Skip Navigation LinksHome > October 22, 1999 - Volume 13 - Issue 15 > Recombinant human growth hormone improves the fat redistribu...
AIDS:
Clinical: Original Papers

Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV

Wanke, Christineab; Gerrior, Julab; Kantaros, Julieb; Coakley, Eoinb; Albrecht, Maryb

Free Access
Article Outline
Collapse Box

Author Information

From the aDivision of Infectious Disease, Beth Israel Deaconess Medical Center, Harvard Medical School; and bDivision of Nutrition and Infection, Department of Community Health, Tufts School of Medicine, Boston, MA, USA.

Sponsorship: This work was partly supported by NIH grant no. 1PO1DK45734-01A2 and by GCRC grant no. MO1-RR00054.

Correspondence to: Christine Wanke, MD, Division of Nutrition and Infection, Department of Community Health, Tufts School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Tel: +1 617 636 0921; fax: +1 617 636 3810; e-mail: cwanke@infonet.tufts.edu

Received: 12 April 1999; revised: 1 July 1999; accepted: 26 July 1999.

Collapse Box

Abstract

Objective: To determine the efficacy of recombinant human growth hormone (rhGH) in the treatment of the fat redistribution syndrome (FRS) in patients with HIV.

Design: A prospective, open-label study.

Setting: An urban, university-affiliated Infectious Disease Clinic.

Patients: Ten HIV-infected patients (seven men, three women) with FRS.

Interventions: Treatment with 6mg of rhGH a day, subcutaneously for 12 weeks.

Main outcome measures: Body mass index (BMI), body composition by bioelectrical impedance analysis (BIA), body composition by anthropometrics (including waist/hip ratio), buffalo hump.

Results: The mean age was 41.7 years, the CD4 cell count was 247, and the HIV RNA was 95735 copies/ml; 50% had undetectable viral RNA. The BMI was significantly increased from baseline to the end of treatment with growth hormone (25.3-26.9kg/m2; P<0.04); the waist/hip ratio significantly decreased from baseline levels, after treatment with growth hormone (1.03-0.9; P<0.04); mid-thigh circumference increased significantly when baseline was compared with measures after treatment (49.1-51.8cm; P<0.03). One patient had to discontinue therapy because of hyperglycemia.

Conclusion: Short-term treatment with rhGH improved the alterations in body shape that occur with FRS in HIV-infected patients. Waist/hip ratios and mid-thigh circumference are useful measures to follow alterations in body shape in FRS.

Back to Top | Article Outline

Introduction

Body shape changes, also known as the fat redistribution syndrome (FRS) or lipodystrophy have been noted with increasing frequency in patients infected with HIV, often in those taking protease inhibitors[1-7]. These body shape changes include thinning of the face, thinning of the extremities, truncal obesity and breast enlargement. A buffalo hump, or increased dorsocervical fat pad, may also be noted, although less frequently[8-10]. Metabolic abnormalities including glucose intolerance, insulin resistance, elevated triglycerides and cholesterol have also been noted in this syndrome[11-14]. The syndrome has been difficult to define rigorously because body weight may not change and bioeletrical impedance analysis (BIA), which is the measure of body composition that is most readily available, does not measure regional body fat. Total body computerized axial tomography scanning and magnetic resonance imaging may provide better definition of regional body composition, but are not routinely available for monitoring clinical status[15-17]. Dual energy X-ray absorptiometry may also provide measurement of regional body composition, but this method has not been validated, nor is it routinely available for clinical use[18].

The best method of treating this syndrome is not clear. Discontinuing or changing antiretroviral agents may not be a feasible clinical option and may not benefit the body shape changes[19]. Recombinant human growth hormone (rhGH) has been proposed as a potential therapeutic agent, with case reports of successful therapy reported at the 12th International AIDS Meeting in Geneva in 1998[20]. We describe 10 patients who presented with FRS and the results of treatment with 3 months of rhGH.

Back to Top | Article Outline

Methods

Population

Patients either self-identified FRS or their primary care physician noted the body shape changes. Patients thus identified were referred to a research dietitian with a special interest in HIV at an urban Infectious Disease Clinic, which provides care for 1000 HIV-infected patients. Patients were asked about their medication usage and their level of exercise. A patient was considered to exercise if he or she partook in active aerobic or resistance exercise for 30min at least three times per week. Patients were encouraged to follow their usual exercise pattern and not to initiate or discontinue an exercise program during the period of the study. Dietary advice was not provided to patients during this time and patients were encouraged to eat as they had previously.

Back to Top | Article Outline
Nutritional assessment

Height and weight were obtained on a calibrated scale and were measured to the nearest 0.1cm and 0.1kg, respectively. Anthropometric measurements were taken of the triceps and subscapular skin folds by a trained dietitian in triplicate; the same dietitian performed all of the patient measurements. Calculation of body fat from anthropometric measurements was performed by the sex-specific equations of Durnin and Wormersley[21]. Fat-free mass was obtained by subtraction of fat mass from total body weight.

The waist circumference was measured at the thinnest area below the rib cage and above the umbilicus. The hip was measured at the greatest circumference around the hip or buttocks with the subject standing, relaxed, with feet together and arms by the side. The waist/hip ratio was calculated from these measures[22].

Chest (male) and breast (female) measurements were taken at the nipple level to the nearest 0.1cm. Mid-arm and mid-thigh circumference measurements were obtained at the measured mid-point of the upper right arm and right thigh to the nearest 0.1cm. Mid-arm muscle circumference was determined using the standard equation of Frisancho[23]. BIA was performed using a Quantum hand-held analyser (RJL Systems, Clinton, MI, USA).

Back to Top | Article Outline
Chart review

Laboratory data were abstracted from the patients‚ clinic records from values obtained within 1 month of the visit for FRS. Current medications, including antiretroviral agents and anabolic agents, were confirmed by chart review.

Back to Top | Article Outline
Growth hormone

Ten patients were treated with rhGH (Serono Laboratories, Norwood, MA, USA). Treatment was instituted at 6mg subcutaneously on a daily basis and was continued at the same dose for 12 weeks.

Back to Top | Article Outline
Consent

All patients provided informed consent, approved by the Institutional Review Board of the Beth Israel Deaconess Medical Center.

Back to Top | Article Outline
Statistical analysis

The data were entered into Statview (SAS Institute, Cary, NC, USA). Descriptive statistics were performed. Groups were compared by analysis of variance. Continuous variables were compared by paired t-test or Fisher‚s exact test.

Back to Top | Article Outline

Results

The demographic characteristics of 10 patients with FRS are presented in Table 1. Two of the patients (20%) had HIV RNA levels greater than 100000copies/ml. Five of the 10 patients (50%) had undetectable levels of HIV RNA, most by ultrasensitive assays. Three of the 10 patients had been on replacement testosterone for more than 3 months and one of the three was also taking oxandrolone. Fifty per cent of the patients reported that they exercised regularly. Of note was the fact that the fasting glucose, triglyceride and cholesterol levels in these patients were only moderately abnormal (see Table 1).

Table 1
Table 1
Image Tools

The body composition measures of the patients at baseline are presented in Table 2. All of the women in the study (n=3) also reported an increase in bra cup size. Only one of the patients who was treated with growth hormone had a dorsocervical fat pad (buffalo hump).

Table 2
Table 2
Image Tools

The results of the treatment with rhGH are shown in Table 2. The waist/hip ratio and the mid-thigh circumference were significantly improved after therapy; the mid-arm circumference was also improved, but this difference did not reach statistical significance. Three patients exhibited significant side-effects with the administration of rhGH: one patient complained of severe myalgias, and one complained of hand swelling. Both of these patients elected to continue rhGH at the same dose every other day and completed the 12 weeks. The third patient was noted to have an elevated glucose (243mg/dl) and a hemoglobin A1C of 7.9mg/dl at week 6. This patient‚s physician discontinued the growth hormone at this point. Follow-up laboratory values were available for eight of the remaining nine patients; there was no significant difference in follow-up glucose, triglyceride or cholesterol levels after therapy (data not shown).

All patients who were treated with rhGH subjectively felt that their body shape had improved while on the therapy. Two of the patients have had a subjective and objective regression of the improvements in body shape at a visit 2 months after discontinuing treatment. One patient had discontinued growth hormone and was lost to follow-up. The remaining seven patients have elected to continue growth hormone every other day with maintenance of their body shape improvements.

Back to Top | Article Outline

Discussion

Self-identification of patients with FRS is the usual way that the diagnosis has been made and has proved to be very accurate[24]. All of the patients in this study who complained of body shape changes did indeed have such alterations when measured by a dietitian. Patients presented with reasonably advanced HIV disease, although they represented the full spectrum of HIV disease, with a wide range of CD4 cell counts and an equally wide range of HIV RNA and response to antiretroviral therapy. The laboratory abnormalities seen in this group of patients were moderate; the glucose, triglyceride and cholesterol values were not within the normal range but were not extremely abnormal. These data suggest that the biochemical abnormalities are not universally severe, and that not all patients with alterations in body shape will have biochemical abnormalities. Thirty per cent of the patients were being treated with anabolic agents, either as replacement for low testosterone or for assistance in building lean body mass, suggesting that androgens or androgen analogues may not provide protection from FRS, nor will they be effective therapy for the syndrome. Although the exercise data was self-reported and not fully quantified, this was a relatively physically active group of patients, which suggests that exercise alone may not be sufficient to prevent or treat FRS.

The body mass index (BMI) of these patients suggests that they are not wasted patients, nor is the lean body mass of these patients (by BIA or mid-arm muscle circumference) in an unfavorable range. The percentage of body fat as measured by BIA and two-site anthropometry is quite different, 25.8 and 13.4%, respectively, suggesting that these methods may not adequately measure the redistribution of body fat in this population and are less useful in following response to therapy.

Short-term treatment of FRS with subcutaneous rhGH was successful in objectively improving body shape for the treated patients. This is not surprising because rhGH has been successful in decreasing visceral fat (as determined by waist/hip measurements) and subcutaneous fat in growth hormone-deficient adults[25]. In this study, the most useful measurements to monitor the response to treatment with growth hormone were the waist/hip ratio and the thigh circumference. The desired waist/hip ratio is <0.9 for men and <0.8 for women[22]. Waist/hip ratios above this level are associated with an increased risk of diabetes and cardiovascular disease[26]. These measurements are readily available to clinicians and appear to demonstrate objectively the patients‚ subjective impression of improvement. The single patient with a buffalo hump also responded visibly to treatment with rhGH, but there is not a readily apparent means to quantify this reduction. The side-effects of rhGH were not significant, except in the one patient who developed elevated serum glucose.

FRS does not appear to resolve without intervention. rhGH appears to be an effective, albeit expensive, therapy for the body shape changes in HIV-infected patients with FRS. It seems to modulate but not correct the underlying metabolic deficit, as the body shape changes do not totally resolve and may recur after the cessation of therapy with rhGH. Further studies to demonstrate the optimal dose and dosing interval of growth hormone, as well as the ideal length of therapy, are necessary.

A working definition of FRS needs to be formalized to promote the ability to study this syndrome and to demonstrate changes caused by therapeutic interventions. Any definition of the alteration in body shape in FRS should include the waist/hip ratio and the mid-thigh circumference. Further studies are need to provide a better understanding of the pathophysiology of this syndrome, so that interventions that directly target the underlying pathogenetic mechanisms may be developed.

Back to Top | Article Outline

References

1. Carr A, Samaras K, Burton S, Law M, Freund J, Chisolm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlidemia and insulin resistance due to HIV protease inhibitors. AIDS 1998, 12:F51-F58.

2. Wong-Beringer A, Beringer P, Lovett MA. Hypertrophy of breasts in a patient treated with indinavir [letter]. Clin Infect Dis 1997, 25:937.

3. Striker R, Conlin D, Marz M, Wiviott L. Localized adipose tissue hypertrophy in patients receiving immunodeficiency virus protease inhibitors. Clin Infect Dis 1998, 27:218-220.

4. Lipsky, J. Abnormal fat accumulation in patients with HIV-1 infection. Lancet 1998, 351:847-848.

5. Miller KK, Daly PA, Sentochnik D, Doweiko J, Samore M, Basgoz NO, Grinspoons. Pseudo-Cushings syndrome in human immunodeficiency virus-infected patients. Clin Infect Dis 1998, 27:68-72.

6. Roth VR, Kravcik S, Angel JB. Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 1998; 27:65-70.

7. Dong K, Flynn MM, Dickinson BP, Rich JR, Tashima K, Flanigan TP, Carpenter CCJ. Changes in body habitus in HIV+ women after initiation of protease inhibitor therapy. 12th World AIDS Conference, Geneva, July 1998 [Abstract no. 12373].

8. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. Buffalo hump in HIV infected patients on antiretroviral therapy. Lancet 1998, 351:867-870.

9. Wurtz, R. Buffalo hump in HIV. Lancet 1998, 351:1735-1736.

10. Schindler JT, Sponer KM, Decker CF. Buffalo humps associated with protease inhibitors [letter]. Ann Intern Med 1998, 129:164.

11. Mulligan K, Tai VW, Algren H, Chernoff DN, Lo JC, Schambelan M. Evidence of unique metabolic effects of protease inhibitors. 5th Conference on Retroviruses and Opportunistic Infections, 1998 [Abstract no. 414].

12. Sullivan AK, Feher MD, Nelson MR, Gazzard BG. Marked hypertriglyceridemia on ritonavir therapy [letter]. AIDS 1998; 12:1393-1394.

13. Walli RK, Hefort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1 infected patients. AIDS 1998; 12:F167-F173.

14. Carr A, Samaras K, Chisolm DJ, Cooper DA. Pathogenesis of HIV-1 protease inhibitor associated peripheral lipodystrophy, hyperlipidemia, and insulin resistance. Lancet 1998, 352:1881-1883.

15. Miller K, Jones E, Yanovski J, Shankar R, Feuerstein I, Falloon J. Visceral abdominal fat accumulation associated with use of indinavir. Lancet 1998, 351:871-875.

16. Engelson EE, Kotler DP, Tan XY, Agin D, Bashist B, Wang J, Heymsfield SB. Altered body fat distribution in HIV infections: regional body composition measurements by whole body MRI and DXA scans. 12th World AIDS Conference, Geneva, July 1998 [Abstract no. 32181].

17. Kotler DP, Rosenbaum KB, Wang RN, Pierson RN. Alterations in body fat distribution in HIV-infected men and women. 12th World AIDS Conference, Geneva, July 1998 [Abstract no. 32173].

18. Wanke CA. Epidemiological and clinical aspects of the metabolic complications of HIV infection: the fat redistribution syndrome. AIDS 1999; 13:1287-1293.

19. Hirsch M, Klibanski A. What price progress? Pseudo-Cushing‚s syndrome associated with antiretroviral therapy in patients with human immunodeficiency virus infection. Clin Infect Dis 1998, 27:73-75.

20. Torres R, Unger KW. Treatment of dorsocervical fat pads (buffalo hump) and truncal adiposity with Serostim (recombinant human growth hormone) in patients with AIDS maintained on HAART. 12th World AIDS Conference, Geneva, July 1998 [Abstract no. 32164].

21. Durnin JVGA, Wormersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurement of 481 men and women aged 16 to 72 years. Br J Nutr 1974, 32:77-96.

22. Callaway CW, Chumlea WC, Bouchard C, et al. Circumference, in anthropometric standardization reference manual. Lohman TG, Roche AF, Martovell R, editors. Champagne, IL: Human Kinetics Books; 1988.

23. Frisancho AR. New norms of upper limb fat and muscle areas for assessment for nutritional status. Am J Clin Nutr 1981, 34:2540-2545.

24. Pettit R, Muurahainen N, Falutz J, et al. HIV related truncal obesity: a comparison of physician and patient diagnosis. 6th Conference on Antiretroviral Therapy, Chicago, 1999 [Abstract no. 651].

25. Cuneo RC, Judd S, Wallace JD, et al. The Australian multicenter trial of GH treatment in GH-deficient adults. J Clin Endocrinol Metab 1998; 83:107-116.

26. Spiegelman D, Israel RG, Bouchard C, Willett WC. Abdominal fat mass, percent body fat, and body fat distribution: which is the real determinant of blood pressure and glucose. Am J Clin Nutr 1992; 55:1033-1044.

Keywords:

Lipodystrophy; fat redistribution syndrome; HIV; growth hormone; body composition

© 1999 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.