Tesamorelin - an overview | ScienceDirect Topics
Chapters and Articles You might find these chapters and articles relevant to this topic. Use for Diagnosis and Treatment Sermorelin, a functional peptide fragment of GHRH1–29, has been used in the diagnosis and treatment of children with idiopathic growth horm
Chapters and Articles
You might find these chapters and articles relevant to this topic.
Use for Diagnosis and Treatment
Sermorelin, a functional peptide fragment of GHRH1–29, has been used in the diagnosis and treatment of children with idiopathic growth hormone deficiency [13]. Tesamorelin, a stabilized synthetic peptide analog of GHRH1–44, received US Food and Drug Administration approval in 2010 for the treatment of lipodystrophy in HIV patients under highly active antiretroviral therapy, and was investigated for effects on certain cognitive functions in adults with cognitive impairment and healthy older adults [4].
URL: https://www.sciencedirect.com/science/article/pii/B9780128010280001434
Tesamorelin
GH secretion in HIV-infected patients with GHD documented by impaired response to GHRH + Arg test, however, is partially rescued compared with that of hypopituitary patients [40]. Therefore, pituitary GH reserve is still recruitable in HIV, probably accounting for the efficacy in the HIV population of GH secretagogues, such as GHRH [118] and tesamorelin [101], a GHRH analogue. Biochemical GHD occurs in about one-third of patients with HIV infection, and GHRH analogues are effective in increasing serum IGF-1 [108,109,119] as the pituitary GH reserve is unaffected, even though less elicitable [39,40]. No data are available on the relationship between the efficacy of GHRH analogues and patient's GH/IGF-1 baseline status [110].
Tesamorelin is effective in counteracting body fat changes caused by HIV-related lipodystrophy [101,107,119], and is safe even when the treatment period is extended [107–109]. Tesamorelin decreases visceral fat by about 15% without side-effects related to GH excess [101,107,119]. Lipid profile also improves with tesamorelin [21,119]. Usually, discontinuation of tesamorelin results in a relapse of visceral adiposity [109].
Tesamorelin has been approved by the regulatory agency FDA in the USA, although it is not available in Europe where it remains an off-label treatment.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X17300064
3.1.11 Growth Hormone Releasing Hormone (GHRH) analog
Growth hormone (GH) has emerged as an important potential target for NAFLD. Several case reports and clinical studies suggest that the GH deficiency state in adults is associated with an increased prevalence of NAFLD and NASH [114,115]. Consistently, GH replacement therapy significantly improved NAFLD, evidenced by improved liver function parameters, including ALT, AST, and GGT, improved histological changes in the liver, and reduced fibrotic markers [116]. Tesamorelin is a GHRH analog approved for treating human immunodeficiency virus (HIV)-associated lipodystrophy. In a recent clinical trial in HIV patients with NAFLD, tesamorelin reduced liver fat content and prevented liver inflammation and fibrosis progression [117]. A prospective phase II trial with tesamorelin in targeted NAFLD patients is underway (NCT03375788).
URL: https://www.sciencedirect.com/science/article/pii/S0026049521002250
20 Tesamorelin Acetate (HIV Lipodystrophy) [139–142]
| Class | Growth hormone-releasing factor |
| Country of origin | Canada |
| Originator | Theratechnologies |
| First introduction | United States |
| Introduced by | Theratechnologies |
| Trade name | Egrifta™ |
| CAS registry no. | 804475-66-9 |
| Molecular weight | 5135.9 Da |
| 44-Amino acid polypeptide-trans-3-hexenoyl-YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 |
Tesamorelin acetate is an analog of growth hormone-releasing hormone (GHRH) that was approved in the United States in 2010 for treatment of lipodystrophy in HIV patients. With the advent of potent antiretroviral treatment (ART) in the 1990s as a treatment regime for HIV infection, some patients were observed to have either a loss or an accumulation of fat, termed lipodystrophy. Individuals with lipodystrophy can develop excess fat notably in the abdominal visceral adipose tissue (VAT), liver, trunk, and breasts. Up to 30% of patients undergoing ART experience increases in abdominal fat. Patients with HIV-associated lipodystrophy have an increased need for health services when compared to ART patients without lipodystrophy. The market size for the treatment of HIV-associated lipodystrophy in the United States is currently projected to be $800 million to $1.2 billion [139]. Lipodystrophy has both medical and social implications. Increased VAT has been associated with dyslipodemia, thereby increasing the risk of the progression of metabolic diseases. Excess VAT is associated with increased coronary artery calcification, increasing the risk of cardiovascular events. The pathogenesis of lipodystrophy is not clearly understood, but several biological processes have been implicated. Impaired fatty acid metabolism in the adipocyte, deficiencies in adiponectin, increases in leptin, and alteration in growth hormone secretion have all been studied. Decreased growth hormone (GH) levels are found in HIV patients with increased VAT. The impairment of the GH secretion through suppression of GH by elevated fatty acids and decreases in ghrelin levels may contribute to lipodystrophy. The observation of lower GH levels in patients with lipodystrophy and the observation that GH treatment to prevent HIV-related wasting results in improved lipodystrophy have led to efforts to target the GH axis to treat lipodystrophy [140,141].
Tesomorelin is an analog of GHRH. GHRH stimulates the synthesis and release of GH. In the pituitary, GH is secreted in a pulsatile manner. GH control is regulated by somatostatin and the negative feedback regulator, IGF-1. Direct administration of GH to patients with lipodystrophy decreases VAT but has associated side effects such as fluid retention and joint swelling. Because of the side effects associated with direct GH administration, GHRH represents a attractive mechanism for increasing GH levels. Tesomorelin is an analog of GHRH in which the N-terminal amino acid, Tyr, is amidated with a trans-3-hexenoyl group. Capping of the N-terminus protects GHRH from cleavage by DPP-4. Tesomorelin demonstrates enhanced stability compared with GHRH in animal models. After subcutaneous administration, GH levels were increased out to 8 h when tested in rats, dogs, and pigs. In healthy male volunteers, tesamorelin administered subcutaneously showed a linear increase in pharmacokinetic parameters when dosed at 0.5, 1, or 2 mg per day. In Phase II studies comparing 1 and 2 mg doses of tesamorelin, the 2 mg dose showed better efficacy at reducing trunk and visceral fat. IGF-1 levels were found to be significantly increased relative to placebo. In two Phase III clinical trials, tesamorelin was shown to significantly reduce VAT and to improve body image. Significant reductions in trunk fat were observed in the tesamorelin-treated group. Lean body mass increased and waist circumference decreased. Tesamorelin was found to affect metabolic biomarkers by reducing triglycerides and total cholesterol levels [141,142]. In November 2010, tesamorelin, a GRF analog, was approved by the U.S. FDA for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Tesamorelin is marketed under the trade name Egrifta™ by Theratechnologies and EMD Serono. Egrifta™ is available as a subcutaneously administered 2 mg dose. Egrifta™ is the first FDA-approved treatment specifically approved for lipodystrophy.
URL: https://www.sciencedirect.com/science/article/pii/B9780123860095000023
Pharmacological interventions
Testosterone increased lean mass and decreased subcutaneous fat, but it had no impact on visceral adipose tissue of HIV-infected patients with abdominal obesity.98 Therapy with metformin either alone or in combination with rosiglitazone has shown inconsistent effects on visceral fat accumulation in HIV-positive patients.99–102 Moreover, metformin reduces subcutaneous fat and therefore it may contribute to worsen lipoatrophy.
Because growth hormone deficiency is associated with visceral adiposity in the general population103 and also in patients with HIV-associated lipodystrophy,104 growth hormone at different doses has been used to treat HIV-associated lipohypertrophy.97 The reduction in visceral adipose tissue was directly proportional to the dose used but also the frequency and intensity of adverse events. In an attempt to reduce side effects, an analogue of growth hormone releasing hormone (tesamorelin) that mimics more closely the physiological dose and function of growth hormone has been successfully used to decrease VAT.105,106 The effects of growth hormone or tesamorelin will be further described in another chapter.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X10001466
Pharmacotherapy
Metformin
The biguanide metformin is used in type 2 diabetes and polycystic ovarian syndrome as it increases insulin sensitivity in peripheral tissue and can lead to weight loss. Treatment with metformin has also demonstrated improvements in insulin sensitivity103,104 and reduction in visceral fat105 in HIV-infected individuals. However its use is associated with loss of subcutaneous adipose tissue,106 and has been rarely associated with lactic acidosis,107 so its use with the continuation of NRTIs should be closely monitored. Current guidelines recommend the use of metformin in HIV in the setting of diabetes79 but not insulin resistance without diabetes.
Thiazolidinediones
Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear receptor which is important in adipocyte differentiation and insulin sensitivity108 and markedly downregulated in HIVLD.109 Thiazolidinediones (“glitazones”) are PPARG agonists that improve insulin sensitivity in diabetic subjects. Their effect in treating HIV-associated lipoatrophy has been mixed, with some studies demonstrating improvement in peripheral fat mass,110–113 and others showing no improvement.114,115 Similarily, in some studies, insulin sensitivity improved with thiazolidinedione therapy as measured by euglycemic clamp,110,116 or markers of insulin sensitivity such as fasting insulin or insulin concentration during the OGTT,111,114 but these changes are not consistently observed, with some studies having seen no improvement.112,113 The disparity between these results again be explained by mitochondrial dysfunction in those who continued tNRTIs.117 Therefore efforts should be made to switch away from tNRTIs prior to considering glitazone therapy. The most commonly prescribed thizaolidinedione rosiglitazone has been associated with an increased risk of myocardial infarction in diabetic patients so it should be used with caution in individuals with high cardiovascular risk,118 and it is currently under review by the Food and Drugs Administration and has very recently been withdrawn by the European Medicines Agency.119
Newer agents
Manipulation of the growth hormone/IGF-1 axis in HIV-infected patients with excess VATGrowth hormone has been used to successfully reduce visceral adiposity in HIV-infected patients, but its use at supraphysiological doses increases concentrations of insulin-like growth factor (IGF-1), which is thought to explain the increases in IR and development of diabetes in some patients being treated with growth hormone.120 The use of the growth hormone releasing hormone (GHRH) analogue tesamorelin reduces VAT, and triglyceride concentrations, without the associated IGF-1-induced increase in IR.121 Tesamorelin is currently awaiting approval from the U.S. Food and Drugs Administration for treatment of visceral adiposity in HIV. It has yet to be proven to improve insulin sensitivity and thus cannot yet be recommended for treatment of IR alone. A recombinant insulin-like growth factor (IGF-1)/IGF binding protein3 (rhIGF-1/IGFBP3) has been shown to improve peripheral insulin sensitivity in type I diabetes.122 In a small open-label study in HIV-infected individuals with VAT accumulation and insulin resistance, rhIGF-1/IGFBP3 improved peripheral insulin sensitivity and reduced both total body fat and triglyceride concentrations but increased hepatic glucose production after 3 months of use.123 Further studies are required for safety, efficacy and to assess whether the effect of increased hepatic glucose production will offset the benefits on insulin sensitivity.
The incretin axisIncretins are gut-derived hormones that stimulate glucose-dependent insulin secretion, reduce gastric emptying and increase satiety.124 The incretin mimetic exanetide is used in the treatment of type 2 diabetes in conjunction with other oral agents, and its use can be associated with improvements in insulin sensitivity and weight loss.125 There has been one case report of its successful use in HIV.126 The DPP-4 inhibitors such as sitagliptin (which inhibit the enzyme which metabolises incretins) have also been shown to improve insulin sensitivity with associated minor weight reductions in individuals with type 2 diabetes.127 These agents may be of use in insulin resistance in HIV, but currently data are lacking, drug interactions are unknown, and any potential use should be in close consultation with endocrinologists experienced with their use.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X10001727
Cardiovascular disorders
In humans, cIMT is an excellent surrogate of coronary atherosclerosis. In adults with hypopituitarism who have increased atherosclerosis, rhGH replacement improves IMT of major arteries and endothelial function after several years of treatment compared to progression of cIMT in GHD untreated patients, which progressed at a similar rate as matched controls without GHD.41 The reductions in cIMT may occur as early as three months after initiating rhGH treatment. In a recent study of the GHRH analog (tesamorelin), 12 months of treatment (2 mg/d subcutaneously) in 60 abdominally obese volunteers with peak GH stimulation ≤4.2 μg/L significantly decreased cIMT, VAT, CRP and triglycerides compared to placebo.42 It's not clear whether the treatment benefits on cIMT were due to direct effects of IGF-1 (increased by 86 ± 21ug/L) on the vasculature or reductions in VAT, C-reactive protein or triglycerides. Regardless, the composite cardiometabolic risk profile was markedly improved.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X13000535
Future directions and areas for research
Future directions in HAART
Newer antiretroviral agents and different HAART components are being developed. Non-ritonavir boosting agents such as cobicistat (GS-9350) which are thought to have less potential for the adverse effects of ritonavir on lipids and insulin sensitivity128 are currently in phase III trials and have the potential to be useful adjuncts with PIs, such as atazanavir or darunavir, or newer agents such as integrase inhibitors and CCR5 antagonists that do not appear to cause significant insulin resistance in early studies.129 In order to avoid the mitochondrial toxicity of NRTIs, the use of boosted PI monotherapy is currently being examined as a treatment option, particularly for individuals who are already virally suppressed.130
Research agenda
•Better data on prevalence of and risk factors for insulin resistance in HIV-infected patients;
•Does presence of insulin resistance play a role in increased cardiovascular disease prevalence in HIV?
•Examining insulin resistance and body fat changes in resource poor settings where tNRTIs are still commonly used;
•Studies examining effects of switching away from tNRTIs/PI on insulin resistance in larger groups;
•Effects of tesamorelin or IGF-1 agonists on insulin sensitivity;
•Close monitoring for IR with use of newer antiretroviral agents.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X10001727
6 Therapeutic perspectives of fatty liver in lipodystrophy
Currently, metreleptin, or in the future leptin analogues or leptin receptor agonists, are rational choice(s) for the treatment of lipodystrophy, representing a partial replacement treatment, when endogenous leptin levels are lower than normal. Other medications, especially those that would increase adiponectin levels in a condition characterized by low adiponectin, have also been used or tested in clinical trials. Other classes of medications, acting through other pathways or acting downstream of leptin and/or adiponectin, are currently in trials and may be used for the treatment of lipodystrophy. The hepatic effects of these medications are hereby presented. The proposed management of lipodystrophy with potential beneficial hepatic effect is presented in Fig. 4.
Fig. 4. Proposed management of lipodystrophy with potential beneficial hepatic effect. Diet and exercise is regarded as the standard care for all types of lipodystrophy. Fibrates should be used, if needed, for the management of hypertriglyceridemia in all types of lipodystrophy. Insulin should be used for the management of diabetes, if needed, in CGL and AGL, whereas TZDs may be initially used in partial lipodystrophy, including HAALS. Metreleptin seems to be beneficial for the treatment of steatosis and early NASH in patients with CGL and AGL, as well as in those with FPLD and APL. Existing data for metreleptin in HALS are not sufficient to propose for or against its use. Given the limited data, metreleptin use is not proposed for lipodystrophic patients with NASH and advanced fibrosis or cirrhosis (fibrosis stage 3–4), until novel data clarify the efficacy and safety of its use in these patients. In patients with partial lipodystrophy, including HALS, TZDs may exert beneficial effects on the liver, via upregulating adiponectin. In patients with acquired lipodystrophy, ADs, including autoimmune hepatitis, should be managed; the avoidance or minimization of corticosteroid would be beneficial for the liver. In patients with HALS, HIV infection should be managed preferably with newer HAART, considered to be less hepatotoxic. Furthermore, co-existing HCV and/or HBV infection should be managed. In the future, recombinant adiponectin may be used as a replacement treatment, possibly in all types of lipodystrophy, whereas, selective PPARγ modulators (e.g., INT131) may be also investigated.
Abbreviations: ADs, autoimmune diseases; AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; CGL, congenital generalized lipodystrophy; FPLD, familial partial lipodystrophy; GLP, glucagon-like peptide; HAART, highly active antiretroviral therapy; HALS, HIV-associated lipodystrophy syndrome; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PPAR, peroxisome proliferator-activated receptor; SGLT, sodium-glucose cotransporter; TZDs, thiazolidinediones.
6.1 Metreleptin
Despite the disappointing results of trials on recombinant leptin in common obesity and related disorders [3], metreleptin is valuable for patients with leptin deficiency, including those with lipodystrophy [95]. Although leptin replacement seems to ameliorate metabolic and non-metabolic derangements, and quality of life of lipodystrophic patients, data comes mainly from uncontrolled studies, and therefore randomized controlled trials (RCTs) are required. This is mainly due to the lack of a concerted effort by pharma to design multicenter RCTs and/or crossover RCTs that would be able to eliminate problems related to the rarity of disease. Progress in this area requires establishment and collaboration of multicenter registries to achieve sufficient numbers for double-blind, placebo controlled RCTs of adequate sample size [1]. Main characteristics of most relevant studies are the observational design, the relatively small sample size, the lack of control group and the high dropouts rates, which are summarized in Table 3, focusing on the hepatic effects of metreleptin.
Table 3. The effect of metreleptin on hepatic components in clinical studies with lipodystrophic patients.
| Referencea | Study design | Type of lipodystrophy | Metreleptin dose | Patients/controls (n; females; age [years]) | Duration | Baseline/repeat liver biopsy | Hepatic effect | Remarks |
|---|---|---|---|---|---|---|---|---|
| [101]c | Prospective case series, open label | CGL, FPLD or AGL | 0.015–0.08 mg/kg/d | 9; 9; 15–42/ NA | 4 mo | No/No | 1) Decrease in AST and ALT levels. 2) Decrease in hepatic volume (MRI). | |
| [61] | Prospective case series, controlled, open label; Group 1: CGL vs. Group 2: Control (baseline only) | CGL | 0.015–0.08 mg/kg/d | 3; 3; 26 ± 5/ 6; 6; 26 ± 5 | 3–8 mo | No/No | 1) Decrease in hepatic and systemic IR. 2) Decrease in hepatic lipid content. | |
| [69] | Prospective case series | CGL or AGL | 0.015–0.08 mg/kg/d | 3; 2; 15–33/ NA | 8–10 mo | No/No | Decrease in hepatic lipid content (MRS). | |
| [163]c | Prospective cohort, open label | CGL, FPLD or AGL | 0.015–0.08 mg/kg/d | 14; 11; 12–67/ NA | 1 y | No/No | Decrease in hepatic volume (MRI). | Data available for 8 patients at 12 mo. |
| [164]b | Prospective cohort, open label | GGL, FPLD or AGL | 0.015–0.06 mg/kg/d | 10; 8; 17–67/ NA | 4 mo – 1.5 y | Yes/Yes | 1) Decrease in AST and ALT levels. 2) Decrease in hepatic volume and liver fat content (MRI). 3) Decrease in NASH rates. 4) Improvement in steatosis and ballooning. 5) No effect on parenchymal inflammation and fibrosis. | |
| [108] | RCT, double-blind, crossover, placebo controlled Group 1: metreleptin vs. Group 2: placebo | HALS | 0.04 mg/kg/d | Group 1: 7; 0; 45.8 ± 2.0/ Group 2: 7; 0; 45.8 ± 2.0 | 2 mo | No/No | No effect on hepatic volume and lipid content (CT) | |
| [110]d | Prospective case series, open label | CGL | 0.015–0.06 mg/kg/d | 7; 1; 2–14/ NA | 4 mo | No/No | 1) Decrease in AST and ALT levels. 2) Decrease in hepatic volume (CT). | |
| [103] | Prospective case series, open label | CGL or AGL | 0.02–0.08 mg/kg/d | 7; 5; 11–29/ NA | 3 y | No/No | 1) Decrease in AST and ALT levels. 2) Improvement in liver-to-spleen ratio (CT) 3) Decrease in liver fat content (MRI; 1 patient). | |
| [98] | Prospective case series, open label | FPLD | 0.08 mg/kg/d | 6; 6; 33–64/ NA | 1 y | No/No | Modest, non-significant decrease in hepatic volume (MRI). | |
| [104] | Case report | FPLD | 0.08–0.12 mg/kg/d | 1; 1; 36/ NA | 1.5 y | No/No | Decrease in hepatic volume (MRI). | |
| [97] | Prospective case series, open label | AGL | 0.08 mg/kg/d | 2; 1; 13 & 14/ NA | 1 y | Yes/Yes | 1) Decrease in AST and ALT levels in patient #1, but increase in patient #2. 2) Decrease in hepatic volume (MRI). 3) Resolution of steatosis, but stable inflammation (patient #1). 4) Worsening of inflammation (patient #2). | 1) Both T1DM patients. 2) Worsening of pre-existing proteinuria (patient #2). 3) Patient #2 had been also on pioglitazone for 10 mo. |
| [112]d | Prospective case series, open label | CGL | 0.06–0.12 mg/kg/d | 8; 2; 5–16/ NA | 2.3 y | No/No | 1) Decrease in hepatic volume (CT; 5 patients). 2) Decrease in steatosis (CT; 5 patients) | |
| [99] | Prospective cohort, open label | CGL, FPLD, AGL or APL | 2.8 ± 0.4 mg/d (males) and 5.6 ± 0.3 mg/d (females) | 55; 44; 7–68/ NA | 2.5 y (<6 mo – 9 y) | No/No | Decrease in AST and ALT levels at 4 mo and sustained throughout 3 y. | 13 patients withdrew from the study. |
| [109] | RCT, double-blind, placebo controlled Group 1: metreleptin + pioglitazone vs. Group 2: pioglitazone | HALS | Metreleptin; 0.04 mg/kg/d + Pioglitazone; 30 mg/d vs. Pioglitazone; 30 mg/d | Group 1: 5; 0; 43–57/ Group 2: 4; 0; 43–57 | 3 mo | No/No | Non-significant decrease in AST and ALT levels in Group 1 and non-significant increase in AST and ALT levels in group 2. | |
| [96] | Case report | AGL | 0.06 mg/kg/d | 1; 1; 10/ NA | 2.5 y (intermittent) | Yes/Yes | 1) Decrease in AST and ALT levels after restarting metreleptin. 2) Histology (NASH) unchanged (at 2 y). | She received metreleptin for 2y, then she discontinued for 9 mo and restarted for at least 1 y. |
| [111] | Prospective, parallel group, open label; Group 1: severe hypoleptinemia vs. Group 2: moderate hypoleptinemia | FPLD | 0.08 mg/kg/d | Group 1: 14; 14; 40.8 ± 13.1/ Group 2: 10; 10; 36.3 ± 16.6 | 6 mo | No/No | 1) Decrease in AST levels in group 1, but not group 2. 2) ALT unchanged in both groups. 3) Similar decrease in hepatic lipid content in both groups (MRS) | |
| [73] | Case report | AGL | 0.08 mg/kg/d | 1; 1; 41/ NA | 6 mo | Yes/Yes | 1) Decrease in hepatic lipid content (MRS). 2) Resolution of NASH in the liver transplant. | Recurrence of NASH early after orthoptic liver transplantation. |
| [70]b | Prospective cohort, open label | CGL, FPLD, AGL or APL | 0.06–0.24 mg/kg/d | 50; 42; 26 ± 2/ NA | 4–68 mo | Yes/Yes (n = 27; 54%) | 1) Decrease in AST and ALT levels. 2) Decrease in NASH rates. 3) Improvement in steatosis, ballooning and NAS. 4) No effect on lobular and portal inflammation, and fibrosis. | 27 patients were included in the analysis. |
| [71] | Retrospective case series, open label | CGL or FPLD | 0.05–0.24 mg/kg/d | 9; 5; 2–43/ NA | 9 mo – 5 y | No/No | Decrease in AST, ALT and GGT levels in <6 mo. | |
| [100] | Prospective case series, open label | AGL | 0.02–0.04 mg/kg/d | 3; 2; 9–16/ NA | 3–6 y | No/No | 1) Decrease in AST, ALT and GGT levels at 6 mo. 2) Improvement in hepatomegaly (physical examination). | All patients had concomitant autoimmune diseases. |
| [68] | Prospective cohort, open label | FPLD or APL | 0.02–0.08 mg/kg/d | 23; 22; 63–67/ NA | 3 mo – 1 y | No/No | AST and ALT unchanged. | AST, ALT data available for 6 patients at 12 mo. |
| [102] | Prospective case series, open label | CGL or AGL | 0.06–0.13 mg/kg/d | 3; 2; 10–19/ NA | 3 mo – 3 y | No/No | Decrease in AST and ALT levels. | |
| [6] | Prospective cohort, open label | CGL, FPLD or AGL | 0.02–0.19 mg/kg/d | 53; 41; 0.5–18/ NA | 14 mo – 14.2 y | Yes (17; 32%)/ Yes (17; 32%) | 1) Decrease in AST and ALT levels. 2) Improvement in ballooning and NAS. 3) No effect on steatosis, lobular and portal inflammation, and fibrosis. | |
| [105] | Prospective cohort, open label | CGL or AGL | 0.03–0.21 mg/kg/d | 66; 51; 1–68/ NA | 63 ± 46 mo | No/No | 1) Decrease in ALT levels. 2) Decrease in hepatic volume (MRI). | |
| [106] | Non-randomized, cross-over | CGL, FPLD or AGL | 10 mg/d | 23; 17; 14–70/ NA | 14d and 6 mo | No/No | 1) Increase in insulin sensitivity and decrease in hepatic fat after treatment initiation independently from its effect on food intake. 2) Decrease in insulin sensitivity after treatment discontinuation. |
Studies with nine or less patients were conventionally considered as case series, whereas those with 10 or more patients as cohort studies.
Abbreviations: AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CGL, congenital generalized lipodystrophy; CT, computed tomography; d, day(s); FPLD, familial partial lipodystrophy; GGT, gamma-glutamyltransferase; HALS, HIV-associated lipodystrophy syndrome; HIV, human immunodeficiency virus; IR, insulin resistance; mo, months; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NA, not applicable; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; RCT, randomized controlled trial; T1DM, diabetes mellitus type 1; y, years.
aReferences are presented in publication time order.bThe Safar Zadeh et al. study includes partial data of 10 patients previously described by Javor et al. study.cThe Moran et al. study possibly includes partial data of patients previously described by Oral et al. study.dThe Beltrand et al. (2007) study includes the 4-mo data of 7 of 8 patients described by Beltrand et al. (2010) study.As expected, metreleptin treatment increased circulating leptin levels in all studies. However, it should be emphasized that measuring leptin levels provides a non-specific indication for the diagnosis and follow-up of patients with lipodystrophy. After metreleptin treatment, the interference of anti-leptin antibodies with leptin assays renders the interpretation of leptin measurements difficult. There is also lack of standardized leptin assays among laboratories and thus absence of widely applicable cut-off diagnostic criteria, which further complicates the interpretation of leptin measurements [1]. It should be underlined that, despite ameliorating the metabolic derangements of lipodystrophy, metreleptin does not cause regeneration of adipose tissue [96].
Specifically for the liver, metreleptin decreased AST and ALT levels, hepatic volume and hepatic fat in most studies (Table 3). Mean NAFLD activity score (NAS) improved in cohorts with paired liver biopsies after metreleptin treatment [6,70]. However, improvement occurred in approximately 65–75% of patients, whereas NAS remained unchanged or even worsened in some patients [6,70]. Concomitant autoimmune hepatitis may be hypothesized as a possible cause of no improvement or worsening [6,97], thus possibly relating more with the disease itself rather than metreleptin treatment, but the numbers of cases are too limited to reach safe conclusions. Regarding specific hepatic lesions, ballooning was improved in both cohorts [6,70] and steatosis in one of them [70]. On the other hand, lobular and portal inflammation, and fibrosis remained largely unchanged after metreleptin treatment (Table 3). The effect of metreleptin on hepatic components seems to be less prominent in FPLD patients, similar to its effect on glucose and triglyceride levels [68,71,98].
Regarding liver cirrhosis, in one of the above cohorts [70], one patient had stable liver function and thrombocytopenia, and another had stable hepato-pulmonary syndrome during 6.5 and 3.5 years on metreleptin, respectively. A third patient with esophageal varices, splenomegaly, thrombocytopenia and prior episodes of hepatic encephalopathy, experienced an additional episode of hepatic encephalopathy during 2 years on metreleptin. A fourth patient died of hepatic failure after 1.5 years of metreleptin treatment [70]. In the above pediatric cohort, three patients with cirrhosis prior to metreleptin treatment died of complications of cirrhosis after four, six, and 12 years of metreleptin treatment [6]. However, the cases are very limited to support an adverse effect of metreleptin in advanced NASH and NASH-related cirrhosis; in this regard, they may simply represent the natural history of NASH-related cirrhosis, but it remains to be shown. Regarding liver transplantation, there is only one case with early recurrence of NASH, in whom metreleptin improved steatosis and resolved NASH within 6 months [73].
A parallel decrease in IR, glycated hemoglobin (HbA1c), triglyceride levels and insulin requirements were reported in most studies [70,71,99–106]. In a meta-analysis, metreleptin was shown to decrease glucose, HbA1c, triglycerides and total cholesterol, but not insulin, high- (HDL-C) and low-density lipoprotein cholesterol (LDL-C) [107]. Hepatic fat and IR are specifically improved after metreleptin treatment, as reflected by increased insulin suppression of glucose production during the hyperinsulinemic clamp [61,106]. Importantly, the effect of metreleptin on hepatic IR and fat are independent from its effect on food intake [106].
Discontinuation of leptin results in rapid deterioration of metabolic abnormalities, including LFTs, which, however, improve again, if metreleptin restarts [96]. Metreleptin discontinuation may unmask the worsening of metabolic abnormalities that occur due to the natural history of the disease [96].
Metreleptin was also administered in patients with HALS in two proof-of-concept RCTs. Although metreleptin had a beneficial metabolic effect in both of these studies, it tended to, but did not significantly decrease hepatic volume and lipid content [108] or LFTs [109]. However, studies of larger samples and longer duration are required in HALS.
Metreleptin was generally well tolerated with usually mild and transient side effects, including injection site events (erythema, urticarial), decreased appetite, weight loss, fatigue, nausea, vomiting, flushing, urinary tract infections and myalgia [6,68,99,101,105,110,111]. Hypoglycemia has been also reported [6,68,99,105,111], but it usually occurs due to inappropriate adjustment of concomitant anti-diabetic treatment, mainly insulin. Sporadic cases of peripheral T-cell lymphoma have been described [6,105], but it is unknown whether they are related to metreleptin or the natural course of the disease.
Other reported side effects, e.g., alopecia [99], myopathy [71], autoimmune hepatitis [70], worsening of pre-existing proteinuria [97], may not be related to metreleptin, since autoimmune diseases may coexist, most commonly with AGL and APL [15,97]. Notably, metreleptin did not appear to alter the clinical course of autoimmune diseases nor clinical efficacy of immunosuppressive treatments [100]. The development of binding antibodies to metreleptin has been reported in two of seven patients in one study [69], one of three patients in another [100] and two of 53 in a third one [6]. In a pediatric cohort, binding antibodies increased in all patients at 28 months, but more dramatically in patients with negative response to treatment [112]. Antibodies are not an issue in most protein therapeutics to the extent they are not usually neutralizing; neutralizing antibodies have been rarely reported with the current metreleptin formulation; neutralizing antibodies have been associated with reduced metreleptin efficacy, but not consistently with adverse clinical consequences [113]. Newer leptin analogues, currently in development, are not expected to have these side effects.
6.2 Adiponectin
Apart from leptin, adiponectin administration seems to be an appealing strategy for a more integrated management of lipodystrophy, including a potentially beneficial hepatic effect. Adiponectin is considered to exert hepatic anti-steatotic, anti-inflammatory, anti-fibrotic and anti-apoptotic effects in cell lines and animal models [114]. In non-lipodystrophic individuals, lower levels of adiponectin in patients with SS than controls, and even lower in those with NASH were shown in a meta-analysis [14]. However, producing functionally active recombinant adiponectin is demanding, since it needs extensive post-translational modifications and appropriate multimerization [115]. Adiponectin analogues could be an alternative option. For example, osmotin, a plant antifungal protein, has been proposed as an adiponectin analogue [116], which has recently shown beneficial hepatic effects in ob/ob and db/db mice by activating adiponectin receptors (AdipoR1/R2) and their downstream pathways [117]. This finding warrants investigation of osmotin or other adiponectin analogues in lipodystrophy.
Except for recombinant adiponectin and adiponectin analogues, upregulation of endogenous adiponectin seems a rational approach in lipodystrophy. Towards this goal, TZDs have been tested, whereas the use of SPARMs is emerging and promising. However, the use of these medications theoretically requires a remaining functional adipose tissue (i.e., FPLD, APL, HAALS), whereas recombinant adiponectin or its analogues might be useful even in the total absence of adipose tissue (i.e., CGL, AGL).
6.2.1 ThiazolidinedionesTZDs are a family of compounds binding to PPARγ and thus causing redistribution of adipose tissue to subcutaneous compartment and activating several downstream molecules, including elevating adiponectin, thereby improving IR. In non-lipodystrophic patients with NAFLD, pioglitazone showed favorable effects, including improvement in steatosis and inflammation and has been proposed for the management of NAFLD [118]. The studies reporting the hepatic effects of TZDs in patients with lipodystrophy are summarized in Table 4. Troglitazone was the first TZD used in patients with lipodystrophy. It decreased the hepatic volume, in parallel with its beneficial effect on HbA1c and triglycerides, but was discontinued in 10% of lipodystrophic patients due to ALT increase, possibly due to drug hypersensitivity [119]. Troglitazone, officially introduced for T2DM treatment, was withdrawn due to relatively rare, but severe, hepatic failure [120].
Table 4. The effect of insulin sensitizers (metformin and thiazolidinediones) on hepatic components in clinical studies with lipodystrophic patients.
| Referencea | Study design | Type of lipodystrophy | Medication; dose | Patients/controls (n; females; age [years]) | Duration | Baseline/repeat liver biopsy | Hepatic effect | Remarks |
|---|---|---|---|---|---|---|---|---|
| Metformin | ||||||||
| [138] | RCT, double-blind, placebo controlled Group 1: metformin vs. Group 2: placebo | HALS | Metformin; 1000 mg/d | Group 1: 14; 3; 44.1 ± 2.1/ Group 2: 12; 3; 45.6 ± 1.9 | 3 mo | No/No | No effect on AST levels. | |
| Thiazolidinediones | ||||||||
| [119] | Prospective cohort, open label | CGL, FPLD, AGL or APL | Troglitazone; 200–600 mg/d | 20; 18; 6–65/ NA | 6 mo | No/No | Decrease in hepatic volume (MRI). | 1) Two patient discontinued treatment because of increase in ALT levels. 2) No effect on leptin levels. |
| [77] [76,122] | RCT, double-blind, placebo controlled Group 1: rosiglitazone vs. Group 2: placebo | HALS | Rosiglitazone; 8 mg/d | Group 1: 15; 3; 44 ± 3/ Group 2: 15; 2; 42 ± 2 | 6 mo | No/No | 1) Decrease in ALT levels. 2) Decrease in liver fat (MRS). | |
| [123] | Case report | HALS | Pioglitazone; 30 mg/d | 1; 1; 50/ NA | NA | No/No | Decrease in steatosis (CT) | |
| [132] | Case report | FPLD | Pioglitazone; 15–30 mg/d | 1; 1; 25/ NA | 1.5 y | No/No | 1) Decrease in AST and ALT levels. 2) Improvement of steatosis (US) | |
| [124] | RCT, double-blind, placebo controlled Group 1: rosiglitazone vs. Group 2: placebo | HALS | Rosiglitazone; 8 mg/d | Group 1: 23; 2; 46.7 ± 2.1/ Group 2: 17; 1; 45.4 ± 2.1 | 6 mo | No/No | 1) No effect on AST, ALT and GGT levels. 2) No effect on hepatic IR. 3) No effect on hepatic insulin clearance. | |
| [165] | Prospective case series, open label | FPLD | Rosiglitazone; 8 mg/d | 5; 4; 19–50/ NA | 1 y | No/No | Decrease in AST and ALT levels. | |
| [121] | Prospective case series, open label | FPLD | Rosiglitazone; 8 mg/d | 2; NA; 14 & 16/ NA | 1.8 y | No/No | Decrease in liver fat content (MRI). | |
| [166] | Case report | AGL | Pioglitazone; 15 mg/d | 1; 0; 19/ NA | 1.5 y | No/Yes (after treatment) | 1) Slight decrease in AST and ALT levels. 2) Slight improvement in steatosis (transient elastography). | The patient received metreleptin (0.02 mg/kg/d) after pioglitazone, but was not compliant to treatment. |
| Head-to-head comparisons | ||||||||
| [128] | Randomized, 2 active arms, open label, no placebo Group 1: metformin vs. Group 2: rosiglitazone | HALS | Metformin; 1000 mg/d vs. Rosiglitazone; 8 mg/d | Group 1: 18; 3; 48 ± 2/ Group 2: 19; 3; 47 ± 2 | 6 mo | No/No | Similar decrease in AST and ALT levels in both groups. |
Studies with nine or less patients were conventionally considered as case series, whereas those with 10 or more patients as cohort studies.
Abbreviations: AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CGL, congenital generalized lipodystrophy; CT, computed tomography; d, day(s); FPLD, familial partial lipodystrophy; GGT, gamma-glutamyltransferase; HALS, HIV-associated lipodystrophy syndrome; HIV, human immunodeficiency virus; mo, months; IR, insulin resistance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NA, not applicable; RCT, randomized controlled trial; US, ultrasound; y, years.
aReferences are presented primarily in pharmaceutical category order and secondarily in publication time order.Both rosiglitazone [121,122] and pioglitazone [123] decreased LFTs and hepatic fat and this has also been shown in HALS [76,77,122], although no effect of rosiglitazone on LFTs was reported in one study with HALS [124] (Table 4). This effect was similar to that shown in NASH patients without lipodystrophy [125–127].
Despite an increase in subcutaneous fat reported in one study after rosiglitazone treatment in HALS [128] and in two cases with FPLD [121], both pioglitazone and rosiglitazone do not generally seem to affect body weight, subcutaneous and visceral fat in lipodystrophic patients, including HALS [76,77]. Even long-term (up to eight years) treatment with rosiglitazone and pioglitazone in two patients with FPLD did not restore adipose tissue in lipodystrophic areas [129]. To compare with, in T2DM patients, rosiglitazone increases fat mass by 3–4 kg in 12 weeks [130,131]. Likewise, TZDs increase body weight and fat in NASH patients without lipodystrophy [127]. It seems that TZDs affect subcutaneous and total body fat in non-lipodystrophic individuals, whereas they have limited or null effect in lipodystrophic ones, in whom adipose tissue does not exist or is dysfunctional. This may be the reason why TZDs were evaluated to the most in patients with partial lipodystrophy and HALS, in whom a residual adipose tissue function exists. On the other hand, the near total absence of fat in patients with generalized lipodystrophy renders the effect of TZDs rather questionable (Table 4).
A parallel decrease in glucose and insulin levels and/or HbA1c and IR has been reported after rosiglitazone [76,121,122,124,128] and pioglitazone [132]. As expected, insulin requirements decrease during TZD treatment and rise upon their discontinuation [97]. TZDs also increased adiponectin, but not leptin levels, which is reported mainly in patients with HALS [76,77,122,124,133]. Importantly, adiponectin change was inversely associated with ALT and hepatic fat change [122], which implies that the effect of TZDs is mediated, at least partly, through adiponectin, similar to non-lipodystrophic NASH patients [120].
The effect of rosiglitazone and pioglitazone on triglyceride levels seems to differ in lipodystrophy, similarly to non-lipodystrophic NASH patients [125–127]. More specifically, pioglitazone improves triglycerides [123,132], whereas rosiglitazone increases them [77,122,128]. Furthermore, rosiglitazone increased total cholesterol [77,122] and LDL-C [124] in HALS and increased remnant-like particle cholesterol [128]. These effects of rosiglitazone on lipid profile may adversely affect cardiovascular risk in lipodystrophy, a population with a high cardiovascular risk.
Both pioglitazone and rosiglitazone were reportedly well tolerated in lipodystrophy. No serious events have been reported, including bladder cancer or osteoporotic fractures.
6.2.2 Selective PPARγ modulatorsCurrently, the use of rosiglitazone has been restricted in practice, because of an alleged increase in myocardial infarction risk shown in non-lipodystrophic patients [134], and pioglitazone use has been suspended in some European countries because of a possibly slight increase in bladder cancer risk after long-term use in T2DM patients [135]. In light of these considerations, SPARMs have been developed, including INT131. INT131 is a potent non-thiazolidinedione SPARM designed to exhibit a biological profile of strong efficacy, but minimal side effects compared to PPAR-γ full agonists [120]. Phase I studies in non-lipodystrophic individuals have shown that adiponectin increases in response to INT131 in both a dose and a time dependent manner. In phase 2 trials, INT131 was well tolerated, improved glycemic profile and increased adiponectin in T2DM patients in a dose-dependent manner, similarly to maximum dose of pioglitazone (45 mg/d) [136]. Importantly, less adverse effects, including edema, fluid retention and weight gain were observed compared with rosiglitazone or pioglitazone [120]. Based on these observations, INT131 and other SPARMs that may follow seem to be promising candidates for clinical trials in patients with partial lipodystrophy and HALS, with the potential to improve both glucose metabolism and NAFLD.
6.3 Other medications
Among the oral antidiabetic medications, metformin has been used more frequently in lipodystrophy [15], due to its low cost and long-term availability. Most data for metformin are derived from studies in HALS. Together with a favorable effect on glucose and lipid metabolism [128,137,138], metformin decreased LFTs in some [128], but not all studies (Table 4). It should be underlined that metformin decreased subcutaneous and/or visceral fat [128,137,138]; the decrease in fat mass results in a general IR decrease, which is favorable in non-lipodystrophic T2DM patients, but not in those with lipodystrophy. Therefore, metformin is discouraged in patients with lipodystrophy.
Other medications have also been used in lipodystrophy with, however, minimal or null hepatic effect. Among anti-diabetic drugs, sulfonylureas showed limited efficacy [65]. Glucagon-like peptide (GLP)-1 analogues, including exenatide and liraglutide, showed a beneficial effect on IR in some lipodystrophic patients [139,140], but whether their hepatic effect resembles that of non-lipodystrophic NAFLD patients [141], remains to be shown. Furthermore, ipragliflozin, a sodium–glucose cotransporter (SGLT)-2 inhibitor, showed beneficial effect on steatosis in a patient with CGL [142], as shown in non-lipodystrophic NAFLD.
Growth hormone (GH) deficiency has been associated with both lipodystrophy and NAFLD. HAART in HIV patients alters GH secretion and about one-third of patients have biochemical GH deficiency [143]. Therefore, medications acting on GH axis, including recombinant GH, GH releasing hormone (GHRH) and IGF-1, have been tested for the treatment of HALS [144]. A meta-analysis showed that both recombinant GH and tesamorelin, a GHRH analogue, reduced visceral adipose mass, but only recombinant GH reduced subcutaneous adipose mass [144]. Thus, tesamorelin may be more promising and safer than treatment with recombinant GH for lipodystrophy [143], since the reduction in subcutaneous fat is not desirable in patients with lipodystrophy. The combination of rosiglitazone and recombinant GH may be preferable than GH monotherapy for HALS, since the TZD may abrogate the increase in IR induced by the recombinant GH [145].
Uridine supplementation has been launched as an approach against HAART-associated mitochondrial toxicity. Its beneficial effect on hepatic mitochondrial function was shown in thymidine-analogue treated HIV patients [146]. However, uridine did not affect hepatic fat content and ALT levels in HALS, despite increasing in subcutaneous and/or abdominal adipose mass [147,148].
Cholic acid, a farnesoid X receptor (FXR) agonist, a promising target for the treatment of NASH [141], has been evaluated in a 1-year, double-blind, placebo controlled RCT in patients with FPLD and AGL [149]. Although well tolerated, cholic acid did not affect hepatic triglyceride content or LFTs [149].
Although hypolipidemic medications, including statins, fibrates, ezetimibe, niacin and omega-3 were or are still in use for lipodystrophy [15], and some of them have been proved beneficial for NAFLD in non-lipodystrophic patients [10,141,150], data on their hepatic effects in lipodystrophy are limited. “Heart positive” was an RCT designed to evaluate the effect of niacin, fenofibrate or both medications in HALS [151], but the results of this study have not been reported, possibly due to niacin withdrawal from the market.
Ongoing clinical trials in lipodystrophic patients with primary or secondary hepatic outcomes are summarized in Table 5. There are also many other drugs under investigation for NAFLD in non-lipodystrophic patients, including obeticholic acid and tropifexor (FXR agonists), cenicriviroc (chemokine receptors 2/5 inhibitor), elafibranor (PPARα/δ ligand), saroglitazar (PPARα and PPAR γ agonist), IVA337 (pan-PPARγ agonist), emricasan (caspase inhibitor), selonsertib (apoptosis signaling kinase-1 inhibitor), MGL-3196 (thyroid hormone receptor-β agonist), aramchol (SCD1 inhibitor), BMS 130-045 (pegylated fibroblast growth factor-21) [152]. However, the translation of results of these RCTs in non-lipodystrophic NAFLD patients should be cautiously interpreted, and not be used without trials evaluating their efficacy and safety specifically in lipodystrophic NAFLD patients.
Table 5. Clinical trials for the treatment of lipodystrophy in “recruiting” or “active status” with primary or secondary hepatic outcomes.
| Medication | Disease | Class/mechanism of action | Hepatic outcomes | Status | Sponsor | Primary completion date |
|---|---|---|---|---|---|---|
| ISIS 304801 (Volanesorsen) | FPLD | ASOs for reduction of apoC-III | Hepatic steatosis (MRI) | Phase 2/3 | IONIS Pharmaceuticals | 09/30/2018 |
| ISIS 304801 | Partial lipodystrophy | ASOs for reduction of apoC-III | Hepatic steatosis (MRI) | Phase 2 | NIDDK | 12/31/2018 |
| ISIS 703802 | FPLD | Reduction of ANGPTL3 | Hepatic steatosis (MRI) | Phase 2 | Akcea Therapeutics | 04/30/2019 |
| Gemcabene | FPLD | Small molecule reducing LDL-C and TGs by inhibiting hepatic TG and cholesterol synthesis, and by increasing VLDL-C clearance | Hepatic fat content (MRI-PDFF) Hepatic fibrosis (magnetic elastography) | Phase 1 Phase 2 | University of Michigan | 03/01/2020 |
| Obeticholic acid | FPLD | Selective FXR agonist | Hepatic TG (MRS) | Phase 2 | UT Southwestern Medical Center | 09/2018 |
| Aramchol | HALS | FABACs | Hepatic steatosis (MRI) Serum ALT and AST levels | Phase 2 | University of California | 09/30/2018 |
| Tesamorelin | HALS | Synthetic GHRH | Hepatic lipid content (MRI) | Phase 4 | Columbia University | 04/30/2021 |
Abbreviations: ALT, alanine aminotransferase; ANGPTL, angiopoietin-like; AST, aspartate aminotransferase; apo, apolipoprotein; ASOs, anti-sense oligonucleotides; FABACs, fatty-acid/bile-acid conjugates; FPLD, familial partial lipodystrophy; FXR, farnesoid X receptor; GHRH, growth-hormone-releasing hormone; HALS, HIV-associated lipodystrophy syndrome; HIV, human immunodeficiency virus; LDL-C, low-density lipoprotein cholesterol; MRI, magnetic resonance imaging; MRI-PDFF, MRI-proton density fat fraction; MRS, magnetic resonance spectroscopy; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol.
URL: https://www.sciencedirect.com/science/article/pii/S0026049519300897
Treatment with highly active antiretroviral drugs (HAART) is associated with several endocrine and metabolic comorbidities. Pituitary growth hormone (GH) secretion seems to be altered in human immunodeficiency virus (HIV) infection, and about one-third of patients have biochemical GH deficiency (GHD). We undertake a historical review of the functioning of the GH/insulin-like growth factor-1 (IGF-1) axis in patients with acquired immunodeficiency syndrome, and provide an overview of the main changes of the GH/IGF-1 axis occurring today in patients with HIV. Both spontaneous GH secretion and GH response to provocative stimuli are reduced in patients with HIV infection, especially in those with HIV-related lipodystrophy. The role of fat accumulation on flattened GH secretion is discussed, together with all factors able to potentially interfere with the pituitary secretion of GH. Several factors contribute to the development of GHD, but the pathophysiologic mechanisms involved in the genesis of GHD are complex and not yet fully elucidated owing to the difficulty in separating the effects of HIV infection from those of HAART, comorbidities and body changes. An update on the putative mechanisms involved in the pathogenesis of altered GH secretion in these patients is provided, together with an overview on the therapeutic strategies targeting the GH/IGF-1 axis to counteract fat redistribution associated with HIV-related lipodystrophy. The clinical significance of GHD in the context of HIV infection is discussed. The administration of tesamorelin, a GH releasing hormone analogue, is effective in reducing visceral fat in HIV-infected patients with lipodystrophy. This treatment is promising and safer than treatment with high doses of recombinant human growth hormone, which has several side-effects.
URL: https://www.sciencedirect.com/science/article/pii/S1521690X17300064