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

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1 DOI: /j x r 2011 British HIV Association HIV Medicine (2011), 12, REVIEW Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials T Sivakumar, 1,2,3 OJ Mechanic, 2,4 DA Fehmie 2,5 and BT Paul 2,3 1 Endocrinology Department, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA, 2 The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH, USA, 3 Dartmouth Medical School, Hanover, NH, USA, 4 School of Medicine, University of North Carolina, Chapel Hill, NC, USA and 5 School of Social Sciences, City University London, London, UK 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 ( ), 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 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) cm 2 ; 95% confidence interval (CI) to cm 2 ; Po0.001] and increased LBM (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; Po0.001], but had no significant effect on SAT mass (WMD 3.94 cm 2 ; 95% CI to 3.00 cm 2 ; P ]. 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. Correspondence: Dr Tharsan Sivakumar, Dartmouth-Hitchcock Medical Center, Endocrinology, One Medical Center Drive, Lebanon 03756, NH, USA. Tel: ; doctor_sivakumar@hotmail.com 453

2 454 T Sivakumar et al. 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. Keywords: adipose, AIDS, fat, growth, HIV, hormone, lipoatrophy, lipodystrophy, lipohypertrophy Accepted 4 November 2010 Introduction Disorders of body fat metabolism and associated metabolic alterations are common in patients infected with HIV [1]. While the definition is not standardized, a diagnosis of HIV-associated lipodystrophy describes metabolic derangements including insulin resistance and changes in lipid metabolism, which result in lipoatrophy (peripheral adipose wasting) and lipohypertrophy (visceral adipose accumulation) [1]. The pathogenesis of HIV-associated lipodystrophy is multifactorial and includes genetic predisposition, effects of antiretroviral agents, HIV infection itself, and other host factors [2]. Highly active antiretroviral therapy (HAART) is comprised of potent antiretroviral agents, which have dramatically improved clinical outcomes in patients with HIV infection. Unfortunately, HAART is often associated with the onset, or exacerbation, of HIV-associated lipodystrophy [1]. The prevalence of HIV-associated lipodystrophy is 4% in untreated patients and 13 40% in patients on HAART [3]. The associated fat redistribution syndrome can lead to negative social, psychological and medical consequences [4]. Cosmetic changes in body shape may result in decreased compliance with HAART, which can result in increased viral replication and associated morbidities and mortality [4]. The metabolic derangements in HIV-associated lipodystrophy are difficult to reverse. A number of treatments for this condition have been explored, including metformin, thiazolidinediones (TZDs), testosterone and growth hormone (GH) axis drugs. Metformin has been shown to reduce visceral adipose tissue (VAT) mass but accelerates peripheral adipose tissue loss. TZDs and testosterone are not effective in reducing VAT. However, some studies have shown that GH axis drugs can both decrease VAT and help to maintain or improve peripheral adipose tissue mass [5]. Although the underlying mechanism for the development of HIV-associated lipodystrophy and related disorders such as metabolic syndrome is not fully understood, evidence suggests that neurohormonal dysregulation plays a role in causing these debilitating conditions [6 8]. GH is a polypeptide hormone secreted episodically by the adenohypophysis that affects protein, carbohydrate and lipid metabolism. There is also evidence that it plays a role in skeletal and visceral growth. Specifically, GH affects the metabolism of fats by causing cells to switch from using carbohydrates for fuel to burning fats for energy. It also accelerates the rate at which glycogen stored in the liver is converted into and released into the blood. Thus, it is suspected that augmenting the GH axis in patients with HIVassociated lipodystrophy results in improved utilization of fat stores and subsequent redistribution of adipose tissue [9]. GH axis drugs investigated for the treatment of HIVassociated lipodystrophy include recombinant growth hormone (GH), growth hormone releasing hormone (GHRH), tesamorelin, also known as growth hormone releasing factor (GHRF), and insulin-like growth factor-1 (IGF-1). There are some concerns with this class of drug. GH, the most studied GH axis drug, costs approximately $52 per milligram, and is estimated to cost approximately US$ US$ per year of treatment [10]. Significant treatment-associated side effects of these drugs include arthralgias, myalgias, peripheral oedema, insulin resistance and diabetes [11]. Considering the expense and side effects associated with these drugs, it is important to evaluate the evidence regarding the efficacies of these treatments to allow the patient and health care provider to make informed decisions. In the present systematic review, we evaluate randomized controlled trials comparing the effects of GH axis treatments with those of placebo in changing VAT, subcutaneous adipose tissue (SAT) and lean body mass (LBM) in patients with HIV-associated lipodystrophy. Methods A detailed protocol was written prior to conducting the review. The protocol and documentation of all changes made after construction of the protocol are available upon request. Study eligibility criteria Inclusion criteria were as follows (all were required to be met): (1) the study design must be a randomized controlled trial; (2) study participants were adult patients with HIV-associated lipodystrophy; (3) the intervention was a GH axis drug (GH, GHRH, tesamorelin or IGF-1); (4) the comparison group was treated with placebo; and (5) the study included one of the primary outcomes. There were no exclusion criteria.

3 Growth hormone axis treatments for lipodystrophy 455 Outcome measures Our primary outcomes of interest included changes in VAT mass, SAT mass or LBM. The secondary outcomes included changes in extremity fat, levels of fasting plasma, high-density lipoprotein (HDL) cholesterol and triglycerides, and waist circumference. Potential harms of treatment were also evaluated. Search methods Main databases The following databases were searched for studies: OVID MEDLINE (1996 to present; accessed 6 June 2010), The Cochrane Library [Cochrane Central Register of Controlled Trials and Cochrane Database of Randomized Controlled Trials (CENTRAL); accessed 11 October 2009], Web of Science (accessed 11 October 2009), Summons (accessed 13 October 2009), Google Scholar (accessed 11 October 2009) and PubMed (accessed 5 June 2010). Search terms included: HIV, AIDS, growth hormone, Serostim, GH releasing hormone, tesamorelin, IGF-1, HIV-associated lipodystrophy, adipose tissue and body composition. A comprehensive list of all search terms is available upon request. No limits (including language) were used in the search of the databases, with the exception of excluding newspaper articles and book reviews from the Summons database search. Supplementary searches to find additional published and unpublished studies were conducted in the Food and Drug Administration registry (accessed 11 October 2009) and the Clinical Trials registry (clinicaltrials.gov; accessed 11 October 2009). References of the articles included in our systematic review were also manually reviewed. Study selection Two reviewers independently reviewed all titles and abstracts for eligibility in an unblinded and standardized manner; all disagreements were resolved by a third reviewer. A data extraction form was created, pilot-tested on four eligible studies, and then refined accordingly. Data collected were study design, trial participant characteristics, inclusion/ exclusion criteria, study intervention including dosages and duration of follow-up, and primary/secondary outcome measurements. Data from all of the included studies were then abstracted and summarized independently by two reviewers using the data extraction form. Discrepancies were resolved by repeated review and discussion between reviewers. Data in the clinical trials registry were compared with those of the published journal article when possible. Risk of bias assessment We assessed the methodological quality of all articles included in our systematic review using the Risk of Bias Tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions [12]. The data gathered from the risk of bias assessment are presented in our systematic review to identify studies that were compromised in terms of methodological quality, but these data were not utilized in our calculations of summary effect. Each study was graded as having a low risk, high risk, or unclear risk of bias in accordance with the Cochrane Collaboration Tool. Analysis Measure of treatment effect The summary of the differences in treatment effects between GH axis treatments and placebo is given in terms of weighted mean differences (WMDs). No qualitative measures are included in the treatment effects reported. For nine of our ten included articles, no calculations or estimates were needed to replace data missing from the published reports. We were unable to reach Waters et al. to request additional unpublished data, and thus we estimated values of LBM based on graphs provided in their study. We used a standardized formula to calculate the standard deviations from confidence intervals [12]. Data synthesis Summary treatment effects were calculated with the Cochrane Collaboration Review Manager Version 5 (REVMAN 5) using the random effects model. This model provides a conservative estimation and takes into account variance between studies in terms of quality and sample size. A test of heterogeneitywasappliedtotheincludedstudiestoevaluate the magnitude of differences between the studies for the overall treatment effect of GH axis drugs vs. placebo,aswell as for subgroup analyses for each GH axis drug vs. placebo. Heterogeneity was assessed using REVMAN 5tocalculatethe percentage of variation across the studies and subgroups that was attributable to heterogeneity rather than chance (I 2 ) as well as a w 2 test and associated P-value. If the heterogeneity was above 50% or the P-value was less than 0.10, we planned to explore for the source of heterogeneity and perform appropriate sensitivity analyses. The presence of publication bias was assessed by visual inspection of funnel plots, generated by REVMAN 5, of the primary outcomes reported in the included studies. Subgroup analyses with summary effects were performed for each GH axis drug studied.

4 456 T Sivakumar et al. Table 1 Characteristics of Included Studies Study Total number of patients Number of patients in the intervention arm Number of patients in the placebo arm Outcomes Intervention Dose Duration Falutz et al. [13] BMI, VAT, SAT, LBM, IGF-1, insulin, Tesamorelin 1 mg/day 12 weeks BMI, VAT, SAT, LBM, IGF-1, insulin, 2 mg/day 26 weeks Falutz et al. [15] BMI, VAT, SAT, LBM, IGF-1, insulin, 2 mg/day 26 weeks Falutz et al. [16] VAT, SAT, body image, IGF-I, 2 mg/day 26 weeks insulin, Grunfeld et al. [9, 27] BMI, VAT, SAT, LBM, IGF-1, insulin, Growth 4 mg/day 12 weeks Hormone BMI, VAT, SAT, LBM, IGF-1, insulin, 0.33 mg/day 18 months Luzi et al. [18] Arm/leg/trunk lean and fat tissue 0.2 IU/kg/week 6 months Schambelan et al. [19] Body fluid compartments, work 0.1 mg/kg/day 12 weeks output, quality of life Waters et al. [26] Fat mass, LBM, quality of life 1.4 mg per day 6 and 12 weeks IGF-1 5 mg bid Koutkia et al. [20] BMI, VAT, SAT, LBM, IGF-1, insulin, GHRH 1 mg bid 12 weeks bid, twice per day; BMI, body mass index; GH, recombinant human growth hormone; GHRH, growth hormone releasing hormone; HIV, human immunodeficiency virus; IGF-1, insulin-like growth factor-1; LBM, lean body mass; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue. Results As depicted in Table 1, all 10 included studies were randomized double-blinded placebo-controlled studies. The duration of the intervention in the studies ranged from 12 to 26 weeks. Six studies evaluated GH as their primary intervention, four studies evaluated tesamorelin, one study evaluated GHRH, and one evaluated IGF-1. One article compared two interventions (GH and IGF-1) vs. a placebo group. Changes in VAT As can be seen in Figure 1, the summary effect shows that GH axis drugs produced a significant reduction in VAT compared with placebo (WMD cm 2 ; 95% CI to cm 2 ; Po0.001). Statistically significant reductions were found for GH (WMD cm 2 ; 95% CI to cm 2 ; Po0.001) and tesamorelin (WMD cm 2 ; 95% CI to cm 2 ; Po0.001). GHRH treatment did not result in a statistically significant decrease in VAT (WMD cm 2 ; 95% CI to 1.28 cm 2 ; P ). Changes in SAT As shown in Figure 2, compared with placebo, GH axis drugs significantly reduced SAT mass (WMD 3.94 cm 2 ; 95% CI to 3.00 cm 2 ; P ). Subgroup analyses showed that no significant decrease in SAT mass was found with tesamorelin (WMD 1.02 cm 2 ; 95% CI 8.21 to 6.16cm 2 ; P ) or GHRH (WMD 1.40 cm 2 ; 95% CI to cm 2 ; P ). However, GH treatment did result in a statistically significant decrease in SAT compared with placebo (WMD cm 2 ; 95% CI to 7.97 cm 2 ; Po0.001). Changes in LBM As shown in Figure 3, GH axis drugs produced a significant change in LBM compared with placebo (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; Po0.001). Subgroup analysis showed that there was a significant increase in LBM with tesamorelin (WMD 1.35 kg; 95% CI 1.03 to 1.66 kg; Po0.001) and GHRH (WMD 0.78 kg; 95% CI 0.39 to 1.95 kg; P ), while GH (WMD 1.51 kg; 95% CI 0.22 to 3.24 kg; P ) and IGF-1 (WMD 2.05 kg; 95% CI 0.08 to 4.18 kg; P ) did not produce a significant gain. Secondary outcomes GH axis drugs had an overall effect of increasing fasting plasma (WMD 2.88 mg/dl; 95% CI 1.10 to 4.65 mg/dl; P ), decreasing waist circumference (WMD 1.61 cm; 95% CI 2.33 to 0.89 cm; Po0.001), decreasing extremity fat (WMD 0.25 kg; 95% CI 0.49 to 0.01 kg; P ), and decreasing triglycerides (WMD mg/dl; 95% CI to 3.89 mg/dl; P ). The intervention did not result in a significant change in

5 Growth hormone axis treatments for lipodystrophy 457 Study or Subgroup Weight Growth Hormone versus Placebo Grunfeld et al. [9] 22.6% [ 42.48, 23.72] 2.0% 24.7% [ 67.72, 27.72] [ 41.82, 23.40] Heterogeneity: τ 2 = 0.00; χ 2 = 0.28, df = 1 (P=0.60); I 2 = 0% Test for overall effect: Z = 6.94 (P < ) Tesamorelin versus Placebo Falutz et al. [15] Falutz et al. [16] Falutz et al. [13] Test for overall effect: Z = 4.43 (P < ) 24.5% [ 41.35, 24.45] 6.1% [ 46.83, 4.83] 26.6% [ 27.50, 12.50] 10.5% 9.50 [ 27.82, 8.82] 67.8% [ 32.67, 12.64] Heterogeneity: τ 2 = 57.36; χ 2 = 7.81, df = 3 (P=0.05); I 2 = 62% GHRH versus Placebo Koutkia et al. [23] 7.5% 7.5% Heterogeneity: Not applicable Test for overall effect: Z = 1.85 (P = 0.06) [ 44.28, 1.28] [ 44.28, 1.28] Total (95% CI) 100.0% [ 32.18, 18.22] Heterogeneity: τ 2 = 33.11; χ 2 = 10.69, df = 6 (P=0.10); I 2 = 44% Test for overall effect: Z = 7.07 (P < ) Test for subgroup difference: χ 2 = df= 2 (P = 0.27), I 2 = 23.1% Favours GH Axis Favours Placebo Fig. 1 Change in visceral adipose tissue mass. CI, confidence interval; IV, Instrumental Variables estimation; random, random effects model; SD, standard deviation. HDL cholesterol (WMD 0.53 mg/dl; 95% CI 1.00 to 2.06 mg/dl; P 5 0.5). Adverse events As shown in Figure 4, treatment with GH axis drugs did not result in a significant difference in the overall rate of all moderate-to-severe adverse events compared with placebo [relative risk (RR) 1.09; 95% CI 0.92 to 1.29; P ]. However, the number of cases of arthralgia (RR 1.49; 95% CI ; P ) and oedema (RR 3.95; 95% CI 1.73 to 9.00; P ) were higher in the GH axis drug arm than in the placebo arm. Discussion Efficacy of GH axis treatments Despite the extraordinary progress that has been made in the treatment of HIV infection with HAART, metabolic derangements, including central fat accumulation and peripheral lipoatrophy, have become a serious concern for many patients. Treating HIV-associated lipodystrophy is important for a number of reasons. Loss of SAT, especially in the face, can cause significant emotional distress and can lead to poor self-esteem [21]. Some patients with lipodystrophy become worried that their HIV status is easily apparent [22]. Potential interventions, particularly for abnormal fat deposition, include exercise, medical therapy and surgery. Unfortunately, medical therapeutic options in the treatment of HIV-associated lipodystrophy are limited. Patients with HIV-associated lipodystrophy have decreased secretion of GH, a hormone with lipolytic properties [20]. Therefore, we sought to investigate GH axis treatments. The results of our systematic review demonstrate that GH axis treatments significantly reduced VAT by an average of cm 2. GH and tesamorelin were particularly effective, reducing VAT by and cm 2, respectively. Our results also demonstrate that GH axis treatments significantly increased LBM. Tesamorelin was the most

6 458 T Sivakumar et al. Study or Subgroup Weight Growth Hormone versus Placebo Grunfeld et al. [9] 21.4% [ 24.41, 8.19] 1.0% 3.00 [ 64.03, 70.03] 22.5% [ 24.08, 7.97] Heterogeneity: τ 2 = 0.00; χ 2 = 0.31, df= 1 (P = 0.58); I 2 = 0% Test for overall effect: Z = 3.90 (P < ) Tesamorelin versus Placebo Falutz et al. [13] 11.7% [ 1.05, 30.85] 23.7% 5.60 [ 12.25, 1.05] Falutz et al. [15] Falutz et al. [16] 2.3% 24.2% 61.8% 8.00 [ 52.49, 36.49] 2.00 [ 8.35, 4.35] 1.02 [ 8.21, 6.16] Heterogeneity: τ 2 = 21.69; χ 2 = 5.49, df= 3 (P = 0.14); I 2 = 45% Test for overall effect: Z = 0.28 (P = 0.78) GHRI versus Placebo Koutkia et al. [23] Heterogeneity: Not applicable 15.7% 15.7% Test for overall effect: Z = 0.23 (P = 0.82) 1.40 [ 13.55, 10.75] 1.40 [ 13.55, 10.75] Total (95% CI) 100.0% 3.94 [ 10.88, 3.00] Heterogeneity: τ 2 = 41.38; χ 2 = 14.72, df= 6 (P = 0.02); I 2 = 59% Test for overall effect: Z = 1.11 (P = 0.27) Test for subgroup difference: χ 2 = 8.92, df= 2 (P = 0.01), I 2 = 77.6% Favours GH Axis Favours Placebo Fig. 2 Change in subcutaneous adipose tissue mass. CI, confidence interval; IV, Instrumental Variables estimation; random, random effects model; SD, standard deviation. 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. GHRH was also effective at improving LBM, resulting in an increase of 1.20 kg compared to placebo, but there was only one study [23] in our systematic review that compared GHRH with placebo, and there were only 14 participants in the treatment group and 15 in the placebo group. The overall effects of GH and IGF-1 vs. placebo in improving LBM were not statistically significant (P and 0.06, respectively). Funnel plots were constructed for the primary outcomes to assess publication bias. A symmetric inverted funnel shape was obtained for change in LBM. There were insufficient points in the funnel plots for change in VAT or SAT to allow any meaningful conclusions to be drawn. Thus, no evidence for publication bias was detected. The overall effect of GH axis treatments on improving SAT was not significant. Although adipose is fundamentally the same tissue in the viscera and in subcutaneous locations, loss of SAT (lipoatrophy) and VAT accumulation (lipohypertrophy) appear to be separate processes controlled by different mechanisms [24], and our results support this hypothesis. Since the introduction of HAART, it has become apparent that some patients with HIV-associated lipodystrophy have a pure subcutaneous lipoatrophy and others have only visceral lipohypertrophy. A subset of patients have features of both morphological abnormalities. Patients with lipoatrophy experience a loss of SAT, most noticeably in the limbs and face. Patients with fat accumulation typically have gains of VAT in the abdomen and may have dorsocervical fat pad enlargement. Thus, we feel that if fat atrophy and fat accumulation co-exist in a patient, they should be addressed independently. Our results suggest that GH axis therapy may not be effective for improving SAT. Thus, for patients with both SAT loss and VAT gains, clinicians could consider combined therapy using GH axis drugs for the management of VAT and agents such as thiazolidinediones for the treatment of SAT loss. Thiazolidinediones, such as pioglitazone, have been

7 Growth hormone axis treatments for lipodystrophy 459 Study or Subgroup Weight Growth Hormone versus Placebo Luzi et al. [18] Schambelan et al. [19] Waters et al. [26] 1.1% 10.4% 14.5% 5.2% 31.2% Heterogeneity: τ 2 = 2.09; χ 2 = 13.74, df = 3 (P = 0.003); I 2 = 78% Test for overall effect: Z = 1.71 (P = 0.09) 1.70 [ 3.09, 6.49] 0.72 [ 0.48, 1.92] 3.10 [2.25, 3.95] 0.25 [ 1.74, 2.24] 1.51 [ 0.22, 3.24] Tesamorelin versus Placebo Falutz et al. [13] Falutz et al. [15] Falutz et al. [16] 10.4% 20.1% 1.7% 20.4% 52.6% 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 < ) 2.20 [1.00, 3.40] 1.50 [1.04, 1.96] 1.80 [ 2.04, 5.64] 1.20 [0.76, 1.64] 1.40 [1.09, 1.71] GHRH versus Placebo Koutkia et al. [23] 11.5% 11.5% Heterogeneity: Not applicable Test for overall effect: Z = 2.14 (P = 0.03) 1.20 [0.10, 2.30] 1.20 [0.10, 2.30] IGF-1 versus Placebo Waters et al. [26] 4.7% 4.7% Heterogeneity: Not applicable Test for overall effect: Z = 1.89 (P = 0.06) 2.05 [ 0.08, 4.18] 2.05 [ 0.08, 4.18] Total (95% CI) 100.0% 1.60 [1.08, 2.11] 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 < ) Test for subgroup differences: χ 2 = df = 3 (P = 0.26); I 2 = 52.6% 4 2 Favours Placebo Favours GH Axis Fig. 3 Change in lean body mass. CI, confidence interval; IV, Instrumental Variables estimation; random, random effects model; SD, standard deviation. shown to be beneficial in the treatment of SAT loss, but their use remains investigational [25]. Additionally, clinicians might consider pioglitazone in patients with lipoatrophy who have evidence of insulin resistance. This could reduce SAT loss and improve some metabolic abnormalities. Adverse events The major side effects of GH axis therapies listed in the studies were oedema, arthralgias, myalgias and, less commonly, carpal tunnel syndrome and diabetes mellitus. Although some studies reported no risk of adverse events with treatment, our meta-analyses showed statistically significant increases in the frequencies of oedema and arthralgias in the treatment groups. However, providers must be careful in considering a summary effect of adverse events with these different drugs grouped together. As seen in Figure 4, when considered by itself, tesamorelin did not produce a significant increase in the frequency of arthralgias or oedema. While these summary effects may raise questions about the pathophysiological mechanisms of GH axis drugs, each drug should be considered individually in terms of its adverse effects. Until more results from large, randomized, placebo-controlled studies are available, clinicians must weigh the benefits and risks of each GH axis agent and individualize treatment for their patients.

8 460 T Sivakumar et al. Study or Subgroup Risk Ratio M-H, Random, 95% CI Year Risk Ratio M-H, Random, 95% CI Adverse Events Koutkia et al. [23] Grunfeld et al. [9] Falutz et al. [16] Not estimable 1.19 [1.05, 1.36] 1.10 [0.99, 1.23] 0.65 [0.38, 1.09] 1.06 [0.93, 1.21] 1.09 [0.98, 1.22] Total events Heterogeneity: τ 2 = 0.01; χ 2 = 6.14, df = 3 (P = ); I 2 = 51% Test for overall effect: Z = 1.56 (P = 0.12) Arthralgia Waters et al. [26] Schambelin et al. [19] Koutkia et al. [23] Falutz et al. [13] Grunfeld et al. [9] Falutz et al. [16] 2.00 [0.46, 8.76] 1.40 [1.02, 1.92] Not estimable 1.00 [0.23, 4.40] 1.24 [0.70, 2.18] 2.28 [1.32, 3.92] 0.56 [0.05, 5.80] 1.10 [0.61, 1.98] 1.43 [1.14, 1.78] 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) Edema Waters et al. [26] Schambelin et al. [19] Koutkia et al. [23] Falutz et al. [13] Grunfeld et al. [9] 2.00 [0.46, 8.76] 7.24 [2.98, 17.56] Not estimable 3.00 [0.13, 69.70] [3.53, 32.92] 1.65 [0.73, 3.75] 3.33 [0.14, 78.42] 3.95 [1.73, 9.00] Total events Heterogeneity: τ 2 = 0.50; χ 2 = 11.02, df = 5 (P = 0.05); I 2 = 55% Test for overall effect: Z = 3.27 (P = 0.001) Total (95% CI) 1.40 [1.13, 1.73] Total events Heterogeneity: τ 2 = 0.08; χ 2 = 67.48, df = 16 (P = ); I 2 = 76% Test for overall effect: Z = 3.10 (P = 0.002) Favours experimental Favours control Fig. 4 Adverse events. CI, confidence interval; M-H, Mantel-Haenszel; random, random effects model. Overall completeness and applicability of the evidence The large number of participants across the included studies allows us to form some hypotheses and draw some conclusions regarding GH axis drugs. However, because of the limited number of studies available for each specific drug type, we cannot make any definitive statements about the individual effectiveness of GH, GHRH, IGF-1 or tesamorelin. Furthermore, few studies evaluated whether the benefits of the intervention persisted after discontinuation of treatment, which is an important consideration given the costs and potential long-term side effects of the intervention. Lastly, no long-term studies have examined the benefits and consequences of extended use of these drugs.

9 Growth hormone axis treatments for lipodystrophy 461 Quality of the evidence The quality of the included studies was assessed by evaluating the risk of bias in each study. Overall, the risk of significant biases was low in all studies. The forest plots of the three primary outcomes demonstrate overall agreement in the estimation of treatment effect among all of the studies, which indicates that the results of this review are internally valid and could be replicated by other reviewers undertaking the same project. Potential biases in the review process For one study [3], estimation of changes in LBM from graphs in the published article was required, as numerical data were not available and we could not reach the authors. This may have resulted in inaccuracies of data abstraction. We attempted to minimize this inaccuracy by having three authors extract this data independently and averaging the result. We estimate that any remaining inaccuracy is minimal. Furthermore, we arbitrarily decided that changes in VAT/SAT mass and LBM were the most important consideration, as most of the studies focused on these outcomes as primary outcomes. However, other outcomes that we considered secondary outcomes may be more important in the clinical treatment of patients with HIVassociated lipodystrophy. Limitations in the included studies The major limitation of our review is that there were few studies meeting our inclusion criteria for each specific class of GH axis intervention. Only one study evaluated the effect of IGF-1 or GHRH, and thus it is difficult to draw conclusions about these two treatments. Furthermore, most of the participants in the studies were male. This is an important consideration, as the pattern of fat distribution is different in men and women. Also, the perception of body image is different between men and women, and this was not considered in the studies. The most common route of acquisition of HIV infection is also different between men and women and this may reflect differences in the socioeconomic and social climates of the male vs. female participants. This may have affected the results. Furthermore, there was no consensus definition of HIV-associated lipodystrophy among the included studies, which may affect the clinical applicability of the data. Finally, none of the studies examined the long-term benefits and risks of treatment, and very few evaluated whether the benefits were retained after discontinuation of treatment. Agreements and disagreements with other studies or reviews No previous systematic reviews have evaluated the use of GH axis drugs for the treatment of HIV-associated lipodystrophy. Reviews have compared GH with other treatments, as mentioned above. Our present review complements the growing body of evidence regarding the efficacy of GH axis treatments for HIV-associated lipodystrophy. Conclusion Benefits and side effects of the use of GH axis drugs for the treatment of HIV-associated lipodystrophy Overall, GH axis drugs compared with placebo were effective in significantly reducing VAT mass and increasing LBM. They also reduced SAT mass, but this result was not statistically significant. Statistically significant adverse effects of treatment were arthralgias and peripheral oedema. Implications for practice The results of our review support the current understanding of the role of the GH axis in the alteration of physiological processes affecting fat distribution and metabolism. There is currently insufficient evidence to recommend the long-term or routine use of GH axis drugs for the treatment of HIVassociated lipodystrophy. However, our review shows that these drugs can be effective in producing substantial reductions in VAT mass and significant increases in LBM. This may result in short- or long-term improvements in metabolic derangements and/or self-perceptions of body image. Thus, clinicians may consider using this category of drugs in the treatment of individual patients whom they feel may benefit. Generally, the GH axis drugs were well tolerated, as the overall number of side effects was not significantly different between the intervention and placebo groups. However, subgroup analysis revealed that patients receiving GH axis drugs experienced a higher rate of arthralgias and peripheral oedema. Implications for research The beneficial effect of this category of drugs on VAT mass and LBM provides insights into the pathophysiology of HIV-associated lipodystrophy and its relation to the GH axis. These results may instigate further research into both the pathogenesis of this disorder and other potential treatments for this condition along this axis. Because negative perception of body habitus is a common cause of noncompliance with HAART, future studies should examine the effects of GH axis treatments on compliance with HAART

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