Numbers of patients given are the numbers for whom data were available. For visceral adipose tissue, the aggregated change during months 24 through 36 among the patients initially randomized to growth hormone (GH) and switching to placebo was significant vs initial baseline (P = .046). Insulinlike growth factor 1 (IGF-1) data are presented for safety population for all visits, including safety visits. Error bars indicate standard error of the mean.
Lo J, You SM, Liebau J, Lee H, Grinspoon S. Effects of Low-Dose Growth Hormone Withdrawal in Patients With HIV. JAMA. 2010;304(3):272-274. doi:10.1001/jama.2010.989
To the Editor: In an 18-month randomized placebo-controlled study of patients with human immunodeficiency virus (HIV) having abdominal fat accumulation and relative growth hormone (GH) deficiency, low-dose, long-term GH reduced visceral adipose tissue (VAT) but worsened glucose control.1 To investigate changes in VAT and other parameters after GH discontinuation, data from an extension in which participants crossed over from their initial treatment (months 0-18) to the opposite treatment (immediately after the month 18 visit through month 36) were analyzed.
Of 21 participants originally assigned to receive GH who finished initial treatment (months 0-18), 20 crossed over to receive placebo, 17 of whom (85%) completed the 36-month study. Of 27 participants originally assigned to placebo who finished initial treatment (months 0-18), 24 crossed over to receive GH, 20 of whom (83%) completed the study. Participants who dropped out were not different from completers. Patients but not researchers remained blinded to treatment status.
Determination of aggregate change for months 24, 30, and 36 vs initial baseline was performed as previously described1 for months 6, 12, and 18, using longitudinal mixed modeling and repeated-measures analysis of variance including all available data. All P values are 2-sided and P < .05 was significant. Power calculations were previously reported.1 Analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina). The study was approved by the Massachusetts General Hospital institutional review board, and participants provided written informed consent.
Among participants who received GH during the first 18-month period, VAT increased 9.3% (95% confidence interval [CI], 2.9%-15.8%) within 6 months of crossover to placebo (P = .007 vs 18 months) (Figure). The rebound in VAT after GH discontinuation (months 24, 30, and 36) was large, with an aggregate increase over initial baseline of 8.3% (95% CI, 0.6%-15.9%; P = .046), much larger than the small decrease in VAT seen among those who received placebo during months 0 through 18 (P = .008) (Figure). This result remained significant in sensitivity analyses controlling for age, sex, physical activity, and dietary intake.
After discontinuation of GH, insulinlike growth factor 1 (IGF-1) returned rapidly to initial baseline levels (Figure). For metabolic variables that had changed significantly with GH during the primary efficacy phase, the aggregate changes in triglyceride and diastolic blood pressure values after crossover to placebo were not significantly different from initial baseline. However, aggregate 2-hour glucose levels were significantly higher by 9.8% (95% CI, 0.6%-19.0%; P = .048) after crossover compared with initial baseline, suggesting residual adverse effects after GH discontinuation. A detailed table of all outcome data is available from the authors on request.
None of the patients switching to placebo changed antiretroviral class after GH discontinuation.
Low-dose GH for 18 months significantly reduced VAT, but after GH was discontinued, VAT rebounded rapidly to a level that was significantly above initial baseline values. Rapid rebounds in VAT were seen in studies of HIV-infected patients receiving much higher-dose GH,2,3 but this study is the first to investigate the withdrawal of long-term, low-dose GH in this population. The change in VAT was larger in participants receiving placebo after GH crossover than in those receiving placebo in the first half of the study, and thus likely represents more than the natural history of change in visceral fat among HIV patients.
Levels of IGF-1, which is responsible for certain actions of GH, were not lower than baseline after GH withdrawal, but further studies are necessary to determine whether low-dose GH reduces endogenous GH activity, accounting for the changes seen after GH discontinuation. The conclusions in this study are limited to low-dose GH, and HIV patients using higher doses of GH may experience different changes in VAT and glucose during and after GH discontinuation.
Growth hormone is not approved by the Food and Drug Administration for use to reduce visceral fat in HIV and may be associated with a deleterious rebound in visceral adiposity after discontinuation.
Author Contributions: Dr Grinspoon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lee, Grinspoon.
Acquisition of data: Lo, You, Liebau, Grinspoon.
Analysis and interpretation of data: Lo, You, Lee, Grinspoon.
Drafting of the manuscript: Grinspoon.
Critical revision of the manuscript for important intellectual content: Lo, You, Liebau, Lee, Grinspoon.
Statistical analysis: Lo, Lee, Grinspoon.
Obtained funding: Grinspoon.
Administrative, technical, or material support: Lo, You, Liebau, Grinspoon.
Study supervision: Grinspoon.
Financial Disclosures: Dr Grinspoon reported having served as a consultant for EMD Serono, Theratechnologies, Stratum Medical, and Hoffman LaRoche, and having received research support from Theratechnologies, EMD Serono, Bristol-Myers Squibb, and GlaxoSmithKline. Dr Grinspoon also reported having provided expert testimony before a Food and Drug Administration advisory panel as the principal investigator of a study of growth hormone releasing hormone. Ms You reported having received salary support from Genentech for an unrelated project. No other disclosures were reported.
Funding/Support: The study was funded by grants R01 DK63639 (S.G.), K23 HL092792 (J. Lo), M01 RR01066, and 1 UL1 RR025758 from the National Institutes of Health; by the Harvard Clinical and Translational Science Center; and by the National Center for Research Resources. EMD Serono provided growth hormone and placebo but did not provide funding for the study.
Role of the Sponsor: The funding organizations approved the study and its design but had no role in the conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. EMD Serono had no role in the study design, conduct, or analysis or decisions about manuscript submission. EMD Serono reviewed an early draft of the manuscript as per the Product Donation Agreement but did not review the final version of the manuscript and did not make any decisions regarding content.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Additional Contributions: Jeffrey Wei, BA, Massachusetts General Hospital Program in Nutritional Metabolism, helped with data collection and analysis. Mr Wei did not receive compensation for his role in the study.