Metabolic Effects of a Growth Hormone–Releasing Factor in Patients with HIV

Falutz, Julian; Allas, Soraya; Blot, K; Potvin, Diane; Kotler, Donald P.; Somero, Michael; Berger, Daniel; Brown, Stephen J.; Richmond, Gary; Fessel, Jeffrey; Turner, Ralph R.; Grinspoon, Steven

doi:10.1056/nejmoa072375

Cited by 173 publications

(148 citation statements)

References 33 publications

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“…Thus, treating HIV-infected individuals with documented biochemical evidence of GHD should be considered off-label and inappropriate. However, recent studies suggest beneficial effects of a GHRH analog among HIV-infected patients with central fat accumulation, and this benefit on visceral fat was seen specifically in subanalyses performed among HIV-infected women enrolled in the studies (37,38,39).…”

Section: Discussionmentioning

confidence: 99%

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls

Zirilli

Orlando

Carli

et al. 2012

European Journal of Endocrinology

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Objective: GH secretion is impaired in lipodystrophic human immunodeficiency virus (HIV) patients and inversely related to lipodystrophy-related fat redistribution in men. Less is known about the underlying mechanisms involved in reduced GH secretion in HIV-infected women. Design: A case-control, cross-sectional study comparing GH/IGF1 status, body composition, and metabolic parameters in 92 nonobese women with HIV-related lipodystrophy and 63 healthy controls matched for age, ethnicity, sex, and body mass index (BMI). Methods: GH, IGF1, IGF binding protein 3 (IGFBP3), GH after GHRH plus arginine (GHRHCArg), several metabolic variables, and body composition were evaluated. Results: GH response to GHRHCArg was lower in HIV-infected females than in controls. Using a cutoff of peak GH %7.5 mg/l, 20.6% of HIV-infected females demonstrated reduced peak GH response after GHRHCArg. In contrast, none of the control subjects demonstrated a peak GH response %7.5 mg/l. Bone mineral density (BMD), quality of life, IGF1, and IGFBP3 were lowest in the HIV-infected females with a GH peak %7.5 mg/l. BMI was the main predictive factor of GH peak in stepwise multiregression analysis followed by age, with a less significant effect of visceral fat in the HIV-infected females. Conclusions: This study establishes that i) GH response to GHRHCArg is lower in lipoatrophic HIVinfected women than in healthy matched controls, ii) BMI more than visceral adipose tissue or trunk fat influences GH peak in this population, and iii) HIV-infected women with a GH peak below or equal to 7.5 mg/l demonstrate reduced IGF1, IGFBP3, BMD, and quality of life.

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Section: Discussionmentioning

confidence: 99%

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls

Zirilli

Orlando

Carli

et al. 2012

European Journal of Endocrinology

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“…Several therapeutic strategies involving the GH-IGF1 system, however, have been undertaken in order to improve health in HIV-infected patients, but with the aim to counteract body composition changes and metabolic alterations due to HIV-related lipodystrophy (40). These strategies include tesamorelin, a GHRH analog (41,42), IGF1 (43), and rhGH (44,45) administration. Unfortunately, all these clinical trials do not consider the GH secretive status of enrolled subjects at baseline and do not target the therapy to the correction of the GHD.…”

Section: Clinical Relevance Of Ghd In Patients With Hivmentioning

confidence: 99%

Gender differences in GH response to GHRH+ARG in lipodystrophic patients with HIV: a key role for body fat distribution

Brigante

Diazzi

Ansaloni

et al. 2014

European Journal of Endocrinology

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Objective: Gender influence on GH secretion in human immunodeficiency virus (HIV)-infected patients is poorly known. Design and methods: To determine the effect of gender, we compared GH response to GH-releasing hormone plus arginine (GHRHCArg), and body composition in 103 men and 97 women with HIV and lipodystrophy. The main outcomes were IGF1, basal GH, GH peak and area under the curve (AUC) after GHRHCArg, body composition, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Results: Men had lower GH peak and AUC than women (P!0.001). Of the study population, 21% of women and 37% of men had biochemical GH deficiency (GHD; GH peak !7.5 mg/l). VAT-to-SAT ratio was higher in men than in women with GHD (P!0.05). Unlike women, VAT, SAT, and trunk fat were greater in men with GHD than in men without GHD. IGF1 was significantly lower in women with GHD than in women without GHD, but not in men. At univariate analysis, BMI, trunk fat mass, VAT, and total adipose tissue were associated with GH peak and AUC in both sexes (P!0.05). BMI was the most significant predictive factor of GH peak, and AUC at multiregression analysis. Overall, abdominal fat had a less pronounced effect on GH in females than in males.Conclusions: These data demonstrate that GH response to GHRHCArg is significantly lower in HIV-infected males than females, resulting in a higher percentage of GHD in men. Adipose tissue distribution more than fat mass per se seems to account for GH gender differences and for the alteration of GH-IGF1 status in these patients.

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“…Grunfeld et al [9] Falutz et al [14] Falutz et al [13] Falutz et al [15] Falutz et al [16] Growth hormone axis treatments for lipodystrophy 457 effective GH axis treatment for improving LBM, resulting in an increase of 1.35 kg relative to placebo. With a total of 610 participants in the treatment groups and 281 in the placebo groups, we feel that the results are a reliable measure of the efficacy of tesamorelin.…”

Section: Ghrh Versus Placebomentioning

confidence: 99%

“…Falutz et al [13] Falutz et al [14] Falutz et al [15] Falutz et al [16] Subtotal (95% CI) Heterogeneity: τ 2 = 0.00; χ 2 = 2.73, df = 3 (P = 0.43); I 2 = 0 % Test for overall effect: Z = 8.97 (P < 0.00001) Heterogeneity: τ 2 = 0.29; χ 2 = 20.50, df = 9 (P = 0.02); I 2 = 56% Test for overall effect: Z = 6.07 (P < 0.00001) Test for subgroup differences: χ 2 = 4.03. df = 3 (P = 0.26); I 2 = 52.6%…”

Section: Tesamorelin Versus Placebomentioning

confidence: 99%

“…Lastly, no long-term studies have examined the benefits and consequences of extended use of these drugs. Total events Heterogeneity: τ 2 = 0.01; χ 2 = 6.14, df = 3 (P = 0.0.11); I 2 = 51% Test for overall effect: Z = 1.56 (P = 0.12) 1996 1996 2004 2005 2007 2007 2008 2010 Waters et al [26] Schambelin et al [19] Koutkia et al [23] Falutz et al [13] Falutz et al [14] Grunfeld et al [9] Lo et al [17] Falutz et al [16] Subtotal (95% CI) Total events Heterogeneity: τ 2 = 0.00; χ 2 = 4.94, df = 6 (P = 0.55); I 2 = 0% Test for overall effect: Z = 3.16 (P = 0.002)…”

Section: Overall Completeness and Applicability Of The Evidencementioning

confidence: 99%

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Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials

et al. 2011

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Background HIV‐associated lipodystrophy is a disorder of fat metabolism that occurs in patients with HIV infection. It can cause metabolic derangements and negative self‐perceptions of body image, and result in noncompliance with highly active antiretroviral therapy (HAART). Growth hormone (GH) axis drugs have been evaluated for treatment of this disorder, but no systematic review has been conducted previously. Objectives The aim of the review was to compare the effects of GH axis drugs vs. placebo in changing visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and lean body mass (LBM) in patients with HIV‐associated lipodystrophy. Search methods We searched MEDLINE (1996–2009), CENTRAL (Issue 4, 2009), Web of Science, Summons, Google Scholar, the Food and Drug Administration (FDA) website, and Clinicaltrials.gov from 13 October 2009 to 7 June 2010. We excluded newspaper articles and book reviews from the Summons search; this was the only search limitation applied. We also manually reviewed references of included articles. Selection criteria Inclusion criteria were as follows: randomized placebo‐controlled trial (RCT); study participants with HIV‐associated lipodystrophy; intervention consisting of GH, growth hormone releasing hormone (GHRH), tesamorelin or insulin‐like growth factor‐1 (IGF‐1); study including at least one primary outcome of interest: change in VAT, SAT or LBM. Data collection and analysis Two independent reviewers extracted data and assessed study quality using a standardized form. The authors of one study were contacted for missing information. The main effect was calculated as a summary of the mean differences in VAT, SAT and LBM between the intervention and placebo groups in the included studies. Subgroup analyses were performed to assess different GH axis drug classes. Results Ten RCTs including 1511 patients were included in the review. All had a low risk of bias and passed the test of heterogeneity for each primary outcome. Compared with placebo, GH axis treatments decreased VAT [weighted mean difference (WMD) –25.20 cm2; 95% confidence interval (CI) –32.18 to –18.22 cm2; P<0.001] and increased LBM (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; P<0.001], but had no significant effect on SAT mass (WMD –3.94 cm2; 95% CI –10.88 to 3.00 cm2; P=0.27]. Subgroup analyses showed that GH had the most significant effects on VAT and SAT, but none on LBM. The drugs were well tolerated but statistically significant side effects included arthralgias and oedema. Conclusions Our review indicates that, based on the findings of the 10 included studies, GH axis treatments are effective in reducing VAT and increasing LBM in patients with HIV‐associated lipodystrophy. However, clinicians must decide whether the attributed benefits are clinically significant, considering the costs and potential risks of GH axis treatments. A limitation of this study is the small number of studies available of each GH axis drug class.

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Metabolic Effects of a Growth Hormone–Releasing Factor in Patients with HIV

Abstract: 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] .).

Cited by 173 publications

References 33 publications

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls

Gender differences in GH response to GHRH+ARG in lipodystrophic patients with HIV: a key role for body fat distribution

Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials

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