Efficacy and Safety of Tesamorelin in People Living With HIV (PLWH) With Lipodystrophy: A Systematic Review and Meta-Analysis

Abstract

Background

HIV-associated lipodystrophy, a complication of combined antiretroviral therapy (CART), causes significant physical and psychological distress in people living with HIV (PLWH), compromising treatment adherence. Tesamorelin, a growth hormone-releasing hormone (GHRH) analogue, has emerged as a therapeutic option.

Objective

To systematically evaluate the efficacy and safety of tesamorelin in HIV-infected individuals with lipodystrophy receiving CART, incorporating GRADE assessment.

Methods

We searched PubMed, https://ClinicalTrials.gov, and Scopus from inception to February 9, 2026, for randomized controlled trials evaluating tesamorelin in HIV-associated lipodystrophy. Mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using random-effects models with heterogeneity assessed by I².

Results

Four RCTs (909 patients) were included. Tesamorelin 2mg significantly reduced visceral adipose tissue (MD= -21.47, 95%CI[-34.73,-8.22],I²=74%,p=0.002), waist circumference (MD-1.61cm,95% CI[-2.28,-0.95],I²=0%,p<0.00001), trunk fat (MD-1.20kg, 95%CI[-1.47,-0.93],I²=0%,p<0.00001), and increased lean body mass (MD1.42kg,95% CI[1.13,1.71],I²=0%,p<0.00001). Modest lipid improvements occurred in total cholesterol (MD-0.16mmol/L,95%CI[-0.27,-0.06],I²=0%,p=0.003). Growth hormone-related adverse effects and higher discontinuation rates (RR2.25,95%CI[0.98,5.17],p=0.06) were observed.

Conclusions

Tesamorelin demonstrates efficacy in reducing visceral adiposity in PLWH with lipodystrophy on CART. However, limited data on long-term safety, optimal dosing strategies, and durability of treatment effects warrant caution. Future research should evaluate extended treatment duration, dose-response relationships, and patient-reported outcomes to establish comprehensive clinical utility.

Plain Language Summary

Rarely, people living with HIV can develop changes in their normal body fat distribution, known as lipodystrophy, as a side effect of their treatment with cART. This can cause physical discomfort and emotional distress, and may affect their will to continue their medication. Tesamorelin is a medication that may help reduce these fat changes. In this study, we reviewed and combined results from four clinical trials involving 909 people with HIV. We found that tesamorelin helped reduce harmful fat around the abdomen, and reduced waist size and trunk fat. It also increased lean body mass and slightly improved cholesterol levels. However, some side effects related to growth hormone were reported, and more people stopped treatment compared to those not receiving the drug. Overall, tesamorelin appeared quite useful as long as it is continued, but more research is needed to understand its long-term safety and benefits.

1. Introduction

The introduction of combined antiretroviral therapy (CART) transformed HIV infection into a manageable chronic condition, dramatically reducing AIDS-related mortality and morbidity. ¹ However, this therapeutic revolution was accompanied by the emergence of HIV-associated lipodystrophy, a complex syndrome characterized by abnormal fat redistribution including subcutaneous fat loss (lipoatrophy), visceral fat accumulation (lipohypertrophy), or a mixed presentation of both phenotypes.^2,3 Prevalence estimates vary widely from 10% to 83%, reflecting differences in study design, diagnostic criteria, and follow-up duration.^4,5

HIV-associated lipodystrophy represents a significant clinical challenge beyond its physical manifestations like facial lipoatrophy and central adiposity, profoundly impacting quality of life.^6,7 This compromises adherence to life-saving antiretroviral therapy, with studies demonstrating that lipodystrophy-related symptoms independently predict treatment non-adherence.^8,9 Furthermore, visceral adipose tissue accumulation is associated with serious metabolic complications including insulin resistance, dyslipidemia, hepatic steatosis, and increased cardiovascular risk (CVS risk).^10,11 The pathophysiology of which is multifactorial, involving direct HIV insults, antiretroviral drug-induced toxicity and hormonal dysregulations.^12,13

Although the incidence of severe lipodystrophy has declined with newer antiviral agents, adipose tissue alterations with weight gain persists. ¹⁴ Recent evidence suggests that modern therapies, while causing less overt lipodystrophy, are associated with hypertrophy of specific fat depots contributing to CVS risk. ⁴ Management options are limited, with antiretroviral switching, insulin sensitizers, and surgical interventions yielding modest and often transient benefits. ¹⁵

Tesamorelin, a synthetic 44-amino acid analogue of human growth hormone-releasing hormone (GHRH) with enhanced resistance to enzymatic degradation, was developed to address the reduced growth hormones levels in PLWH.^16,17 Unlike direct growth hormone administration, it stimulates endogenous pulsatile growth hormone secretion through pituitary somatotroph stimulation, thereby increasing insulin-like growth factor-1 (IGF-1) and promoting selective visceral fat reduction.^18,19 Tesamorelin received FDA approval in 2010 as the first and only pharmacological treatment specifically indicated for excess abdominal fat in HIV-associated lipodystrophy following pivotal randomized controlled trials demonstrating visceral adipose tissue reduction.^20,21

Despite accumulating clinical evidence, important questions remain regarding tesamorelin’s comprehensive effects on body composition, metabolic parameters, and safety profile. ²² We conducted a comprehensive systematic review and meta-analysis incorporating GRADE assessment to evaluate the efficacy and safety of tesamorelin in PLWH with lipodystrophy receiving CART, with particular attention to body composition changes, metabolic outcomes, and adverse event profiles across different treatment durations.

2. Methods

This study-level meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. ²³

2.1. Search Strategy and Information Sources

A comprehensive search across PubMed, https://ClinicalTrials.gov, and Scopus from inception to February 9, 2026, was conducted. The search strategy included Medical Subject Headings (MeSH) terms and free-text keywords related to the intervention, condition, and population. Search fields included title, abstract, and keywords with no language or publication date restrictions. Reference lists of included studies and relevant systematic reviews were manually screened to identify additional eligible trials. The detailed search strategy is presented in the Supplementary File (Appendix 1).

2.2. Study Selection Criteria

Studies were included if they met the following criteria: (1) randomized controlled trial (RCT) design; (2) enrolled adults (≥18 years) with HIV infection and documented antiretroviral therapy-associated lipodystrophy characterized by excess visceral abdominal fat; (3) administered tesamorelin 2mg subcutaneously as the intervention; (4) included placebo as the comparator; and (5) reported at least one of the following outcomes of interest: change in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), lean body mass (LBM), body composition parameters, lipid profile, glucose metabolism markers, or safety outcomes.

Studies were excluded if they: (1) utilized non-randomized designs (2) lacked sufficient quantitative data (3) enrolled patients with congenital or non-HIV-related acquired lipodystrophy; (4) evaluated tesamorelin doses other than 2mg subcutaneously; or (5) were not published in English.

2.3. Study Selection Process

Records were imported on Rayyan, and duplicates were removed. Two authors independently screened the articles initially followed by full texts assessment of the remaining articles based on predefined inclusion criteria. Disagreements or conflicts were resolved through discussion with a third independent reviewer.

2.4. Data Extraction

Three independent reviewers extracted data from the included studies, focusing on study characteristics (authorship, publication year, study design, trial type, and follow-up duration), population details (age and gender), interventions, comparators, and efficacy and safety outcomes and data were entered into standardized Google sheet. Discrepancies were resolved by a fourth independent reviewer. All outcome measures were converted into SI units where needed.

2.5. Risk of Bias Assessment

The Cochrane Risk of Bias 2.0 (RoB 2.0) tool was used to assess risk of bias across five domains, including: (1) the randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) outcome measurement, and (5) selection of reported results. Studies were categorized as having a low risk of bias, high risk of bias, or some concerns, based on information provided in the study reports. The risk of bias was visualized using Risk-of-Bias VISualization (robvis), a web-based tool developed with R and Shiny application. ²⁴

2.6. Outcome Measures and Statistical Analysis

The primary outcomes were changes in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), waist circumference (WC), and lean body mass (LBM). Secondary outcomes included changes in limb fat, trunk fat, body mass index (BMI), VAT/SAT ratio, lipid parameters (triglycerides, total cholesterol, HDL cholesterol, total cholesterol/HDL ratio), glycemic indices (fasting blood glucose, 2-hour oral glucose tolerance test, fasting insulin), CD4 count, and insulin-like growth factor-1 (IGF-1). Safety outcomes comprised serious adverse events, discontinuations due to adverse events, and specific treatment-emergent adverse events including arthralgia, injection site bruising, upper respiratory tract infection, nasopharyngitis, paresthesia, headache, diarrhea, limb pain, and myalgia. Pooled mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using random-effects model and the Mantel-Haenszel method. Statistical heterogeneity was assessed using Higgins I² statistics (I² <50%– low, 50-75% –moderate, >75%– substantial). Statistical significance was set at p<0.05. Leave-one-out sensitivity analyses were conducted. Data from the longest follow-up period were extracted from included studies to avoid unit-of-analysis errors. Subgroup analyses stratified by treatment duration (short-term <26 weeks versus long-term ≥26 weeks) were performed to explore temporal effects on clinical outcomes. Publication bias assessment using funnel plots was not conducted. All statistical analyses were performed using Review Manager (RevMan) version 5.4 (The Cochrane Collaboration, 2020).

2.7. Certainty of Evidence

It was assessed by two reviewers independently, using the GRADE approach. The Summary of Findings table was generated using GRADEpro software.

3. Results

3.1. Study Selection Process

The search string yielded 150 references from three databases. After removing 31 duplicates in Rayan, 190 records were screened based on titles and abstracts, resulting in 19 relevant studies. After reviewing their full texts, 4 studies met our inclusion criteria for this systemic review and meta-analysis. The study selection process is illustrated in the PRISMA flow chart (Figure 1).

Figure 1.

PRISMA flow diagram illustrating the results of the study selection process

*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. ²³

3.2. Risk of Bias Assessment

The risk of bias for included randomized controlled trials was evaluated using Cochrane Risk of Bias 2.0 (RoB 2.0) tool, assessing five domains: randomization process, deviation from intended interventions, missing outcome data, measurement of outcome, and selection of reported result. Two studies Falutz et al 2010 and Stanley et al 2019 were assessed to have low risk of bias, with adequate random sequence generation and allocation concealment, minimal deviations from intended interventions, low level of missing outcome data, and blinded outcome assessment with reduced risk of selective reporting bias. And two studies, Falutz et al 2005 and Falutz et al 2007 were assessed to have overall high risk of bias due to missing outcome data and bias in selection of the reported result (Figure S2 and S3).

3.3. Baseline Characteristics and Patients’ Demographics

Across the four randomized controlled trials (RCTs), 909 patients were included. They had mean age of 48.5 years, with predominantly male population making up to 83.4 % of demographics and only 16.6% of females. Most participants were White, followed by Black and other ethnicities. The mean BMI was 29.1(4.4) kg/m² with waist circumference of 104.79 (9.8) cm. The mean Waist-Hip Ratio was 1.04(0.06). The duration of follow up was from 12 weeks to 52 weeks (Table 1).

Table 1.

Baseline Characteristics of Included Studies

Baseline variables	Falutz et al 2005		Falutz et al 2007		Falutz et al 2010		Stanley et al 2019
	TESA	Placebo	TESA	Placebo	TESA	Placebo	TESA	Placebo
Dose	2mg		2mg		2mg		2mg
Country	USA, Canada		USA, Canada		USA, Canada, France, Spain Belgium		USA
Duration (weeks)	12		26		26		52
Sample size (n)	21	21	273	137	270	126	31	30
Age (years), Mean SD	44.6 (7.1)	46.5 (6.4)	47.3 (7.3)	48.3 (7.5)	47.7 (7.5)	47.7(7.7)	52 (8)	54 (7)
White n(%)	17 (81)	18 (85.7)	209 (76.6)	99 (72.3)	209(77.4)	96 (76.2)	21 (67.7)	19 (63.3)
Black n(%)	2 (9.5)	1 (4.8)	37 (13.6)	22(16.1)	34 (12.6)	12 (9.5)	8 (25.8)	10 (33.3%)
Male n (%)	18 (85.7)	18 (85.7)	237 (86.8)	115(83.9)	228 (84.4)	105 (83.3)	24 (77.4)	24 (80%)
Female n (%)	3 (14.3)	3 (14.3)	36 (13.2)	22(16.1)	42 (15.6)	21 (16.7)	7 (22.6)	6 (20%)
BMI(kg/m2)	27.3(4.1)	28.9(2.7)	29.2(4.2)	29.2(4.2)	28.8(4.3)	28.7(4.2)	30.1(6)	32.9(6.2)
WC(cm)	100.7(9.1)	103.4(8.0)	104(10)	105(9)	105(9)	104(9)	107(15)	114(12)
WHR	1(0.1)	1.0(0.1)	1.05(0.06)	1.05(0.07)	1.05(0.07)	1.05(0.07)	NA	NA
VAT(cm2)	160.2(53.5)	190.5(75.7)	178(77)	171(77)	186(87)	195(96)	232(91)	250(104)
Lean body mass(Kg)	65.2(6.9)	63.9(9.8)	62(10.1)	61.4(9.6)	62.4(10.3)	50.5(11.2)	NA	NA
TAG(mmol/l)	2.8(1.8)	3.1(2.5)	2.84(2.12)	2.64(164)	2.69(2.94)	2.51(1.62)	1.71(0.95)	1.45(0.52)
Fasting insulin(uU/ml)	12.1(12.5)	15.2(18)	20(26)	18(12)	25(30)	20(18)	NA	NA
CD4 cell count (cells/mm3)	577(327.2)	540.9(252.9)	616(299)	585(284)	588(290)	600(278)	733(290)	798(260)
Current drug therapy %
PI	19	52.4	55.1	64.2	58.9	55.60	29	20
NNRTI	71.4	52.4	53.7	41.6	39.60	35.70	38.7	36.7
NRTI	100	100	97.8	97.8	90.40	88.10	87.1	96.7
Use of lipid loweringagent %	NA	NA	50	41	40.40	47.60	41.9	50

BMI, WC, WHR, CD4 cells, insulin, VAT, LBM values in Mean (SD).

3.4. Outcomes

The efficacy and safety outcomes of Tesamorelin 2mg compared to placebo, including adverse events, are summarized in Tables 2 and 3.

Table 2.

Baseline Changes in Outcome Measures Across Included Studies

Outcome measure	Falutz et al 2005		Falutz et al 2007		Falutz et al 2010		Stanley et al 2019
	Placebo (n=21)	TES 2mg (n=21)	Placebo (n=137)	TES 2mg (n=273)	Placebo (n=126)	TES 2mg (n=270)	Placebo (n=30)	TES 2mg (n=31)
Body Composition
VAT (cm2)	-12.0 ± 32.5	-11.9 ± 28.7	5.1 ± 36.4	-27.8 ± 38.6	-1.0 ± 34.0	-21.0 ± 42.0	14.0 ± 40.0	-21.0 ± 77.0
SAT (cm2)	-10.5 ± 31.6	4.4 ± 19.8	2.3 ± 29.5	-3.3 ± 28.8	1.0 ± 28.0	-1.0 ± 34.0	12.0 ± 46.0	24.0 ± 72.0
VAT:SAT ratio	-0.01 ± 0.10	-0.14 ± 0.18	0.07 ± 0.59	-0.25 ± 0.65	0.03 ± 0.90	-0.23 ± 1.03	NR	NR
Trunk fat (kg)	0.10 ± 1.10	-1.10 ± 1.30	0.40 ± 1.60	-1.00 ± 1.90	0.20 ± 1.50	-0.80 ± 2.10	NR	NR
Waist circumference (cm)	NR	NR	-0.80 ± 4.00	-2.60 ± 4.90	-0.80 ± 4.70	-2.20 ± 5.40	1.00 ± 3.00	0.00 ± 9.00
Limb fat (kg)	0.10 ± 0.70	-0.30 ± 0.80	0.20 ± 1.00	0.00 ± 0.80	0.10 ± 0.90	-0.10 ± 1.00	NR	NR
Lean body mass (kg)	-0.50 ± 1.60	1.70 ± 2.30	-0.20 ± 1.80	1.30 ± 2.40	0.00 ± 1.90	1.20 ± 2.40	0.00 ± 2.60	1.90 ± 3.70
BMI (kg/m2)	-0.10 ± 1.60	0.30 ± 1.20	0.01 ± 1.15	-0.12 ± 1.26	0.10 ± 1.10	0.20 ± 1.30	0.40 ± 1.10	0.90 ± 2.30
Lipid Profile
Triglycerides (mmol/L)	-0.20 ± 1.30	0.90 ± 1.20	0.10 ± 1.34	0.56 ± 1.64	0.03 ± 1.20	-0.25 ± 1.48	-0.05 ± 0.54	0.21 ± 0.59
Total cholesterol (mmol/L)	0.30 ± 0.70	-0.10 ± 0.70	-0.08 ± 0.65	-0.26 ± 0.85	0.13 ± 0.75	0.03 ± 0.83	NR	NR
HDL cholesterol (mmol/L)	0.00 ± 0.20	0.10 ± 0.10	-0.05 ± 0.26	0.03 ± 0.23	0.00 ± 0.26	0.00 ± 0.21	-0.03 ± 0.16	0.05 ± 0.16
TC:HDL ratio	0.30 ± 1.10	-0.30 ± 0.60	0.21 ± 0.95	-0.31 ± 0.98	0.15 ± 0.92	-0.05 ± 1.01	NR	NR
Glucose Metabolism
Fasting glucose (mg/dL)	3.60 ± 14.40	1.80 ± 12.60	1.00 ± 15.00	3.00 ± 13.00	1.00 ± 19.00	2.00 ± 18.00	4.00 ± 13.00	7.00 ± 13.00
2-hour glucose (mg/dL)	10.80 ± 32.40	12.60 ± 30.60	8.00 ± 44.00	1.00 ± 37.00	-3.00 ± 41.00	6.00 ± 37.00	NR	NR
Fasting insulin (μU/mL)	5.10 ± 15.80	7.40 ± 6.30	3.00 ± 22.00	2.00 ± 29.00	0.00 ± 22.00	-2.00 ± 30.00	NR	NR
Hormonal Markers
IGF-1 (ng/mL)	21.80 ± 33.20	102.50 ± 79.30	-16.00 ± 66.00	109.00 ± 113.00	3.00 ± 59.00	106.00 ± 110.00	-1.00 ± 39.00	116.00 ± 84.00
Immunological Parameters
CD4 count (cells/mm3)	NR	NR	28.00 ± 104.00	-40.00 ± 77.00	13.00 ± 144.00	-6.00 ± 152.00	-28.00 ± 118.00	-11.00 ± 141.00

Data presented as mean ± SD representing change from baseline. TES = tesamorelin; VAT = visceral adipose tissue; SAT = subcutaneous adipose tissue; BMI = body mass index; TC = total cholesterol; HDL = high-density lipoprotein; IGF-1 = insulin-like growth factor-1; NR = not reported.

Table 3.

Adverse Outcomes of Included Studies

Adverse event	Falutz2005		Falutz2007		Falutz2010		Stanley 2019
	TES (n=21)	PBO (n=21)	TES (n=273)	PBO (n=137)	TES (n=270)	PBO (n=126)	TES (n=31)	PBO (n=30)
Serious Adverse Events
Any SAE	3 (14.3%)	2 (9.5%)	11 (4.0%)	3 (2.2%)	9 (3.3%)	8 (6.3%)	4 (12.9%)	2 (6.7%)
SAE → discontinuation	3 (14.3%)	1 (4.8%)	33 (12.1%)	4 (2.9%)	27 (10.0%)	11 (8.7%)	4 (12.9%)	1 (3.3%)
Musculoskeletal Events
Arthralgia	3 (14.3%)	3 (14.3%)	37 (13.6%)	15 (10.9%)	33 (12.2%)	14 (11.1%)	3 (9.7%)	3 (10.0%)
Myalgia	0 (0%)	1 (4.8%)	21 (7.7%)	3 (2.2%)	—	—	2 (6.5%)	0 (0%)
Limb pain	3 (14.3%)	0 (0%)	17 (6.2%)	9 (6.6%)	19 (7.0%)	3 (2.4%)	—	—
Neurological Events
Paresthesia	3 (14.3%)	0 (0%)	15 (5.5%)	3 (2.2%)	—	—	2 (6.5%)	2 (6.7%)
Headache	6 (28.6%)	3 (14.3%)	44 (16.1%)	25 (18.2%)	15 (5.6%)	4 (3.2%)	—	—
Injection Site Events
Injection site bruising	1 (4.8%)	2 (9.5%)	25 (9.2%)	13 (9.5%)	15 (5.6%)	13 (10.3%)	11 (35.5%)	11 (36.7%)
Gastrointestinal Events
Diarrhea	3 (14.3%)	1 (4.8%)	22 (8.1%)	13 (9.5%)	20 (7.4%)	9 (7.1%)	—	—
Respiratory Events
URTI	1 (4.8%)	2 (9.5%)	25 (9.2%)	13 (9.5%)	8 (3.0%)	8 (6.3%)	5 (16.1%)	5 (16.7%)
Nasopharyngitis	0 (0%)	2 (9.5%)	16 (5.9%)	7 (5.1%)	9 (3.3%)	8 (6.3%)	—	—

Data presented as n (%). TES = tesamorelin 2mg; PBO = placebo; SAE = serious adverse event; URTI = upper respiratory tract infection; — = not reported.

3.4.1. Change in Baseline Visceral Adipose Tissue (VAT) in cm2 at <26 weeks and ≥ 26 weeks

Tesamorelin demonstrated a significant reduction in VAT compared to placebo (MD= -21.47, 95%CI [-34.73,-8.22]; I²=74%; p=0.002). Subgroup analysis by treatment duration revealed substantial heterogeneity in treatment effect, with longer duration (≥26 weeks) showing markedly greater VAT reduction (MD-27.15cm²,95%CI[-38.08, -16.22]; I²=0%; p<0.00001), whereas short-term trials(<26 weeks) demonstrated no significant effect (MD0.10 cm²,95% CI[-18.44,18.64]; I²=0%; p=0.99) (Figure 2A).

Figure 2.

Baseline changes in body composition. (A) Visceral adipose tissue (B) Waist circumference (C) Subcutaneous adipose tissue (D) Lean body mass

3.4.2. Change in Baseline Waist Circumference (cm) at ≥ 26 weeks

Tesamorelin significantly reduced WC compared to placebo(MD-1.61cm, 95%CI[-2.28,-0.95]; I²=0%; p<0.00001), demonstrating low heterogeneity across studies (Figure 2B).

3.4.3. Change in Subcutaneous Adipose Tissue (cm2) at <26 weeks and ≥ 26 weeks

Tesamorelin demonstrated a non-significant minimal reduction in SAT compared to placebo (MD-0.26cm²,95%CI[-7.69, 7.17]; I²=77%; p=0.95) with modest reduction in longer treatment duration (≥26 weeks:MD-3.66 cm²,95%CI[-8.00, 0.67]; I²=0%; p=0.10), whereas short-term treatment (<26 weeks) showed a paradoxical increase in SAT (MD14.90cm²,95% CI[-1.05, 30.85]; p=0.07) (Figure 2C).

3.4.4. Change in Lean Body Mass (kg) at <26 weeks and ≥ 26 weeks

Tesamorelin significantly increased lean body mass (MD1.42kg,95%CI[1.13,1.71]; I²=0%; p<0.00001) versus placebo with greater gains in<26 weeks treatment duration(MD2.20kg, 95%CI[1.00, 3.40]; p=0.0004) compared to ≥26 weeks(MD1.37 kg,95%CI[1.07,1.67]; p<0.00001), with no significant between-group differences (p=0.19) (Figure 2D).

3.4.5. Change in Trunk Fat (kg) at <26 weeks and ≥ 26 weeks

Tesamorelin significantly reduced trunk fat versus placebo (MD-1.20kg, 95%CI[-1.47,-0.93]; I²=0%; p<0.00001) with comparable reductions among<26 weeks (MD-1.21 kg,95%CI[-1.61,-0.81]; p<0.00001) and ≥26 weeks treatment (MD-1.20 kg,95%CI[-1.53, -0.87]; p<0.00001), with no significant between-group differences (p=0.99) (Figure 3A).

Figure 3.

Baseline changes in body composition. (A) Trunk fat (B) Limb fat (C) BMI (D) VAT: SAT

3.4.6. Change in Limb Fat (kg) at <26 weeks and ≥ 26 weeks

Tesamorelin minimally reduced limb fat versus placebo (MD-0.22kg,95% CI[-0.35,-0.08]; I²=0%; p=0.001) with comparable reductions among <26 weeks (MD-0.40kg,95%CI[-0.85,0.05]; p=0.08) and ≥26 weeks treatment (MD-0.20 kg,95%CI[-0.34, -0.06]; p=0.005), with no between-group differences (p=0.41) (Figure 3B).

3.4.7. Change in BMI (Kg/m2) at <26 weeks and ≥ 26 weeks

Tesamorelin showed no significant effect on BMI (MD0.02kg/m²,95%CI[-0.17,0.21]; I²=0%; p=0.84) versus placebo with non-significant increases in <26 weeks (MD0.40 kg/m²,95%CI[-0.46,1.26]; p=0.36) compared to ≥26 weeks (MD 0.00kg/m²,95%CI[-0.21, 0.21]; p=1.00), with no between-group differences (p=0.38) (Figure 3C).

3.4.8. Change in VAT: SAT at <26 weeks and ≥ 26 weeks

Tesamorelin significantly reduced VAT:SAT (MD-0.23,95%CI[-0.36,-0.10]; I²=0%; p=0.0004) versus placebo with greater reduction in ≥26 weeks (MD-0.30, 95%CI[-0.40, -0.20]; p<0.00001) compared to <26 weeks (MD-0.13,95%CI [-0.22 -0.04]; p=0.005), with significant between-group differences (p=0.01) (Figure 3D).

3.4.9. Change in Triglyceride(mmol/L) at <26 weeks and ≥ 26 weeks

Tesamorelin showed no significant effect on triglycerides (MD0.02mmol/L,95% CI[-0.53, 0.57]; I²=78%; p=0.94) versus placebo with reduction in ≥26 weeks (MD -0.23mmol/L, 95% CI [-0.73, 0.27]; p=0.37) versus, increase in TAG with <26 weeks (MD1.10mmol/L, 95% CI [0.34, 1.86]; p=0.005), with significant between-group differences (p=0.004) (Figure 4A).

Figure 4.

Baseline changes in lipid profile. (A) TAG level (B) HDL cholesterol (C) Total cholesterol (D) Total cholesterol: HDL

3.4.10. Change in HDL Cholesterol (mmol/L) at <26 weeks and ≥ 26 weeks

Tesamorelin non-significantly increased HDL (MD0.05mmol/L,95%CI [-0.01,0.11]; I²=0%; p=0.09) versus placebo with greater increase in <26 weeks (MD0.10 mmol/L, 95% CI [0.00, 0.20]; p=0.04) compared to ≥26 weeks (MD0.04mmol/L,95%CI [-0.04,0.11]; p=0.30), with no between-group differences (p=0.31) (Figure 4B).

3.4.11. Change in Total Cholesterol (mmol/L) at <26 weeks and ≥ 26 weeks

Tesamorelin minimally decreased total cholesterol(MD-0.16mmol/L,95%CI [-0.27,-0.06]; I²=0%; p=0.003) versus placebo with greater decrease in <26 weeks (MD -0.40mmol/L,95%CI[-0.82,0.02]; p=0.06) compared to ≥26 weeks (MD-0.15mmol/L,95%CI [-0.26,-0.04]; p=0.009), with no between-group differences (p=0.26) (Figure 4C).

3.4.12. Change in Total Cholesterol: HDL at <26 weeks and ≥ 26 weeks

Tesamorelin reduced TC:HDL ratio (MD-0.40,95%CI[-0.66,-0.14]; I²=0%; p=0.003) versus placebo with greater reduction in <26 weeks (MD-0.60,95%CI[-1.14,-0.06]; p=0.03) compared to ≥26 weeks (MD-0.36,95%CI[-0.67,-0.05]; p=0.02), with no between-group differences (p=0.45) (Figure 4D).

3.4.13. Change in Fasting Glucose Level (mg/dl) at <26 weeks and ≥ 26 weeks

Tesamorelin non-significantly increased fasting glucose versus placebo (MD1.51mg/dL,95% CI[-0.66,3.69]; I²=0%; p=0.17) with reduction in <26 weeks (MD-1.80mg/dL,95%CI[-9.98, 6.63]; p=0.68) versus increase with ≥26 weeks (MD1.77mg/dL,95%CI[-0.49,4.02]; p=0.12), with no between-group differences (p=0.41) (Figure S3).

3.4.14. Change in 2-hr glucose(mg/dl) at <26 weeks and ≥ 26 weeks

Tesamorelin non-significantly increased 2-hour glucose versus placebo (MD 1.20mg/dL,95%CI[-10.46,12.86]; I²=0%; p=0.84) with comparable increases among <26 weeks (MD1.80mg/dL,95%CI[-17.26,20.86]; p=0.85) and ≥26 weeks (MD1.02 mg/dL,95% CI[-14.66,16.70]; p=0.90), with no between-group differences (p=0.95) (Figure S4).

3.4.15. Change in Fasting Insulin (μU/ml) at <26 weeks and ≥ 26 weeks

Tesamorelin minimally and non-significantly reduced fasting insulin versus placebo (MD-0.72μU/mL,95% CI[-3.98,2.53]; I²=0%; p=0.66) with greater decrease in ≥26 weeks (MD-1.48μU/mL,95%CI[-5.12,2.16]; p=0.43) compared to <26 weeks (MD2.30 μU/mL,95% CI[-4.98,9.58]; p=0.54), with no between-group differences (p=0.36) (Figure S5).

3.4.16. Change in Insulin Like Growth Factor (ng/ml) at <26 weeks and ≥ 26 weeks

Tesamorelin significantly increased IGF-1 versus placebo (MD109.10ng/mL,95%CI [91.68,129.52]; I²=0%; p<0.000001) with greater increase in ≥26 weeks (MD114.22ng/mL, 95%CI[98.50,129.94]; p<0.00001) compared to <26 weeks (MD80.70ng/mL,95%CI[43.93, 117.47]; p<0.0001), with no between-group differences (p=0.10) (Figure S6).

3.4.17. Change in CD4 (Cells/mm3) at <26 weeks and ≥ 26 weeks

Tesamorelin minimally reduced CD4 count versus placebo (MD-18.57cells/mm³,95%CI [-46.04,8.91]; I²=0%; p=0.19) with greater reduction in <26 weeks (MD-68.00cells/mm³,95% CI[-123.35,-12.65]; p=0.02) compared to ≥26 weeks (MD-9.35cells/mm³,95%CI[-31.38, 12.65]; p=0.41), with no between-group differences (p=0.05) (Figure S7).

3.5. Adverse Events

Tesamorelin showed a trend toward higher discontinuation rates due to adverse events versus placebo (RR 2.25,95%CI[0.98,5.17]; I²=43%; p=0.06). Serious adverse events were comparable between groups (RR1.07,95%CI[0.53,2.18]; I²=17%; p=0.85). Specific adverse events with numerically higher risk in the tesamorelin group included paresthesia (RR2.19, 95%CI[0.83,5.78]; I²=0%; p=0.11), myalgia (RR2.80,95%CI[0.96,8.12]; I²=1% p=0.06), and limb pain (RR1.81,95%CI[0.63,5.16]; I²=47%; p=0.27). Arthralgia, injection site bruising, headache, diarrhea, upper respiratory tract infections, and nasopharyngitis were comparable between tesamorelin and placebo (Figure S8-S18).

3.5.1. Sensitivity Analysis

Sensitivity analyses showed that the direction and magnitude of effects were generally robust for most outcomes but for Subcutaneous adipose tissue and 2-hour glucose, omitting certain trials shifted the pooled effect in opposite directions although all estimates remained statistically non-significant. However, heterogeneity remained moderate to high for VAT, SAT, and triglycerides (Table S3).

3.6. Summary of Findings

The certainty of evidence was evaluated using the GRADE approach and presented in the supplementary table. Waist circumference, BMI, lean body mass, trunk fat mass, limb fat and total cholesterol were rated as high.VAT, VAT: SAT,HDL level, TC: HDL ratio, fasting glucose, fasting insulin, IGF-1,CD4 count and serious adverse events were rated as moderate due to heterogeneity or risk of bias, but direction of effect consistent.SAT, TAG and 2hrs glucose level, serious adverse events leading to discontinuation were rated as low due to serious imprecision or risk of bias (Table S1 and S2).

4. Dicussion

This systematic review and meta-analysis of four randomized controlled trials involving 909 participants provides evidence that tesamorelin 2mg daily significantly reduces visceral adiposity and improves select body composition parameters in PLWH with lipodystrophy on CART. Our findings demonstrate a mean reduction in visceral adipose tissue of 21.47 cm², representing clinically meaningful fat loss in this population. Notably, these effects were highly selective for central adiposity, with minimal impact on subcutaneous fat and preservation of lean body mass, which increased by 1.42 kg. These body composition changes were accompanied by modest improvements in lipid parameters including total cholesterol and total cholesterol/HDL ratio, without significant adverse effects on glucose homeostasis or immune function.

The selective reduction of visceral adipose tissue observed in our analysis is particularly relevant given the established association between visceral fat accumulation and CVS risk in both general and PLWH.^25,26 VAT is metabolically active, contributing to systemic inflammation, insulin resistance, and atherogenic dyslipidemia through excessive free fatty acid release and pro-inflammatory adipokine secretion. ²⁷ VAT levels above 130-150 cm² are associated with increased risk of metabolic abnormalities and cardiovascular events, and it is independently associated with prevalent cardiovascular disease in PLWH.^28,29 Our finding of a 21.47 cm² reduction in VAT suggests that tesamorelin achieves clinically significant reductions comparable to those obtained through surgical interventions or intensive lifestyle modifications, while preserving peripheral fat. ²⁰

Treatment duration emerged as a critical determinant of efficacy in our subgroup analyses. Trials with duration ≥26 weeks demonstrated markedly superior VAT reduction (MD -27.15 cm²) compared to shorter treatment durations, which showed no significant effect. This temporal relationship suggests that sustained tesamorelin therapy is necessary to achieve meaningful visceral fat reduction, with effects becoming more pronounced over time. However, previous studies have demonstrated rapid VAT reaccumulation upon treatment discontinuation, indicating that the beneficial effects are not sustained after cessation. ¹⁹ This observation has important implications for clinical practice, suggesting that tesamorelin requires long-term continuous administration raising considerations regarding treatment burden, cost-effectiveness, and patient adherence.

Visceral adipocytes, unlike subcutaneous adipocytes, demonstrate enhanced sensitivity to lipolytic stimuli, including catecholamines and growth hormone. ³⁰ The growth hormone-mediated increase in lipolysis preferentially targets metabolically active visceral depots which may render it more responsive to growth hormone-based interventions ³¹ However, this suggests that tesamorelin addresses symptoms rather than underlying pathophysiologic mechanisms driving lipodystrophy.

The lipid profile improvements though modest, may contribute to CVS risk reduction. The significant decreases in total cholesterol (0.16 mmol/L) and total cholesterol/HDL ratio (0.40) align with known observations of growth hormone stimulation on lipid metabolism. ³² However, the clinical significance of these lipid changes remains uncertain, given the non-significant effects on triglycerides and the lack of established cardiovascular outcome data. A recent meta-analysis reported similar findings, with tesamorelin associated with significant VAT reduction but unclear effects on CVS risk markers. ³³ The long-term safety of tesamorelin remains unknown, as acknowledged in FDA labelling, underscoring the need for extended follow-up studies evaluating clinical endpoints.

Metabolic safety had reassuringly neutral effects on glucose metabolism parameters. Fasting glucose, 2-hour post-prandial glucose, and fasting insulin levels showed no significant changes despite theoretical concerns about growth hormone’s counter-regulatory effects on insulin sensitivity. This suggests that any potential diabetogenic effects of growth hormone stimulation are offset by the metabolic benefits of visceral fat reduction.^34,35 Nevertheless, continued glucose monitoring remains prudent, especially in PLWH with pre-existing insulin resistance or diabetes mellitus.

The safety profile of tesamorelin was generally acceptable. However, growth hormone-related adverse effects including myalgia, paresthesia, and limb pain showed numerical increases, though statistical significance was not achieved for most events. Discontinuation rates trended higher with tesamorelin (RR 2.25, p=0.06), suggesting tolerability may limit adherence. These findings align with a recent comprehensive meta-analysis reporting manageable non-serious adverse events without increased serious adverse event risk. ³³ Clinicians should counsel patients about potential musculoskeletal symptoms and monitor IGF-1 levels periodically, due to theoretical concerns regarding malignancy risk, leading to contraindication in active cancer. ³⁶

Our study has several important limitations. First, the analysis included only four trials, limiting statistical power for subgroup analyses and precluding assessment of publication bias through funnel plots. Second, all included studies evaluated only the 2mg daily dose, preventing dose-response evaluation. Third, treatment duration in most trials was limited to 12-52 weeks, providing insufficient data on long-term efficacy and safety beyond one year. Fourth, patient-reported outcomes including quality of life and body image distress, which are critically important given lipodystrophy’s psychosocial impact, were inconsistently reported and could not be meta-analyzed. Fifth, the included populations were predominantly male (>85%), limiting generalizability to women living with HIV. Sixth, cost-effectiveness was not evaluated, which is relevant given tesamorelin’s substantial expense and requirement for ongoing treatment.

The clinical implications of our findings warrant careful consideration as tesamorelin represents the only FDA-approved pharmacological option specifically targeting HIV-associated central adiposity. Ideal candidates include PLWH with documented excess VAT (typically >130-150 cm²), metabolic syndrome features, and significant body image concerns affecting quality of life or treatment adherence. However, the requirement for continuous therapy, potential for adverse effects and high cost, it should be viewed as one component of comprehensive lipodystrophy management. Future research should prioritize several key areas including longer trials duration to long term safety outcomes. Studies evaluating different dosing strategies and comparative effectiveness via intensive lifestyle interventions or surgical approaches would help define its role in the treatment algorithm. Investigation of predictive biomarkers or optimal treatment responders could enhance patient selection with rigorous cost-effectiveness analyses for coverage decisions.

In conclusion, tesamorelin demonstrates efficacy in reducing visceral adiposity and improving select body composition and lipid parameters in PLWH with lipodystrophy on CART, with an acceptable short-term safety profile. However, the requirement for continuous therapy, modest metabolic benefits, uncertain long-term cardiovascular implications, and incomplete understanding of optimal patient selection and treatment duration limit current clinical application. Tesamorelin provides a targeted therapeutic option for carefully selected patients with significant visceral fat accumulation and psychosocial or metabolic complications but should be implemented within a comprehensive management strategy addressing the multifactorial nature of HIV-associated lipodystrophy. Ongoing treatment requires continued monitoring, and long-term studies are essential to fully characterize the risk-benefit profile and establish tesamorelin’s role in reducing clinically meaningful endpoints including cardiovascular events and quality of life in this vulnerable population.

Appendix.

Abbreviation

HAL

HIV associated lipodystrophy

PLWH

People living with HIV

CART

Combined Antiretroviral therapy

AT

Adipose tissue

VAT

Visceral adipose tissue

SAT

Subcutaneous adipose tissue

WC

Waist circumference

BMI

Body mass index

IGF-1

Insulin-like growth factor-1

TESA

Tesamorelin

TAG

Triglyceride

PBO

Placebo

CVS risk

Cardiovascular Risk

ORCID iD

Husam Abu Dawood https://orcid.org/0009-0005-3109-2600

Ethical Considerations

Ethical approval and participant informed consent were not required for this study, as it is a systematic review and meta-analysis based entirely on previously published, publicly available secondary data. No primary human or animal subjects were directly involved, and all analyzed data were completely anonymized at the source.

Consent for Publication

Consent for publication is not available as this study involves publicly available data.

Data Availability Statement

All data analyzed during this study were obtained from previously published studies and are included in this published article and its supplementary information files.*