LIPODYSTROPHY CASE STUDY- VISCERAL FAT

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Case Study

A 56-year-old white man presents complaining of increased abdominal girth. He was diagnosed as HIV infected in 1990. He originally received NRTI monotherapy, then dual-NRTI therapy. In 1993, weight loss of 14% was noted, and he took part in an National Institutes of Health–funded clinical study of the effect of an anabolic steroid on body composition, which had modest benefit. The patient’s CD4+ cell count at that time was 205 cells/mm3.

Cytomegalovirus (CMV) retinitis developed in the right eye in late 1994. An induction course of intravenous ganciclovir was given, followed by intravenous cidofovir. Because of persistent disease flares, intravenous foscarnet therapy was added. A few months later, weight loss recurred. Progression of CMV retinitis then was documented in the right eye and appeared in the left eye as well. The patient’s CD4+ cell count at this time was 54 cells/mm3.

In mid-1996, the patient was started on a regimen of ritonavir 300 mg twice daily, saquinavir 600 mg twice daily, stavudine 40 mg twice daily, and lamivudine 150 mg twice daily, and he stabilized clinically, reaching a CD4+ cell count of 233 cells/mm3 in early 1997. Several months later, he developed uveitis not associated with active CMV retinitis, with features similar to those seen in autoimmune diseases, which led the treating ophthalmologist to suggest that reconstitution of the immune system might be the underlying cause. For this reason, the patient was treated with topical steroids for several months, with eventual resolution of the uveitis. He went on to make a complete recovery, except for visual scotomata, and he returned to full-time employment.

The patient was seen again late in 1998. He had remained on the same antiretroviral regimen, with an undetectable viral load, and his CD4+ cell count was 266 cells/mm3. He complained of abdominal bloating and a decrease in physical mobility in his trunk. There were no changes in bowel habits. His body mass index was 24 and by visual examination, he had central obesity as well as mild to moderate loss of facial fat and limb fat. Routine laboratory analyses were unremarkable, although his fasting glucose level was 110 mg/dL (6.11 mmol/L). Serum triglycerides and cholesterol concentrations were all elevated to varying degrees, although specimens were not drawn in the fasting state.

The patient agreed to participate in a community-based, open-label, 6-month study of the effects of recombinant human growth hormone (rhGH) 6 mg/day administered subcutaneously, the approved dose for the treatment of AIDS-related wasting syndrome.[1] The study was expanded to include a 12-week washout period after Month 6, after which laboratory and clinical assessments were repeated, then rhGH retreatment was commenced with 4 mg every other day subcutaneously, for an additional 6 months. The table presents the patient’s dual energy x-ray absorptiometry (DEXA) data from this study.

The patient gained around 4.5 kg during the initial 6 months of rhGH therapy, despite losing more than 5.0 kg of fat. He complained of joint stiffness, which improved somewhat with reduced salt intake and low doses of diuretics. The effect of rhGH therapy was most marked in the abdomen, as demonstrated by a reduction of 3.3 inches in waist circumference and a decrease in the waist-to-hip ratio from 1.00 to 0.91 at 6 months. The effects of the 4 mg every other day dose of rhGH were much smaller than those of the 6 mg/day dose, but the patient maintained a noticeable improvement in body habitus, especially compared with his original baseline values.

The patient then was seen intermittently over the next several years. He remained on the same antiretroviral regimen of stavudine, lamivudine, saquinavir, and ritonavir, maintaining undetectable viral load. He developed severe facial lipoatrophy and eventually was treated with poly-L-lactic acid facial injections, with excellent results. The patient remained dissatisfied regarding his central obesity. Testosterone therapy was tried—initially with pharmacologic doses given by intramuscular injection, then with transdermal therapy—but the effects were mainly emotional and psychological, and little change in the patient’s habitus was noted. There were other medical issues, including psychological issues that interfered with his productivity and which were managed with the help of a psychiatrist.

In early 2007, the patient has a body shape that is not very different from that of the summer of 1998, and his abdominal symptoms and physical limitations remain similar to those at that time. He has remained on the same antiretroviral regimen for the past 10 years. His latest CD4+ cell count is 544 cells/mm3 and his plasma viral load is undetectable.

What are the patient’s options?

Discussion

Epidemiology, Etiology, and Clinical ImpactOf all the alterations reported in the HIV-associated lipodystrophy syndrome, the accumulation of intra-abdominal fat, especially visceral fat, is the most poorly understood. Lipodystrophy syndrome is sometimes referred to as “fat redistribution,†which implies some inverse relationship between the areas losing fat and the areas gaining fat. Although an increase in abdominal fat is observed in approximately one third of patients receiving HAART, it is uncertain whether this change is in any way related to the development of lipoatrophy or other metabolic perturbations, including dyslipidemia and insulin resistance.

In particular, the Fat Redistribution and Metabolism (FRAM) study examined a cohort of almost 1200 HIV-infected subjects and 300 controls with a diversity that parallels the HIV epidemic in the United States, published separate reports on men[2] (Capsule Summary) and women (Capsule Summary).[3] The results of body fat compartment analyses by whole body magnetic resonance imaging measurements demonstrated that lipoatrophy was associated with HIV infection in both men and women, whether or not they had noticed a change. The results of DEXA scanning, anthropometric analyses, and self-report were similar. The results of visceral adipose tissue (VAT) measurements differed in men and women, being lower in HIV-infected men than in control men and higher in HIV-infected women than in control women. Importantly, there was no statistical association between the amount of subcutaneous fat and visceral fat in either men or women. Similar results were obtained in the Women’s Interagency HIV Study.[4] Wand and colleagues[5] reported on the relative changes in VAT and subcutaneous adipose tissue in patients who either changed the NRTIs in their HAART regimen or were treated with rosiglitazone and found a direct, rather than an inverse, association between changes in the 2 compartments. These latter data also do not support the notion that accumulation of visceral fat and depletion of subcutaneous fat are tightly linked.

The relationship between central and peripheral fat in HIV infection may be affected by the presence of the metabolic syndrome in HIV-infected individuals and in the general population. Many studies have estimated the prevalence of the metabolic syndrome in HIV-infected cohorts and have found rates from 20% to 35%, similar to the rates seen in the US general population. Since the development of the metabolic syndrome is at least in part genetically based, a proportion of HIV-infected individuals carry susceptibility genes. A study validating a case definition score for lipodystrophy noted that subjects who met the proposed criteria for lipodystrophy were more likely also to meet the criteria for the metabolic syndrome compared with subjects who did not meet the lipodystrophy case definition criteria.[6] Studies of single nucleotide polymorphisms by microarray in a well-defined cohort of HIV-infected subjects undergoing HAART found associations between a polymorphism of the resistin gene and both a cluster of metabolic abnormalities[7] (Capsule Summary) as well as lipoatrophy.[8] A polymorphism of a susceptibility gene for hemochromatosis was found to be protective against the development of lipoatrophy in the same cohort.[9] No study has specifically examined genetic relationships to visceral fat accumulation in HIV-infected individuals.

The development of visceral adiposity significantly disrupts patients’ assessment of their body image and impairs many domains of health-related quality of life.[10] Several uncontrolled studies have found evidence of adverse outcomes, such as decreased adherence to treatment.[11] The relationship between an individual’s body image assessment and health-related quality of life is complex. Using a Body Image Quality of Life Inventory instrument, Huang and colleagues[12,13] found significant differences in sense of self, social functioning, sexuality, emotional well-being, and activities of daily living in men and women with lipodystrophy. The impact of visceral adiposity on quality of life was found to be similar to or greater than that produced by other chronic diseases, including essential hypertension and both type 1 and type 2 diabetes mellitus.[14]

ManagementThe cornerstones for managing the various manifestations of the HIV-associated lipodystrophy syndrome are 3-fold: avoid, switch, and treat.

There are no data demonstrating that an increase in visceral fat can be avoided by specific management choices. An early increase in trunk fat and visceral fat has been reported in many of the treatment studies of antiretroviral-naive subjects. Although treatment-associated differences in limb fat or subcutaneous fat contents have been noted in several studies such as GS 903,[15] GS 934 (Capsule Summary),[16] and KLEAN (Capsule Summary),[17] no study has reported a difference in the increase in visceral fat based on the choice of antiretroviral agents.

A change in antiretroviral regimen, and particularly the cessation of high-dose ritonavir, would be an obvious treatment initiative in this individual, who has a near-pathologic attachment to the specific regimen that changed the course of his disease. However, there is no evidence from controlled clinical trials that modification or discontinuation of PI therapy affects visceral fat content.[18,19] By contrast, several studies have documented changes in body composition with switching from NRTIs, particularly stavudine,[20] although the observed effect is an increase in fat, including trunk fat. This patient had developed severe facial lipoatrophy with only moderate loss of limb fat despite continued stavudine therapy.

Lifestyle interventions are key elements in the management of visceral obesity in otherwise healthy adults. Roubenoff and colleagues[21] performed a proof-of-principle study demonstrating the ability of a program of diet and exercise to reduce visceral fat content. Fitch and colleagues[22] performed a randomized trial of intensive lifestyle modification for 6 months that included weekly meetings and demonstrated mild benefits in some measures, including an approximately 1 inch decrease in waist size; of note, serum lipids did not change (Capsule Summary). Engelson and colleagues[23] performed an uncontrolled study of diet and supervised exercise 3 times per week in obese, HIV-infected women and demonstrated a 7% loss of weight over 3 months, with a decrease in waist size of almost 2 inches. The loss of visceral fat in this group was relatively small, although baseline VAT was not elevated despite substantial obesity (baseline body mass index = 34 kg/m2). In this study, weight loss did not lead to improvements in either insulin resistance, as measured by the frequently sampled, intravenous glucose tolerance test, or in fasting lipids.

No therapies are approved by the US Food and Drug Administration (FDA) for the treatment of visceral fat accumulation. Pilot studies in HIV infection had suggested that metformin could lead to less abdominal fat, and studies in HIV-uninfected subjects suggested that its use in diabetics could lower visceral fat to some extent. Mulligan and colleagues[24] recently reported the results of the ACTG 5082 study examining the effects of metformin (1000 mg twice daily) and rosiglitazone (4 mg once daily), alone or in combination, on insulin resistance and body fat distribution in HIV-infected individuals with insulin resistance and fat redistribution, as reflected in an elevated waist-to-hip ratio. Both therapies improved insulin resistance, with combination therapy having the greatest effect. Neither therapy significantly affected body fat content or distribution. Metformin therapy led to mild weight loss with decreases in both visceral and subcutaneous fat contents.

Shikuma and colleagues[25] presented the results of the ACTG 5079 study, a randomized, controlled, 24-week trial of transdermal testosterone therapy in HIV-infected individuals with low testosterone levels and evidence of visceral fat accumulation. Therapy was found not to affect visceral fat content but to reduce subcutaneous fat.

The use of recombinant human growth hormone (rhGH) as a treatment for visceral fat accumulation seems counterintuitive because its approved use in HIV infection is as a treatment for wasting, based on the results of a randomized controlled trial.[26] Although those studies documented an increase in lean mass as a result of rhGH therapy, they also documented a decrease in fat content, consistent with the known lipolytic effect of growth hormone. In addition, there is an inverse association between visceral fat content and growth hormone secretion in both HIV-infected and HIV-uninfected subjects. Growth hormone deficiency—either congenital or related to trauma, surgery, or tumor—is associated with visceral fat accumulation, and growth hormone replacement decreases visceral fat content. In addition, decreased growth hormone secretion has been documented by overnight sampling in both HIV-infected and HIV-uninfected adults.[27] Johannsson and colleagues[28] documented a decrease in visceral fat content in response to low-dose rhGH therapy (1 mg/day) in men with visceral obesity. Therapy was associated with an increase in insulin resistance after 1 month of therapy, with return to baseline by Month 6 of continued therapy.

Preliminary observations had suggested that rhGH therapy was associated with reductions in breast size in women and in buffalo hump size. A 6-month, open-label study of rhGH at 6 mg/day, the dose prescribed for wasting, was performed in a collaborative effort between a community-based clinical trials organization and an academic medical center.[29] The trial was expanded to include a 12-week washout phase followed by 6 months of therapy with a dose of 4 mg every other day. The patient described in the case vignette was a subject in this study. The results showed a strong effect of rhGH at 6 mg/day, with a 45% reduction in VAT volume. However, therapy had significant toxicities. The gain in “lean mass†was approximately 60% greater than that seen in the treatment of AIDS wasting,[26] and symptoms and signs of fluid overload were common. The results of this study also showed metabolic associations including an improvement in serum cholesterol concentrations but a worsening of insulin resistance, both as elevations of fasting insulin and glucose, as well as elevations in the area under the curve of glucose and insulin concentrations during an oral glucose tolerance test. Ten percent (3 of 30 subjects) became reversibly diabetic during the trial. In addition, prompt reversibility of the benefits of therapy were demonstrated during the washout phase of the trial. The lower dose of rhGH administered during the extension phase also promoted a loss of VAT but to a lesser extent than the higher dose. Several other small studies have been performed using doses ranging from 1-6 mg/day. Analysis of the published results suggest that there is a clear dose-response relationship in the amount of visceral fat lost over a 3-month period.

Two randomized, double-blind, placebo-controlled trials of rhGH were undertaken in HIV-infected individuals chosen on the basis of anthropometric characteristics predicting the presence of excess visceral fat content.[30,31] Both studies compared a dose of 4 mg/day with placebo, and one study also examined 4 mg on alternate days. Significant decreases in VAT were demonstrated at both doses of rhGH after 3 months. Other experimental manipulations were made after the first 12 weeks to examine different strategies of maintenance therapy. The reaccumulation of visceral fat off therapy was confirmed although reversal was not complete within the time frame studied. The metabolic benefits of reducing total and non-high density lipoprotein cholesterol concentrations and raising high density lipoprotein cholesterol concentrations were confirmed in this study. Once again, rhGH treatment was associated with an increase in insulin resistance, as measured at 12 weeks with a return to baseline by 24 weeks. One area of concern in these studies was the demonstration of a significant elevation in mean serum insulin-like growth factor 1 (IGF-1) concentration. Such a result is to be expected, since rhGH acts through IGF-1. There is a concern that elevated IGF-1 levels might be associated with the promotion of cancer growth, even though the elevation is modulated by the simultaneous elevation of an IGF-binding protein. Three cancers had been seen in the small study by Engelson and colleagues,[29] but no evidence of an increase in cancer detection was noted during the larger studies that have followed.

and colleagues[14] reported on quality of life and body image evaluations that were made during the rhGH trials. Baseline observations indicated psychological distress related to body image, with the greatest distress directed at the appearance of the belly. Therapy with rhGH was associated with a change in body image and an associated change in the level of distress, once again greatest in the evaluation of the belly. The changes in body image assessments were associated with the changes in body composition, implying clinical relevance to the self-perceived outcomes. Of note, these positive changes occurred despite evidence of negative outcomes in quality of life, especially in the development of pain.

Falutz and colleagues[32] have taken a slightly different approach by studying the effects of a once-daily injection of a growth hormone releasing factor, TH9507. This trial and drug development are based on the studies of Koutkia and colleagues,[33] who demonstrated efficacy of a different form of growth hormone-releasing factor in patients with HIV-associated lipodystrophy. The rationale for using a releasing factor is that the resultant growth hormone secretion is pulsatile, as in the normal state, and the pituitary gland is subject to normal feedback inhibition. It is postulated that the agent may be safer or less subject to abuse than is rhGH. The results of the studies demonstrated efficacy for TH9507, with an effect size roughly corresponding to around 1.5 mg of rhGH (Capsule Summary).[32,34] Beneficial effects of therapy on lipids, predominantly cholesterol, also were demonstrated and no significant adverse effects on glucose metabolism could be demonstrated. Serum IGF-1 concentrations increased by an average of 81%, although the mean IGF-1 concentration at 3 months remained within the normal range.

The future of treatment for visceral fat accumulation in HIV infection is uncertain. At the time of writing, an application for FDA approval has been made for treatment with rhGH. A second phase III trial of growth hormone-releasing factor is starting, and an application for FDA approval is expected once this trial is completed. In addition to balancing efficacy and safety, successful application of this therapy will require validating clinically useful methods for diagnosis and monitoring of therapy and the underlying condition. Balancing the cost of therapy with other clinical mandates as well as ensuring access to therapy by all those who would benefit from therapy are other barriers to optimal application of this therapy.

References

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19. Drechsler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis. 2002;35:1219-1230.

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25. Shikuma C, R, Sattler F, et al. Effects of physiologic testosterone supplementation on fat mass and distribution in HIV-infected men with abdominal obesity: ACTG 5079. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 149.

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27. Rietschel P, Hadigan C, Corcoran C, et al. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab. 2001;86:504-510.

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30. Kotler DP, Muurahainen N, Grunfeld C, et al. Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients. J Acquir Immun Defic Syndr. 2004;35:239-254.

31. Grunfeld G, M, Brown SJ, et al. Recombinant human growth hormone (r-hGH) to treat HIV-associated adipose redistribution syndrome (HARS): 12-week induction and 24-week maintenance therapy. J Acquir Immun Defic Syndr. In press.

32. Falutz J, Allas S, Kotler D, et al. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS. 2005;19:1279-1287.

33. Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA. 2004;292:210-218.

34. Falutz J, Allas S, Potvin D, et al. Effects of TH9507, a growth hormone releasing factor (GRF) analog, on HIV-associated abdominal fat accumulation: a multicenter, double-blind placeboRegards, Vergelpowerusa dot orgSee what's free at AOL.com.