD4 cell count (cells/mm

) 603 ⫾295 592 ⫾281

CD4 cell classification (%)

⬍250 cells/mm

8.8 8.7

ⱖ250 cells/mm

91.2 91.3

Lipodystrophy rating (%)

Abdominal lipohypertrophy 100 100

Lipoatrophy of face or limbs 69.8 69.2

Fasting blood glucose (%)

ⱕ110 mg/dl 70.2 69.2

110–125 mg/dl 22.4 22.7

ⱖ125 mg/dl 7.4 8.1

Use of testosterone (%) 21.4 17.5

Use of lipid-lowering agents (%) 45.7 44.9

4Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000

TABLE 2. Changes from baseline in body composition, lipid levels, biochemical measures, glycemic measures, belly image, and HRQOL parameters in the

primary efficacy phase

Variables

Baseline value Change from baseline (%) at 26 wk

Absolute

difference (95% CI)

Relative

difference (%) Pvalue

Tesamorelin

(n ⴝ543)

Placebo

(n ⴝ263)

Tesamorelin

(n ⴝ543)

Placebo

(n ⴝ263)

Body composition

VAT (cm

) 182 ⫾82 182 ⫾87 ⫺24 ⫾41 (⫺13.1) 2 ⫾35 (2.3) ⫺26 (⫺32 to ⫺21) ⫺15.4 ⬍0.001

SAT (cm

) 231 ⫾124 233 ⫾123 ⫺2⫾32 (0.7) 2 ⫾29 (1.3) ⫺4(⫺9–0) ⫺0.6 0.08

Ratio of VAT to SAT 1.27 ⫾1.60 1.22 ⫾1.41 ⫺0.24 ⫾0.86 (⫺13.1) 0.05 ⫾0.59 (2.2) ⫺0.29 (⫺0.38 to ⫺0.18) ⫺15.3 ⬍0.001

Trunk Fat (kg) 15.1 ⫾5.5 15.2 ⫾5.4 ⫺0.9 ⫾2.0 (⫺6.5) 0.3 ⫾1.5 (2.4) ⫺1.2 (⫺1.5 to ⫺0.9) ⫺8.9 ⬍0.001

Waist circumference (cm) 105 ⫾9 105 ⫾9⫺2.4 ⫾5.2 (⫺2.3) ⫺0.8 ⫾4.4 (⫺0.8) ⫺1.6 (⫺2.3 to ⫺0.9) ⫺1.5 ⬍0.001

Waist-to-hip ratio 1.05 ⫾0.07 1.05 ⫾0.07 ⫺0.03 ⫾0.05 (⫺2.4) ⫺0.01 ⫾0.05 (⫺1.3) ⫺0.02 (⫺0.02 to ⫺0.01) ⫺1.1 ⬍0.001

Fat in limbs (kg) 7.3 ⫾4.5 7.5 ⫾4.4 ⫺0.1 ⫾0.9 (0.2) 0.2 ⫾0.9 (3.0) ⫺0.3 (⫺0.4 to ⫺0.1) ⫺2.8 0.001

Lean mass (kg) 62.2 ⫾10.2 61.0 ⫾10.4 1.3 ⫾2.4 (2.1) ⫺0.14 ⫾1.9 (⫺0.1) 1.4 (1.1–1.8) 2.2 ⬍0.001

BMI (kg/m

) 29.0 ⫾4.2 29.0 ⫾4.2 0.01 ⫾1.31 (0.1) 0.05 ⫾1.15 (0.2) ⫺0.04 (⫺0.3– 0.2) ⫺0.1 0.68

Lipid levels

Triglycerides (mg/dl) 245 ⫾227 228 ⫾144 ⫺37 ⫾139 (⫺2.6) 6 ⫾112 (9.7) ⫺43 (⫺54 to ⫺21) ⫺12.3 ⬍0.001

Cholesterol

Ratio of total cholesterol to HDL

cholesterol

4.62 ⫾1.53 4.45 ⫾1.44 ⫺0.18 ⫾1.00 (⫺1.6) 0.18 ⫾0.94 (5.6) ⫺0.36 (⫺0.46 to ⫺0.19) ⫺7.2 ⬍0.001

Total (mg/dl) 194 ⫾44 192 ⫾38 ⫺4⫾33 (⫺0.7) 1 ⫾27 (1.6) ⫺5(⫺10 to ⫺1) ⫺2.3 0.01

HDL (mg/dl) 45 ⫾14 46 ⫾15 1 ⫾8 (3.4) ⫺1⫾10 (0.4) 2 (⫺0 –2.5) 3.0 0.06

Non-HDL (mg/dl) 149 ⫾42 146 ⫾36 ⫺5⫾31 (⫺1.0) 2 ⫾26 (2.9) ⫺7(⫺10 to ⫺3) ⫺3.9 0.001

Biochemical measures

IGF-I (ng/ml) 154 ⫾63 159 ⫾69 108 ⫾112 (84.1) ⫺7⫾64 (0.0) 115 (99 –128) 84.1 ⬍0.001

Glycemic measures

Glucose (mg/dl)

Fasting 98 ⫾14 98 ⫾16 3 ⫾16 (3.8) 1 ⫾17 (2.0) 2 (⫺0–4) 1.8 0.10

At 2 h 113 ⫾37 114 ⫾40 3 ⫾38 (7.7) 3 ⫾43 (9.1) 0 (⫺7– 6) ⫺1.4 0.82

Fasting insulin (

␮

IU/ml) 22 ⫾29 19 ⫾14 0 ⫾29 (40.4) 1 ⫾22 (26.3) ⫺1(⫺2–4) 14.1 0.50

HbA

(%) 5.26 ⫾0.50 5.28 ⫾0.48 0.14 ⫾0.40 (2.9) 0.02 ⫾0.36 (0.6) 0.12 (0.05–0.17) 2.3 ⬍0.001

Belly image and HRQOL parameters

(scores)

Belly appearance distress 22.1 ⫾23.0 22.1 ⫾24.1 9.8 ⫾28.0 5.9 ⫾25.8 4 (1.4– 6.4) 0.002

Patient-reported belly profile 3.3 ⫾1.3 3.3 ⫾1.3 ⫺0.6 ⫾1.3 ⫺0.3 ⫾1.1 ⫺0.3 (0.1– 0.5) 0.003

Physician-reported belly profile 3.1 ⫾1.2 3.1 ⫾1.2 ⫺0.6 ⫾1.1 ⫺0.3 ⫾1.1 ⫺0.3 (0.1–0.4) ⬍0.001

HRQOL global analog scale 6.8 ⫾1.6 6.7 ⫾1.6 0.0 ⫾1.5 ⫺0.2 ⫾1.5 0.2 (0.1–0.3) 0.029

Data are reported as mean ⫾SD unless otherwise indicated. To convert the values for triglycerides to millimoles per liter, multiply by 0.0113; to convert the values for total cholesterol and HDL

cholesterol to millimoles per liter, multiply by 0.0259; to convert the values of IGF-I to nanomoles per liter, multiply by 0.131; to convert the values for glucose to millimoles per liter, multiply by

0.0555; to convert the values for insulin to picomoles per liter, multiply by 6.945. Pvalues are for the comparison between the changes from baseline in the tesamorelin group and the placebo

group.

J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000 jcem.endojournals.org 5

(HRQOL) global analog scale, subjects assigned to pla-

cebo deteriorated, whereas there was no change for sub-

jects assigned to tesamorelin (P⫽0.029) (Table 2). The

changes in body image were significantly associated with

the degree in reduction of VAT among the tesamorelin-

treated patients (Table 3).

Data from the safety extension phase (wk 26–52)

Baseline characteristics of subjects entering the exten-

sion phase are shown in Table 4. At wk 52, improvements

in VAT (⫺35 ⫾50 cm

), trunk fat (⫺1.1 ⫾2.2 kg), waist

circumference (⫺3.4 ⫾6.0 cm), triglycerides (⫺48 ⫾182

mg/dl), total cholesterol (⫺8⫾38 mg/dl), and IGF-I (78 ⫾

110 ng/ml) were sustained in the T-T group (all P⬍0.001

vs. baseline) whereas SAT and limb fat were preserved

(Table 5). Seventy-seven percent of patients treated with

tesamorelin for 52 wk had an age- and gender-based

IGF-I SDS of 3 or less. No changes in glucose or insulin

were seen after 52 wk of tesamorelin in the T-T group

(Table 5).

Patients in the T-P group regained VAT after switching

to placebo. The VAT level in this group was not signifi-

cantly different from baseline at wk 52 (⫺2⫾48 cm

,P⫽

0.18 vs. baseline) (Fig. 2). A similar pattern was observed

for trunk fat, although waist circumference remained re-

duced from baseline by 2 cm at 52 wk in

those switching to placebo (Table 5).

Improvements in belly appearance dis-

tress as well as in physician- and patient-

rated belly profile persisted among pa-

tients in the T-T group. Patients in the T-P

group (vs. T-T group) tended to lose im-

provements in belly appearance and pa-

tient-rated belly profile seen at wk 26, al-

though the changes in these parameters at

wk 52 were still significantly different

from baseline (Table 5).

Safety

Overall AEs and treatment-related

AEs were higher in the tesamorelin

group, whereas AE’s resulting in study

discontinuation and SAEs were not different between the

two groups based on 95% CIs in the primary efficacy

phase (Table 6). One patient died in the tesamorelin group

(lung adenocarcinoma metastatic), and one patient died in

the placebo-treated group (arrhythmia). Events occurring

in more than 10% of patients, arthralgias, headaches, and

injection site bruising, were not different between the tesa-

morelin and placebo groups. For AEs occurring at more

than 5% frequency, injection site erythema, pruritis, pe-

ripheral edema, and myalgias occurred more frequently in

the tesamorelin group, with 95% CIs that did not overlap

0. No differences were seen in other AEs. The majority of

patients in each of the treatment groups had undetectable

viral load, and most had CD4 cell counts at least 250

cells/mm

at baseline (Table 1). At wk 26, the percentages

of patients shifting to higher viral load category were com-

parable between the groups and were 11.8% in the tesa-

morelin and 12.1% in the placebo group. Furthermore,

the proportion of patients shifting from CD4 cell counts of

at least 250 cells/mm

to a lower CD4 cell count category

was 2% in the two groups.

In the extension phase, overall AEs and SAEs were also

similar between the tesamorelin and placebo groups (Ta-

ble 7). Two deaths occurred, one in the T-T group (cor-

FIG. 2. Percent change from baseline in VAT and SAT at 26 (A) and 52 (B) weeks. Data are

mean ⫾SEM. **, P⬍0.001 vs. placebo; §, P⬍0.001 vs. baseline and vs. T-P; †, P⬍0.001

vs. baseline.

TABLE 3. Correlation between percent change in VAT and changes in belly image parameters at wk 26 in the

primary efficacy phase

Belly image parameters

Tesamorelin (n ⴝ542) Placebo (n ⴝ263)

Correlation

coefficient

Pvalue

Correlation

coefficient

Pvalue

Belly size ⫺0.179 ⬍0.001 ⫺0.059 0.344

Belly appearance distress ⫺0.229 ⬍0.001 0.047 0.445

Patient-reported belly profile 0.341 ⬍0.001 0.016 0.796

Physician-reported belly profile 0.219 ⬍0.001 0.096 0.123

Spearman’s rank correlation (

␳

6Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000

onary artery arteriosclerosis) and one in the P-T group

(postprocedure hemorrhage) (Table 7). At wk 52, the per-

centages of patients shifting to higher viral load category

were comparable between the groups and were 10.5% in

the T-T, 11.5% in the T-P, and 8.0% in the P-T group. The

percentages of patients shifting from CD4 cell counts of at

least 250 cells/mm

to the lower CD4 cell count category

were 2.1% in the T-T, 0% in the T-P, and 2.1% in the P-T

group.

During the primary efficacy phase, hypersensitivity re-

actions were seen in 2.9% of tesamorelin and 0.4% of

placebo patients. Only one event, which occurred in a

placebo-treated patient, was reported as an SAE. During

the extension phase, hypersensitivity reactions were ob-

served in 1.2, 0, and 4.1% of patients in the T-T, T-P, and

P-T groups, respectively.

Antibodies

See Supplemental Results and Methods.

Compliance

Compliance from the first dose to wk 26 was 98.1 and

97.8% in the tesamorelin and placebo groups, respec-

tively. In the extension phase, mean compliance was 95.2,

94.2, and 96.1% in the T-T, T-P, and P-T groups,

respectively.

Discussion

Increased abdominal fat accumulation has been described

in approximately 30% of HIV patients in the current era

of highly active ART (HAART) (1, 13). The excess ab-

dominal fat is uniquely composed primarily of excess

VAT, because SAT is reduced (14). The excess in VAT may

contribute to reduced QOL and patient distress (2). More-

over, excess VAT is associated with dyslipidemia (3) and

increased coronary artery calcification in HIV patients (4).

In a recent longitudinal study involving HIV patients on

ART, increased VAT was one of three factors, along with

age and low-density lipoprotein to contribute to coronary

artery calcium progression (4). It is also known that GH

secretion is inversely correlated with excess VAT in HIV

patients and that reduced GH secretion may itself con-

tribute independently to metabolic abnormalities in this

population (6, 15). We hypothesized that increasing en-

dogenous GH secretion via the use of a GH-releasing fac-

tor, tesamorelin, would improve body composition and

metabolic endpoints in HIV patients receiving ART with

excess abdominal fat. We have previously shown in two

large, multicenter randomized phase-3 studies that use of

tesamorelin reduces VAT in association with mean IGF-I

levels comparable to what is observed in young adults

(8–10). New data from the pooled analysis demonstrate

that the great majority of patients treated for 1 yr with

TABLE 4. Baseline demographics and clinical characteristics of the patients entering the extension phase (n ⫽578)

Variables T-T (n ⴝ246) T-P (n ⴝ135) P-T (n ⴝ197)

Age (yr) 47.7 ⫾7.2 48.1 ⫾7.1 48.3 ⫾7.7

Male/female ratio (%) 89.0/11.0 88.1/11.9 86.8/13.2

Race (%)

White 79.3 83.7 78.2

Black 11.8 7.4 10.7

Other 8.9 8.9 11.1

Weight (kg) 88.7 ⫾13.3 90.7 ⫾15.1 88.7 ⫾14.5

BMI (kg/m

) 28.6 ⫾4.1 29.4 ⫾4.3 28.8 ⫾4.2

Waist circumference (cm) 104 ⫾9 105 ⫾10 104 ⫾9

Waist-to-hip ratio 1.05 ⫾0.07 1.05 ⫾0.06 1.05 ⫾0.06

Viral load (%)

Undetectable 75.6 71.9 76.6

50– 400 copies/ml 15.4 18.5 16.2

⬎400 copies/ml 8.9 8.9 7.1

CD4 cell count (cells/mm

) 623 ⫾309 596 ⫾284 586 ⫾270

CD4 cell classification (%)

⬍250 cells/mm

6.5 9.6 8.6

ⱖ250 cells/mm

93.5 90.4 91.4

Lipodystrophy rating (%)

Abdominal lipohypertrophy 100 100 100

Lipoatrophy of face or limbs 70.7 70.4 71.6

Fasting glucose (%)

ⱕ110 mg/dl 71.8 67.4 71.3

110–125 mg/dl 25.3 22.2 21.5

ⱖ125 mg/dl 2.9 10.4 7.2

Use of testosterone (%) 23.6 20.0 17.3

Use of lipid-lowering agents (%) 49.6 48.9 44.7

J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000 jcem.endojournals.org 7

TABLE 5. Changes from baseline in body composition, lipid levels, biochemical measures, glycemic measures, belly image, and HRQOL parameters in the

extension phase

Variables

Baseline, meanⴞSD Change from baseline (%) at 52 wk, meanⴞSD

T-T

(n ⴝ246)

T-P

(n ⴝ135)

P-T

(n ⴝ197)

T-T

(n ⴝ246)

T-P

(n ⴝ135)

P-T

(n ⴝ197)

Body composition

VAT (cm

) 187 ⫾83 190 ⫾82 186 ⫾89 ⫺35 ⫾50 (⫺17.5)

c,e

⫺2⫾48 (0.3) ⫺25 ⫾44 (⫺13.3)

SAT (cm

) 214 ⫾120 231 ⫾122 224 ⫾121 ⫺3⫾42 (1.4) 1 ⫾39 (2.8) ⫺1⫾39 (0.6)

Ratio of VAT to SAT 1.43 ⫾1.68 1.28 ⫾1.92 1.30 ⫾1.53 ⫺0.31 ⫾0.78 (⫺17.3)

c,e

⫺0.01 ⫾0.60 (⫺1.8) ⫺0.14 ⫾0.56 (⫺13.3)

Trunk fat (kg) 14.4 ⫾5.1 15.7 ⫾5.6 15.0 ⫾5.4 ⫺1.1 ⫾2.2 (⫺7.7)

c,e

0.3 ⫾2.2 (2.6) ⫺0.8 ⫾2.4 (⫺5.7)

Waist circumference (cm) 104 ⫾9 105 ⫾10 104 ⫾9⫺3.4 ⫾6.0 (⫺3.3)

c,e

⫺2.0 ⫾6.0 (⫺1.7)

⫺3.0 ⫾6.0

(⫺2.8)

Waist-to-hip ratio 1.05 ⫾0.07 1.05 ⫾0.06 1.05 ⫾0.06 ⫺0.03 ⫾0.07 (⫺3.1)

c,d

⫺0.02 ⫾0.05 (⫺1.6)

⫺0.03 ⫾0.05 (⫺3.1)

Fat in limbs (kg) 6.7 ⫾4.2 7.1 ⫾4.0 7.1 ⫾4.1 ⫺0.1 ⫾1.0 (0.8) 0.0 ⫾1.3 (2.6) 0.0 ⫾1.4 (1.5)

Lean mass (kg) 62.7 ⫾9.8 63.0 ⫾9.8 61.6 ⫾10.1 1.3 ⫾2.7 (2.1)

c,e

⫺0.1 ⫾2.5 (⫺0.1) 1.4 ⫾2.3 (2.5)

BMI (kg/m

) 28.6 ⫾4.1 29.4 ⫾4.3 28.8 ⫾4.2 ⫺0.11 ⫾1.55 (⫺0.3) 0.05 ⫾1.80 (0.3) 0.15 ⫾1.57 (0.6)

Lipid levels

Triglycerides (mg/dl) 261 ⫾209 219 ⫾155 230 ⫾141 ⫺48 ⫾182 (⫺4.2)

⫺11 ⫾154 (0.6) ⫺14 ⫾138 (3.6)

Cholesterol

Ratio of Total Cholesterol to HDL

Cholesterol

4.69 ⫾1.56 4.53 ⫾1.40 4.42 ⫾1.32 ⫺0.07 ⫾1.44 (2.0) 0.11 ⫾1.04 (4.3) 0.19 ⫾1.06 (6.4)

Total (mg/dl) 194 ⫾46 190 ⫾40 194 ⫾35 ⫺8⫾38 (⫺2.1)

c,d

2⫾36 (3.2) ⫺4⫾33 (⫺1.5)

HDL (mg/dl) 45 ⫾15 44 ⫾13 47 ⫾15 ⫺1⫾10 (⫺0.2)

⫺1⫾8 (1.0) ⫺3⫾9(⫺3.2)

Non-HDL (mg/dl) 149 ⫾44 145 ⫾37 147 ⫾35 ⫺7⫾38 (⫺1.1)

a,d

3⫾34 (4.5) ⫺1⫾32 (0.4)

Biochemical measures

IGF-I (ng/ml) 161 ⫾64 150 ⫾61 163 ⫾73 78 ⫾110 (63.1)

c,e

⫺9⫾52 (⫺0.7)

73 ⫾113 (56.0)

Glycemic measures

Glucose (mg/dl)

Fasting 97 ⫾13 102 ⫾17 99 ⫾17 2 ⫾14 (2.9) ⫺2⫾28 (⫺1.2) 1 ⫾17 (2.2)

At 2 h 112 ⫾34 112 ⫾40 116 ⫾40 1 ⫾39 (6.4) 1 ⫾34 (6.8) 5 ⫾41 (8.1)

Insulin (

␮

IU/ml) 19 ⫾20 26 ⫾31 21 ⫾24 ⫺0⫾20 (28.8) ⫺7⫾31 (8.3) 1 ⫾28 (39.4)

HbA

(%) 5.23 ⫾0.50 5.27 ⫾0.47 5.32 ⫾0.51 0.07 ⫾0.37 (1.7) 0.08 ⫾0.54 (1.8) 0.09 ⫾0.36 (1.8)

Belly image and HRQOL parameters

(scores)

Belly appearance distress 22.5 ⫾23.1 19.3 ⫾19.1 20.6 ⫾23.3 12.6 ⫾29.4

b,e

8.1 ⫾24.0

9.8 ⫾27.4

Patient-reported belly profile 3.3 ⫾1.3 3.3 ⫾1.3 3.3 ⫾1.3 ⫺0.9 ⫾1.4

b,e

⫺0.5 ⫾1.2

⫺0.8 ⫾1.4

Physician-reported belly profile 3.1 ⫾1.2 3.2 ⫾1.2 3.1 ⫾1.3 ⫺1.0 ⫾1.3

⫺0.7 ⫾1.3

⫺0.8 ⫾1.2

HRQOL global analog scale 6.7 ⫾1.6 6.9 ⫾1.6 6.7 ⫾1.5 0.2 ⫾1.5 0.1 ⫾1.5

0.2 ⫾1.4

Data are reported as mean ⫾SD unless otherwise indicated. To convert the values for triglycerides to millimoles per liter, multiply by 0.0113; to convert the values for total

cholesterol and HDL cholesterol to millimoles per liter, multiply by 0.0259; to convert the values of IGF-I to nanomoles per liter, multiply by 0.131; to convert the values for

glucose to millimoles per liter, multiply by 0.0555; to convert the values for insulin to picomoles per liter, multiply by 6.945.

P⬍0.05 for the within-group comparison between baseline and wk 52.

P⬍0.01 for the within-group comparison between baseline and wk 52.

P⬍0.001 for the within-group comparison between baseline and wk 52.

P⬍0.05 for the comparison between the changes from baseline in the T-T group and the T-P group.

P⬍0.001 for the comparison between the changes from baseline in the T-T group and the T-P group.

8Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000

TABLE 6. AEs and SAEs in the primary efficacy phase (0–26 wk)

Events

% Patients

95% CI differenceTesamorelin (n ⴝ543) Placebo (n ⴝ263)

% Patients with any event 78.3 71.1 0.0068 – 0.1365

Related to treatment 53.2 36.5 0.0955– 0.2390

Resulting in study discontinuation 9.6 6.1 ⫺0.0031– 0.0730

Events reported in ⬎10% of patients

Arthralgia 13.3 11.0 ⫺0.0251– 0.0697

Headache 10.9 11.0 ⫺0.0476 – 0.0444

Injection site bruising 7.4 10.3 ⫺0.0718 – 0.0138

Events reported in ⬎5% of patients

Diarrhea 7.6 8.4 ⫺0.0483– 0.0320

Injection site erythema 8.5 2.7 0.0277– 0.0885

Injection site pruritus 7.6 0.8 0.0433–0.0925

Edema peripheral 6.1 2.3 0.0110 – 0.0650

Fatigue 3.7 5.7 ⫺0.0524 – 0.0120

Upper respiratory tract infection 4.2 6.5 ⫺0.0565– 0.0119

Nasopharyngitis 4.2 5.3 ⫺0.0429 – 0.0211

Pain in extremity 6.1 4.6 ⫺0.0171–0.0474

Myalgia 5.5 1.9 0.0109 – 0.0616

Back pain 3.1 5.3 ⫺0.0528– 0.0089

SAE

% Patients with any event 3.7 4.2 ⫺0.0339 – 0.0239

All events reported

Anemia 0.2 0.0

Arrhythmia 0.0 0.4

Cardiac arrest 0.0 0.4

Cardiac failure congestive 0.2 0.0

Abdominal hernia obstructive 0.0 0.4

Diarrhea 0.2 0.0

Small intestinal obstruction 0.2 0.0

Chest pain 0.0 0.4

Cholecystitis acute 0.0 0.4

Hypersensitivity 0.0 0.4

Sepsis 0.4 0.0

Abdominal abscess 0.2 0.0

Appendiceal abscess 0.2 0.0

Appendicitis 0.0 0.4

Bronchitis viral 0.2 0.0

Perianal abscess 0.2 0.0

Upper respiratory tract infection 0.2 0.0

Humerus fracture 0.2 0.0

Procedural pain 0.0 0.4

Rib fracture 0.2 0.0

Electrocardiogram abnomal 0.2 0.4

Dehydration 0.2 0.0

Arthralgia 0.2 0.0

Mobility decreased 0.2 0.0

Basal cell carcinoma

0.2 0.0

Breast cancer in situ 0.0 0.4

Hodgkin’s disease 0.0 0.4

Rectal cancer

0.2 0.0

Cerebellar syndrome 0.2 0.0

Neuropathy peripheral 0.2 0.0

Trigeminal neuralgia 0.2 0.0

Bipolar II disorder 0.2 0.0

Dependence 0.2 0.0

Major depression 0.0 0.4

Benign prostatic hyperplasia 0.2 0.0

Treatment emergent.

This patient was determined to have a previously undisclosed history of cancer before randomization.

J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000 jcem.endojournals.org 9

tesamorelin will have an age- and gender-adjusted SDS

within an acceptable range. The pooled analysis, consti-

tuting over 800 patients, is the largest intervention for

abdominal fat changes in the HIV population.

The pooled analysis demonstrates a net reduction of

VAT of 15.4% over 26 wk relative to placebo. For subjects

rerandomized to placebo after 26 wk of treatment with

tesamorelin, VAT was regained, but among those con-

tinuing with tesamorelin, the net reduction in VAT after

52 wk is approximately 18%, translating into a 3.4-cm

reduction in waist circumference. This reduction in waist

circumference is almost exclusively a result of a reduction

in VAT, because tesamorelin did not have a significant

effect on abdominal SAT. This is important because SAT

is increasingly shown to be a beneficial fat depot contrib-

uting to improved cardiometabolic risk (16). In the general

population, increased waist circumference and VAT have

been shown to contribute independently to mortality

above and beyond BMI (17) (18, 19), and thus, reduction

in waist circumference via a reduction in excess VAT may

also reduce cardiovascular risk. The effects of tesamorelin

were consistent among patients on different ART regi-

mens and among women.

Treatment with tesamorelin resulted in significant re-

ductions in triglycerides (⫺12.3%) and total cholesterol

to HDL cholesterol ratio (-7.2%) relative to placebo in the

pooled analysis. A somewhat stronger effect of tesamore-

lin was observed in the first phase-3 study compared with

the second phase-3 for lipids, but the trends toward im-

provement in the tesamorelin group and deterioration in

the placebo group were consistent in the two studies. In the

combined analysis with additional power, we are able to

show favorable effects of tesamorelin across multiple lipid

parameters using a highly stringent Pvalue. Nonetheless,

the differences between the two studies demonstrate that

heterogeneity may be seen in lipid responses to tesamore-

lin, and for some parameters, including total cholesterol

(⫺2.3%) and HDL (⫹3.0%), the treatment effect vs. pla-

TABLE 7. AEs and SAEs in the extension phase (26–52 wk)

Events

% Patients

T-T (n ⴝ246) T-P (n ⴝ135) P-T (n ⴝ197)

% Patients with any event 62.6 60.0 74.1

Related to treatment 21.5 20.7 42.1

Resulting in study discontinuation 2.0 4.4 8.1

Events reported in ⬎10% of patients

Arthralgia 5.7 5.9 14.7

Events reported in ⬎5% of patients

Diarrhea 2.8 5.2 4.1

Injection site pruritus 2.0 0.0 8.1

Injection site erythema 1.2 0.0 6.6

Injection site pain 0.0 0.0 5.1

Upper respiratory tract infection 7.3 3.7 4.1

Sinusitis 4.9 0.0 5.1

Pain in Extremity 3.3 0.7 7.6

SAE

% Patients with any event 2.8 2.2 3.0

All events reported

Arteriosclerosis coronary artery

0.4 0.0 0.0

Chorioretinopathy 0.4 0.0 0.0

Abdominal pain 0.0 0.7 0.0

Intestinal perforation 0.0 0.0 0.5

Chest pain 0.4 0.0 0.0

Cellulitis 0.4 0.0 0.5

Ludwig’s angina 0.0 0.7 0.0

Pneumonia 0.4 0.0 0.0

Postprocedural hemorrhage 0.0 0.0 0.5

Anal cancer

0.0 0.7 0.0

Hodgkin’s disease 0.0 0.0 0.5

Spontaneous abortion 0.4 0.0 0.0

Mental status changes 0.4 0.0 0.0

Nephrolithiasis 0.0 0.0 0.5

Asphyxia 0.0 0.0 0.5

Dyspnea 0.0 0.0 0.5

Treatment emergent.

This patient had a known history of coronary artery disease.

This patient was determined to have a previously undisclosed history of anal cancer.

10 Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 –0000

cebo, represented as percent change, was small and of

unclear clinical significance. Increasing endogenous GH

may reduce triglycerides and overall cholesterol levels

through inhibition of de novo lipogenesis and increase in

fat oxidation. Recent data suggest that, in the general pop-

ulation, increased waist circumference and triglyceride

level together predict CVD mortality, independent of

other cardiovascular risk markers (20), and thus, the im-

provement in these two parameters in HIV patients may be

useful.

Tesamorelin improved body image distress and re-

duced patient and physician rating of belly image. These

data suggest an important psychological benefit from tesa-

morelin. The improvement in distress related to body com-

position changes may allow patients to be more compliant

with ART use, knowing that excess fat can be reduced even

while therapy with ART is ongoing. In addition, there was

a relative improvement in overall QOL between tesamo-

relin- and placebo-treated patients. The changes in body

image distress and QOL were correlated with the reduc-

tion in VAT.

Glucose parameters, including fasting glucose, 2-h glu-

cose on oral glucose tolerance testing, and fasting insulin

were not significantly increased with tesamorelin relative

to placebo. There was a slight but statistically significant

increase in HbA

in tesamorelin- vs. placebo-treated pa-

tients, but the mean HbA

remained well within the nor-

mal range in the tesamorelin-treated group. With over 800

patients included in the pooled analysis, there was ade-

quate statistical power to detect a safety signal for glucose,

but a clinically meaningful signal was not observed for the

overall group. Nonetheless, for a small number of indi-

vidual patients, glucose levels may rise, and these should

be monitored on therapy. In contrast to tesamorelin, a

GH-releasing factor, even physiological dosing of GH, re-

sulting in the same increase in IGF-I, resulted in a signif-

icant 20-point deterioration in 2-h glucose on oral glucose

tolerance testing (21). The differences between the adverse

effects of GH and minimal adverse effects of tesamorelin

on glucose may relate to the more physiological effects of

a GH-releasing factor to induce endogenous GH pulsatil-

ity. Our data suggest that at least for patients with mild

elevations of fasting glucose (⬎110 and ⬍150 mg/dl),

tesamorelin is unlikely to further perturb glucose ho-

meostasis in a clinically relevant way.

Overall dropout rates were similar in tesamorelin and

placebo groups and had no impact on the results as con-

firmed in sensitivity analyses accounting for missing data.

In terms of AEs, tesamorelin was associated with more

AEs than placebo, but these were generally mild and most

often related to injection site reactions, such as pruritis or

erythema. SAEs and deaths were not different between

tesamorelin and placebo groups. One case of lung cancer

was diagnosed in a tesamorelin-treated patient who had

received tesamorelin for only 3 months in the study and

whose diagnosis was made 5 months after the last dose of

tesamorelin. In this patient, IGF-I levels remained within

the normal range during treatment. From the pooled anal-

ysis, hypersensitivity reactions, defined as an itching ery-

thematosus reaction extending beyond the injection site,

were observed in 2.9%. This percentage was consistent

between the trials. These AEs were largely mild and treated

by discontinuation from the study without known se-

quelae. Therefore, a small percentage, approximately 3%,

of subjects receiving tesamorelin would be expected to

have this side effect, necessitating discontinuation of treat-

ment. Arthralgias were not different between the groups.

In contrast, myalgias (5.5 vs. 1.9%) and edema (6.1 vs.

2.3%), although seen in relatively a small percentage of

patients, were more common in patients receiving tesa-

morelin. A small percentage of patients receiving tesamo-

relin can therefore be expected to develop signs consistent

with relative GH excess. AEs and SAEs during the exten-

sion phase were similar in frequency and scope to those in

the primary efficacy phase and suggest that long-term dos-

ing for up to 1 yr is generally well tolerated and associated

with relatively few AEs, most of only mild to moderate

intensity.

IgG antibodies to tesamorelin were seen in approxi-

mately 50% of subjects after 26 wk of treatment but di-

minished with time once therapy was discontinued, per-

sisting in 18% of patient 26 wk off therapy. We did not

observe any differences in the change in IGF-I or magni-

tude of decrease in VAT in those patients treated with

tesamorelin with and without antibodies. Low-titer neu-

tralizing antibodies were seen in small percentage and did

not affect IGF-I or VAT.

No treatment strategies are now approved specifically

for improvement in body composition among HIV pa-

tients. Although lifestyle modification may be useful to

decrease abdominal fat accumulation in this population

(22) and should be considered as an initial intervention in

appropriate patients, this strategy has not been as consis-

tent or robust in terms of VAT reduction as tesamorelin.

Treatment with metformin has been shown to result in

modest reductions in VAT but may result in loss of sc fat,

whereas treatment with tesamorelin appears to be highly

specific to reduce VAT and neutral to SAT (23). Neither

rosiglitazone nor pioglitazone has been shown to reduce

VAT in HIV-infected patients (24, 25).

The primary results of this pooled analysis demonstrate

the degree to which one can expect critical variables to

change with tesamorelin therapy among HIV-infected pa-

tients with abdominal fat accumulation in the context of

J Clin Endocrinol Metab, September 2010, 95(9):0000 – 0000 jcem.endojournals.org 11

ART. These changes amount to a ⫺26 cm

,⫺15.4% treat-

ment effect for VAT and a ⫺43 mg/dl, ⫺12.3% treatment

effect for triglycerides, with improvement in body image

parameters. These effects have to be balanced against the

safety profile of the drug. A small percentage of patients

will experience local hypersensitivity reactions, and indi-

vidual patients may experience glucose increases and signs

of GH excess. Nonetheless, the overall safety profile in

over 800 patients was good. Data from this pooled anal-

ysis suggest that tesamorelin may be a useful strategy with

an acceptable risk-benefit profile to significantly reduce

VAT and improve body image, while improving lipids in

those HIV-infected patients with excess abdominal fat ac-

cumulation in the context of ART.

Acknowledgments

We thank the patients for their participation in the research stud-

ies. We also thank Drs. Sophie-Elise Michaud and Monika Zol-

towska for their contribution to the study and its analysis and Dr.

Gary Koch for his advice on the statistical analyses.

The following investigators participated in study 1: P. Coˆte ́,

Clinique Me ́ dicale du Quartier Latin, Montreal, Quebec, Can-

ada; J. Falutz, Montreal General Hospital, Montreal, Quebec,

Canada; J. Montaner, St. Paul’s Hospital, Vancouver, British

Colombia, Canada; J. M. Gill, Southern Alberta HIV Clinic,

Calgary, Alberta, Canada; C. Quan, HIV Care Program, Wind-

sor Regional Hospital, Windsor, Ontario, Canada; A. Rachlis,

Sunnybrook and Women’s College Health Sciences Centre, To-

ronto, Ontario, Canada; J. Aberg, New York University Medical

Center, New York, NY; J. Albu, St. Luke’s-Roosevelt Hospital,

New York, NY; S. Ambardar, Infectious Disease Physicians,

Inc., Annandale, VA; R. Arduino, University of Texas Medical

School of Houston, Houston, TX; D. Berger, Northstar Health-

care, Chicago, IL; R. Bedimo, Dallas Veterans Affairs Medical

Center, Dallas, TX; C. Brinson, Central Texas Clinical Research,

Austin, TX; S. Brown, AIDS Research Alliance, West Holly-

wood, CA; T. Brown, Johns Hopkins University School of Med-

icine, Baltimore, MD; P. Cimoch, Center for Special Immunol-

ogy, Fountain Valley, CA; G. Coodley, Fanno Creek Clinic,

Portland, OR; C. Cohen, Community Research Initiative of New

England, Boston, MA; J. Currier, UCLA School of Medicine, Los

Angeles, CA; C. Davis, University of Maryland Institute of Hu-

man Virology, Baltimore, MD; E. DeJesus, Orlando Immunol-

ogy Center, Orlando, FL; M. Dube, Indiana University Depart-

ment of Medicine, Division of Infectious Diseases, Indianapolis,

IN; J. Ernst, AIDS Community Research Initiative of America

(ACRIA), New York, NY; J. W. Fessel, Kaiser Permanente, HIV

Research Unit, San Francisco, CA; J. Feinberg, University of Cin-

cinnati Medical Center, Cincinnati, OH; E. Godofsky, Bach &

Godofsky, MD, Bradenton, FL; S. Grinspoon, Massachusetts

General Hospital, Program in Nutritional Metabolism, Boston,

MA; K. Henry, Hennepin County Medical Center, Minneapolis,

MN; H. Kessler, Rush University Medical Center, Chicago, IL;

R. Myers, Body Positive, Inc., Phoenix, AZ; D. Lee, UCSD Med-

ical Center, Owen Clinic Antiviral Research Center, San Diego,

CA; G. Pierone, Treasure Coast Infections Disease Consultants,

Vero Beach, FL; B. Rashbaum, Capital Medical Associates,

Washington, DC; G. J. Richmond, Fort Lauderdale, FL; S. San-

tiago, Care Resource Inc., Miami, FL; P. Shalit, Swedish Medical

Center, Seattle, WA; D. Skiest, Community Research Initiative of

New England, Springfield, MA; P. Sklar, Drexel University Col-

lege of Medicine, Division of HIV/AIDS Medicine, Philadelphia,

PA; M. Somero, Infectious Disease, Palms Springs, CA; M.

Thompson, AIDS Research Consortium of Atlanta, Inc., At-

lanta, GA; A. Urbina, St. Vincent’s Hospital and Medical Center,

New York, NY; W. Vega, Infectious Diseases Associates, Sara-

sota, FL; and C. Wanke, Tufts New England Medical Center,

Infectious Disease, Boston, MA.

The following investigators participated in study 2: J. Angel,

Ottawa Hospital, Ottawa, Ontario, Canada; A. Antela Lo ́ pez,

Hospital Clínico Universitario de Santiago, Unidad de Enfer-

medades Infecciosas, Santiago de Compostela, Spain; D. Berger,

Hendry Glades Department of Health, Labele, FL; J. Beal,

Northstar Medical Center, Chicago, IL; C. Brinson, Central

Texas Clinical Research, Austin, TX; S. Brown, AIDS Research

Alliance, West Hollywood, CA; L. Cotte, Hoˆ pital de l’Hoˆ tel

Dieu Lyon, Lyon, France; N. Clumeck, Centre Hospitalier Uni-

versitaire (CHU) St. Pierre, Clinique des Maladies Infectieuses,

Brussels, Belgium; J. Currier, UCLA School of Medicine, Los

Angeles, CA; J. Ernst, ACRIA, New York, NY; V. Estrada,

Clínico San Carlos, Enfermedades Infecciosas, Hospital de Dia,

Madrid, Spain; J. Falutz, Montreal General Hospital, Immune

Deficiency Treatment Centre, McGill University Health Centre,

Montreal, Quebec, Canada; W. J. Fessel, Kaiser Permanente,

Clinical Trials Unit—Dr. Dillon, San Francisco, CA; M. Fisher,

Brighton and Sussex University Hospitals National Health Ser-

vice Trust, HIV/Genito-Urinary Medicine Research Depart-

ment, Elton John Centre, Brighton, UK; J. C. Gathe, Therapeutic

Concepts, Houston, TX; S. Grinspoon, Massachusetts General

Hospital, Program in Nutritional Metabolism, Boston, MA; C.

Grunfeld, University of California, San Francisco/Veterans Af-

fairs Medical Center, San Francisco, CA; S. Gupta, Indiana Uni-

versity School of Medicine, Division of Infectious Diseases,

Indianapolis, IN; M. Jain, University of Texas Southwestern

Medical Center at Dallas, Dallas, TX; M. A. Johnson, Royal Free

Hospital, Ian Charleson Day Centre, London, UK; D. Macallan,

St. Georges Hospital, Department of Genito-Urinary Medicine

(Courtyard Clinic), London, UK; C. Martorell, The Research

Institute, Springfield, MA; G. A. McComsey, University Hospi-

tals of Cleveland, Cleveland, OH; S. Moreno, Hospital Ramo ́n

y Cajal, Servicio de Enfermedades Infecciosas, Madrid, Spain;

M. Moutschen, CHU Sart-Tilman, Maladies Infectieuses, Lie` ge,

Belgium; J. Montaner, St. Paul’s Hospital, Canadian HIV Trials

Network, Vancouver, British Columbia, Canada; K. Mulligan,

University of California-San Francisco, San Francisco, CA; G. J.

Moyle, Chelsea and Westminster Hospital, St. Stephen’s Clinic,

London, UK; R. A. Myers, Southwest Center for HIV/AIDS,

Phoenix, AZ; R. G. Nahass, Infections Disease Associates, Hill-

sborough, NJ; A. Piche ́ , CHU de Sante ́ de l’Estrie, De ́ partement

de microbiologie et d’infectiologies, Sherbrook, Quebec, Can-

ada; C. Piketty, Hoˆ pital Europe ́en Georges Pompidou, Service

12 Falutz et al. Tesamorelin in HIV-Infected Patients J Clin Endocrinol Metab, September 2010, 95(9):0000 –0000

d’Immunologie, Paris, France; A. Rachlis, Sunnybrook Health

Sciences Centre, Toronto, Ontario, Canada; F. Raffi, Hoˆ tel

Dieu, Services des Maladies Infectieuses, Nantes, France; G. J.

Richmond, Fort Lauderdale, FL; D. Rouleau, CHU de

l’Universite ́ de Montre ́al, Hoˆ pital Notre-Dame, Pavillon L-C

Simard-Unité hospitalière de recherche, d’enseignement et de

soins sur le sida, Montreal, Quebec, Canada; M. S. Saag, Uni-

versity of Alabama at Birmingham, Center for AIDS Research,

Birmingham, AL; G. Scullard, St. Mary’s National Health Ser-

vice Trust, London, UK; P. Shalit, Swedish Medical Center, Se-

attle, WA; J. C. Shlay, Denver Public Health Department, Terry

Beirn Community Programs for Clinical Research on AIDS, Den-

ver, CO; F. Smaill, Hamilton Health Sciences Center—McMas-

ter University Health Sciences Centre, Hamilton, Ontario, Can-

ada; M. S. Somero, Infectious Disease, Palm Springs, CA; M. A.

Thompson, AIDS Research Consortium of Atlanta, Inc. Atlanta,

GA; S. Trottier, CHU de Que ́ bec, Pavillon CHU de l’Universite ́

de Laval, Quebec, Quebec, Canada; E. H. Van Wijngaerden,

Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; J. P. Vi-

ard, Hoˆ pital Necker, Service des Maladies Infectieuses, Paris,

France; S. Walmsley, University Health Network, Toronto Gen-

eral Hospital, Toronto, Ontario, Canada; C. Wanke, Tufts New

England Medical Center, Nutrition Infection Unit, Boston, MA;

D. Wohl, University of North Carolina at Chapel Hill, AIDS

Clinical Trials Unit, Chapel Hill, NC; and B. G. Yangco, Infec-

tious Disease Research Institute, Inc., Tampa, FL.

Address all correspondence and requests for reprints to:

Steven Grinspoon, M.D., Program in Nutritional Metabolism,

Massachusetts General Hospital, 5 Longfellow Place, Suite 207,

Boston, Massachusetts 02114. E-mail: [email protected].

The studies were funded by Theratechnologies and designed

in consultation with S.G. and J.F.. The sponsor collected the

data, and analyses were performed by Octagon Research Solu-

tions. S.G. drafted the current manuscript and had access to the

data and all analyses.

Clin Trials Registration Numbers: NCT 00123253,

NCT00435136, and NCT00608023.

Disclosure Summary: J.M., D.P, G.S., H.L., and C.M. are

employees of Theratechnologies. J.F. has received consultant

fees from Tibotec, Theratechnologies, Abbott, and Boehringer

Ingelheim; lecture fees from Gilead, Bristol-Myers Squibb, Ab-

bott, and Roche; and grant support from Theratechnologies.

G.M. has received grant support from Theratechnologies, Bris-

tol-Myers Squibb Co., Inc., GlaxoSmithKline, Gilead Sciences,

Merck Inc., Ardea Biosciences, Abbott, and Pfizer and served as

a consultant to Theratechnologies, Bristol-Myers Squibb,

GlaxoSmithKline, Gilead Sciences, Merck, Ardea Biosciences,

Pfizer, Tobira Pharmaceuticals, Tibotec, and Johnson and John-

son. R.T. has received grant support from Theratechnologies and

is employed by Phase V Technologies. S.G. has received grant

support from Theratechnologies, Bristol-Myers Squibb, Glaxo-

SmithKline, and Amgen and served as a consultant to Therat-

echnologies, EMD Serono, and Elixir Pharmaceuticals.

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... Generally well tolerated; Injection-site reactions (pain, redness); musculoskeletal symptoms (arthralgia, myalgia); elevated IGF−1 (theoretical cancer risk); glucose intolerance / insulin resistance (monitoring recommended); rare allergic reactions / peripheral edema (73,75,124,125) No long term safety data available. ↑ endogenous GH secretion and ↑ appetite when administered peripherally in healthy humans (96,97). ...

Aleksander Dominikowski

Zofia Rękoś

Michał Olejarz Marek Ruchała

Performance-enhancing drugs (PEDs) marketed as “research compounds” include unregulated peptides intended to modulate the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis. The agents most commonly encountered in clinical practice and online self-administration protocols include growth hormone-releasing hormone (GHRH) analogues (e.g., sermorelin, tesamorelin, CJC-1295 with Drug Affinity Complex [DAC], CJC-1295 without DAC), growth hormone secretagogues (GHS; e.g., growth hormone-releasing peptide-2 (GHRP-2), growth hormone-releasing peptide-6 (GHRP-6), hexarelin, ipamorelin), the growth hormone (GH) fragment - AOD9604 (hGH 176–191), and insulin-like growth factor-1 (IGF-1) analogues (e.g., pegylated mechano growth factor (PEG-MGF), IGF-1 Long R3 (IGF-1 LR3)). Reported adverse effects span endocrine and metabolic disturbances (including prolactin and cortisol elevations, appetite changes, and dysglycaemia), fluid retention syndromes, musculoskeletal symptoms (myalgia/arthralgia), and injection-site reactions. Given the absence of regulatory approval for physique- or performance-related indications and the uncertainty surrounding product composition, dose, and stacking practices in unregulated supply chains, clinicians increasingly require a pragmatic framework to interpret symptoms and laboratory abnormalities in patients using these compounds. This narrative review contrasts peer-reviewed pharmacokinetic/pharmacodynamic and clinical evidence with commonly encountered online self-administration protocols, stratifying peptides into evidence tiers from regulatory-grade randomized trial data to a complete absence of human studies, and highlights the resulting uncertainty around putative performance and recomposition benefits. We summarise structural characteristics, pharmacologic effects, and commonly reported dosing patterns, and we synthesise clinically relevant adverse effects with particular attention to hormonal imbalance, endocrine–metabolic risk, and biologically plausible but unproven mitogenic concerns. Finally, we propose a clinically oriented assessment algorithm to support exposure history taking, triage of symptom domains, and risk communication without legitimising off-label peptide regimens.

... Visceral fat decreased during therapy, according to several randomized therapeutic trials; however, quick reaccumulation was observed upon medication discontinuation. Care is recommended because tesamorelin may exacerbate glucose intolerance by raising IGF-1 levels [62]. drugs that suppress the immunological system. ...

Omar Thaer Jawad

Sarab Dalaf Khalaf

The impaired reaction of insulin target organs to normal insulin concentrations is known as insulin resistance. One of the main pathologic characteristics of several metabolic illnesses, including type 2 diabetes mellitus, is the process. What causes insulin resistance specifically? No one actually knows, but many valid explanations have been put out. In addition to summarizing the function of insulin in glucose metabolism in the traditional metabolic organs, this review will list the mechanisms (inflammatory response, end-of-retinoid stress, ectopic lipids in the liver, and skeletal muscle) that have been proposed to explain insulin resistance. The other one makes suggestions for possible treatment approaches for the inflammation linked to insulin resistance. The other suggests that medicine may be used to treat any insulin resistance. the failure of adipose tissue to store energy may be the primary cause of insulin resistance. Since there is currently no gold standard test for insulin resistance, it is challenging to define the condition clinically. However, the metabolic effects of insulin resistance, as outlined by the metabolic syndrome and insulin resistance syndrome, are a clinical sign of insulin resistance. Gaining a better understanding of the effects of insulin resistance and the syndromes that arise from it is the aim of this work. Insulin resistance, which can lead to cancer and a host of other hormone-related problems, is caused by DNA damage.

... 28 Tesamorelin, a 44-amino-acid GHRH analog, is FDA approved for HIV-related lipodystrophy and is of interest in orthopaedics due to its anabolic effects on lean body mass. 29,30 Similarly, sermorelin is a GHRH analog that was FDA approved for children with growth hormone deficiency. The established safety profiles of these GH secretagogues in defined populations make them particularly attractive candidates for off-label use in musculoskeletal recovery. ...

Omar F. Rahman Steven J. Lee William A. Seeds

Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.

... Since that time, a 44 amino acid polypeptide analogue of GHRH with an N terminal modification (named tesamorelin; originally TH9507 and marketed as Egrifta Depot) was developed that has improved stability and pharmacokinetics in comparison to native GHRH [172]. Tesamorelin was FDA approved for use in 2010 for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy associated with anti-viral therapy, based on a large clinical trial [173][174][175]. Specifically, in patients with HIV, lipodystrophy characterized by an abnormal fat distribution and hyperlipidemia is a common side effects of anti-retroviral therapy [176,177] which is associated with a reduction in GH and IGF1 levels [178]. ...

Antonio Jesús Montero Hidalgo

Mercedes del Río-Moreno

Jesús Pérez Gómez

Rhonda D Kineman

This review focuses on our current understanding of how growth hormone releasing hormone (GHRH): 1) stimulates GH release and synthesis from pituitary growth hormone (GH)-producing cells (somatotropes), 2) drives somatotrope proliferation, 3) is negatively regulated by somatostatin (SST), GH and IGF1, 4) is altered throughout lifespan and in response to metabolic challenges, and 5) analogues can be used clinically to treat conditions of GH excess or deficiency. Although a large body of early work provides an underpinning for our current understanding of GHRH, this review specifically highlights more recent work that was made possible by state-of-the-art analytical tools, receptor-specific agonists and antagonists, high-resolution in vivo and ex vivo imaging and the development of tissue (cell) -specific ablation mouse models, to paint a more detailed picture of the regulation and actions of GHRH.

Robin Beach Zandraetta Tims-Cook Colleen S McGary Tanushree Thote

Background Excess visceral abdominal fat (EVAF) is a prevalent metabolic complication among people living with HIV-1 (PLWH), occurring even in individuals with normal or mildly elevated body mass index (BMI). This pattern of fat accumulation is associated with metabolic dysfunction, cardiovascular risk, and reduced quality of life. Since EVAF can present without generalized obesity, weight-based assessments may fail to identify it; moreover, addressing EVAF warrants distinct approaches based on a patient's presentation. Two therapeutic classes have been studied in this setting: growth hormone–releasing hormone analog (tesamorelin), which selectively reduces visceral fat, and glucagon-like peptide (GLP-1) receptor agonists, which induces generalized weight loss in a nonspecific way. Case Presentations Two adults with well-controlled HIV presented with central adiposity. The first patient demonstrated a nonobese visceral adiposity phenotype characterized by increased waist circumference (WC) and a BMI of 27 kg/m2. Treatment with tesamorelin led to marked reductions in WC, improved lipid levels, and enhanced functional well-being. The second patient, a woman with higher BMI representative of obesity, received a GLP-1; however, her intermittent access to the medication resulted in fluctuating weight trends and persistent abdominal fat. Incorporation of tesamorelin provided a more targeted approach to reduce visceral adiposity in this context. Results Both cases demonstrated that EVAF may persist independent of BMI category and may respond differently to therapies targeting generalized obesity versus selective visceral abdominal fat. Conclusions These cases highlight the heterogeneity of EVAF in PLWH and support individualized management strategies informed by fat distribution rather than weight alone.

Luiz Felippe Mendes Caquetti

Tesamorelin stands out among growth hormone secretagogues due to its selective mechanism of action through activation of the GHRH receptor, preserving the physiological dynamics of the somatotropic axis. This study aimed to comparatively analyze tesamorelin in relation to other GH secretagogues, considering mechanisms of action, clinical evidence, effects on visceral and hepatic fat, endocrine selectivity, and safety profile. This is a critical narrative review with a qualitative approach, based on randomized clinical trials, mechanistic studies, and regulatory documents. The findings indicate that tesamorelin consistently reduces visceral adipose tissue, with additional effects on hepatic fat, while preserving subcutaneous fat and maintaining controlled IGF-1 modulation. Compared to ghrelin receptor agonists and recombinant growth hormone, tesamorelin demonstrates greater metabolic selectivity and reduced interference with broader neuroendocrine pathways. Its safety profile is predictable and manageable under appropriate monitoring, although surveillance of IGF-1 levels and glycemic parameters remains necessary. It is concluded that the effectiveness of tesamorelin is related to the quality of hormonal stimulation and its adherence to physiological regulation, establishing it as a model of selective intervention in visceral adiposity modulation.

Alexandra Afonso Catarina T. Cavaleiro Miguel A. R. B. Castanho

Marco Cavaco

Protein–protein interactions (PPIs) form an intricate cellular network known as the interactome, which is essential for various cellular processes, such as gene regulation, signal transduction, and metabolic pathways. The dysregulation of this network has been closely linked to various disease states. In cancer, these aberrant PPIs, termed oncogenic PPIs (OncoPPIs), are involved in tumour formation and proliferation. Therefore, the inhibition of OncoPPIs becomes a strategy for targeted cancer therapy. Small molecule inhibitors have been the dominant strategy for PPI inhibition owing to their small size and ability to cross cell membranes. However, peptide-based inhibitors have emerged as compelling alternatives, offering distinct advantages over small molecule inhibitors. Peptides, with their larger size and flexible backbones, can effectively engage with the broad interfaces of PPIs. Their high specificity, lower toxicity, and ease of modification make them promising candidates for targeted cancer therapy. Over the past decade, significant advancements have been made in developing peptide-based inhibitors. This review discusses the critical aspects of targeting PPIs, emphasizes the significance of OncoPPIs in cancer therapy, and explores the advantages of using peptide-based inhibitors as therapeutic agents. It also highlights recent progress in peptide design aimed at overcoming the limitations of peptide therapeutics, offering a comprehensive overview of the current landscape and potential of peptide-based inhibitors in cancer treatment.

Ronald Ellis Florin Vaida Keren Hu Fred R. Sattler

Background In people with HIV (PWH) who are virally suppressed (VS) on antiretroviral therapy (ART), abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting it might mitigate NCI in VS PWH. Methods This 6-month, Phase II randomized, open-label clinical trial compared Tesamorelin versus standard-of-care (SOC) for NCI in abdominally obese PWH. Participants had VS, NCI, and AO (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy. Results Seventy-three participants were randomized 3:2 to Tesamorelin or SOC (2mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well-matched at baseline. The Tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change: 0.146, 95% CI: -0.002 to 0.294, p=0.060), while the SOC group did not (0.103, 95% CI: -0.095 to 0.301, p=0.295), but the between-group difference was not significant (p=0.673). IGF-1 levels increased, but changes did not correlate with sRCS or WC. The Tesamorelin group had a greater reduction in WC than the SOC group (median difference -2.7 cm, p=0.015). Conclusions While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI.

Giovanni Guaraldi

Rita Murri

Gabriella Orlando Albert W Wu

The impact of lipodystrophy (LD) on quality of life is high, but it has not been demonstrated in literature. The objective of the study was to assess the impact of LD on the health-related quality of life (HRQOL) in HIV-infected people on highly active antiretroviral therapy (HAART). Patients with LD phenotype defined by the Multicenter AIDS Cohort Study (MACS) were included. Three different methods were used to define LD severity: both patient and physician evaluation using the HIV Outpatient Study (HOPS) severity scales and the Lipodystrophy Case Definition (LDCD). The HRQOL was evaluated by MOS-HIV Health Survey. Four hundred one patients on HAART for a mean of 108 +/- 52 months were evaluated for LD at the Metabolic Clinic of Modena and Reggio Emilia University were enrolled from January 2003 to July 2006. According to self-perceived or physician-based HOPS, 106 (26.5%) and 122 (30.4%) patients had severe LD. Females had significantly more severe LD. Few HRQOL scores correlated to LD severity using the physician-based score (both HOPSph and LDCD), while all the HRQOL scores correlated with LD severity when a patient-based score was used (HOPSpt). In multiple linear regression analysis, Mental Health HRQOL score, gender, body mass index, age, body image satisfaction were independent predictors of patient-based (HOPSpt) LD, while none of the HRQOL scores, but female gender, age, waist-to-hip ratio, limb fat, and body image satisfaction were correlated with physician-estimated HOPSph LD severity. HRQOL was strongly correlated with LD severity when a patient-based score was used. For an overall assessment of the impact of LD on HIV-infected people, both patient-based and physician-based measures are required.

Stacy A Porter

Joseph Massaro

Udo Hoffmann Caroline S. Fox

Obesity is associated with increased metabolic and cardiovascular risk. The ectopic fat hypothesis suggests that subcutaneous fat may be protective, but this theory has yet to be fully explored. Participants from the Framingham Heart Study (n = 3,001, 48.5% women) were stratified by visceral adipose tissue (VAT) into sex-specific tertiles. Within these tertiles, age-adjusted abdominal subcutaneous adipose tissue (SAT) tertiles were examined in relation to cardiometabolic risk factors. In the lowest VAT tertile, risk factor prevalence was low, although systolic blood pressure in women and rates of high triglycerides, impaired fasting glucose, hypertension, and the metabolic syndrome in men increased with increasing SAT tertile (all P < 0.04). In contrast, in the top VAT tertile, lower triglycerides were observed in men with increasing SAT (64.4% high triglycerides in SAT tertile 1 vs. 52.7% in SAT tertile 3, P = 0.03). Similar observations were made for women, although results were not statistically significant (50.6% high triglycerides in SAT tertile 1 vs. 41.0% in tertile 3, P = 0.10). Results in the highest VAT tertile were notable for a lack of increase in the prevalence of low HDL in men and women and in rates of impaired fasting glucose in men with increasing subcutaneous fat, despite sizable differences in BMI across SAT tertiles (27.1 to 36.3 kg/m(2)[women]; 28.1 to 35.7 kg/m(2)[men]). Although adiposity increases the absolute risk of metabolic and cardiovascular disease, abdominal subcutaneous fat is not associated with a linear increase in the prevalence of all risk factors among the obese, most notably, high triglycerides.

Tobias Pischon H Boeing K Hoffmann

Elio Riboli

Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.

Julian Falutz

Diane Potvin

Jean-Claude Mamputu Steven K Grinspoon

HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH(1-44)) in HIV-infected patients with central fat accumulation. A 12-month study of 404 HIV-infected patients with excess abdominal fat in the context of antiretroviral therapy was conducted between January 2007 and October 2008. The study consisted of 2 sequential phases. In the primary efficacy phase (months 0-6), patients were randomly assigned to receive tesamorelin [2 mg subcutaneous (SC) every day] or placebo in a 2:1 ratio. In the extension phase (months 6-12), patients receiving tesamorelin were rerandomized to continue on tesamorelin (2 mg SC every day) or switch to placebo. Patients initially randomized to placebo switched to tesamorelin. Patients and investigators were blinded to treatment assignment throughout the study. The primary endpoint was visceral adipose tissue (VAT). Secondary endpoints included body image, IGF-I, safety measures, including glucose, and other body composition measures. VAT decreased by -10.9% (-21 cm(2)) in the tesamorelin group vs. -0.6% (-1 cm(2)) in the placebo group in the 6-month efficacy phase, P < 0.0001. Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-hip-ratio (P = 0.001) improved, with no change in limb or abdominal SC fat. Insulin-like growth factor-1 increased (P < 0.001), but no change in glucose parameters was observed. Patient rating of belly appearance distress (P = 0.02) and physician rating of belly profile (P = 0.02) were significantly improved in the tesamorelin vs. placebo-treated groups. The drug was well tolerated. VAT was reduced by approximately 18% (P < 0.001) in patients continuing tesamorelin for 12 months. The initial improvements over 6 months in VAT were rapidly lost in those switching from tesamorelin to placebo. Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose.

Janet Lo

Suhny Abbara Leon Shturman Steven K Grinspoon

The degree of subclinical coronary atherosclerosis in HIV-infected patients is unknown. We investigated the degree of subclinical atherosclerosis and the relationship of traditional and nontraditional risk factors to early atherosclerotic disease using coronary computed tomography angiography. Seventy-eight HIV-infected men (age 46.5 +/- 6.5 years and duration of HIV 13.5 +/- 6.1 years, CD4 T lymphocytes 523 +/- 282; 81% undetectable viral load), and 32 HIV-negative men (age 45.4 +/- 7.2 years) with similar demographic and coronary artery disease (CAD) risk factors, without history or symptoms of CAD, were prospectively recruited. 64-slice multidetector row computed tomography coronary angiography was performed to determine prevalence of coronary atherosclerosis, coronary stenosis, and quantitative plaque burden. RESULTS HIV-infected men demonstrated higher prevalence of coronary atherosclerosis than non-HIV-infected men (59 vs. 34%; P = 0.02), higher coronary plaque volume [55.9 (0-207.7); median (IQR) vs. 0 (0-80.5) microl; P = 0.02], greater number of coronary segments with plaque [1 (0-3) vs. 0 (0-1) segments; P = 0.03], and higher prevalence of Agatston calcium score more than 0 (46 vs. 25%, P = 0.04), despite similar Framingham 10-year risk for myocardial infarction, family history of CAD, and smoking status. Among HIV-infected patients, Framingham score, total cholesterol, low-density lipoprotein, CD4/CD8 ratio, and monocyte chemoattractant protein 1 were significantly associated with plaque burden. Duration of HIV infection was significantly associated with plaque volume (P = 0.002) and segments with plaque (P = 0.0009) and these relationships remained significant after adjustment for age, traditional risk factors, or duration of antiretroviral therapy. A total of 6.5% (95% confidence interval 2-15%) of our study population demonstrated angiographic evidence of obstructive CAD (>70% luminal narrowing) as compared with 0% in controls. Young, asymptomatic, HIV-infected men with long-standing HIV disease demonstrate an increased prevalence and degree of coronary atherosclerosis compared with non-HIV-infected patients. Both traditional and nontraditional risk factors contribute to atherosclerotic disease in HIV-infected patients.

Janet Lo Sung Min You Jeffrey Wei Steven K Grinspoon

Relative growth hormone (GH) deficiency is highly prevalent in patients with HIV. The purpose of this study was to investigate relationships of GH to metabolic and anthropometric parameters in HIV patients and non-HIV controls. Peak GH and metabolic parameters were assessed in a cross-sectional study of 191 HIV patients and 62 age and BMI-matched healthy controls. Peak GH was assessed by GHRH/arginine stimulation testing. HIV patients demonstrated similar BMI, but increased waist circumference (WC) and reduced peak GH to GHRH/arginine compared with control subjects [median = 12.4 (interquartile range: 6.3-24.8) vs. 21.3 (8.8, 34.5) μg/l, P = 0.006, HIV vs. control]. Among HIV and non-HIV groups, peak GH was inversely associated with WC (rho = -0.44, P < 0.0001; rho = -0.63, P < 0.0001; HIV patients and controls, respectively), blood pressure (rho = -0.17, P = 0.02; rho = -0.36, P = 0.004), triglycerides (rho = -0.37, P < 0.0001; rho = -0.43, P = 0.001), glucose (rho = -0.34, P < 0.0001; rho = -0.30, P = 0.02), insulin (rho = -0.43, P < 0.0001; rho = -0.60, P < 0.0001) and CRP (rho= -0.29, P < 0.0001; rho = -0.59, P < 0.0001). Among HIV patients, the inverse association between peak GH and fasting glucose remained significant (β = -0.006 mmol/l change in glucose per μg/l change in GH, P = 0.004) controlling for age, gender, race, BMI, WC, protease inhibitor (PI) and nucleoside reverse transcriptase inhibitors. Similarly, the inverse association between peak GH and triglycerides remained significant (β = -0.01 mmol/l change in triglycerides per μg/l change in GH, P = 0.02) controlling for age, gender, race, BMI, WC, PI and lipid-lowering medications. HIV men with peak GH < 7.5 μg/l demonstrated higher BMI, WC, SBP, triglycerides, glucose and CRP. Reduced GH secretion is independently associated with dyslipidaemia and higher glucose, among HIV patients with abdominal fat accumulation.

Joseph Cofrancesco Jr Eric Freedland

Grace McComsey

Central fat accumulation is increasingly recognized as a problem for patients with HIV infection. The term "lipodystrophy" has been used to describe collectively a constellation of body habitus changes and metabolic abnormalities commonly observed in HIV-infected patients, particularly since the advent of highly active antiretroviral therapy. Visceral fat accumulation can place patients at increased risk of coronary artery disease.Furthermore, body shape changes are a source of distress to patients that may compromise treatment adherence.Reduction of abdominal obesity can therefore be considered part of therapy in HIV-positive patients with visceral adipose tissue (VAT) accumulation. Currently, there are no drugs approved by the Food and Drug Administration for the treatment of HIV-associated central fat accumulation. Lifestyle modifications such as diet and exercise and switching antiretroviral therapies appear to be of limited value in reducing VAT. Metformin has shown some benefit in reducing VAT but at the expense of accelerating peripheral fat loss, and the thiazolidinediones have no effect on VAT. Similarly, testosterone does not appear to reduce VAT in these patients,and there are no data on anabolic steroids. Two large, randomized controlled trials have demonstrated the efficacy of recombinant human growth hormone (rhGH) in reducing visceral adipose tissue. There are also promising data regarding treatment with growth hormone releasing hormone (GHRH).

Julian Falutz Soraya Allas

Jean-Claude Mamputu Steven K Grinspoon

Treatment of HIV patients with daily tesamorelin, a growth hormone-releasing factor analogue, for 26 weeks resulted in a significant decrease in visceral adipose tissue (VAT) and improvement in lipids. The objective of the 26-week extension phase was to evaluate long-term safety and effects of tesamorelin. HIV patients with central fat accumulation in the context of antiretroviral therapy were randomized to tesamorelin 2 mg (n = 273) or placebo (n = 137) s.c. daily for 26 weeks. At week 26, patients originally on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 154) or placebo (T-P group, n = 50), whereas patients originally on placebo were switched to tesamorelin (P-T group, n = 111). Safety included adverse events and glucose parameters. Tesamorelin was generally well tolerated. The prevalence of adverse events and serious adverse events during the extension phase was comparable with the initial phase. Changes in glucose parameters over 52 weeks were not clinically significant and similar to those after 26 weeks. The change in VAT was sustained at -18% over 52 weeks of treatment (P < 0.001 versus baseline) as was the change in triglycerides (-51 mg/dl, P < 0.001 versus baseline). Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein decreased minimally over 52 weeks. Upon discontinuation of tesamorelin, VAT reaccumulated. Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose. Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment.

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